WO2014113620A2 - Phthalazinones and isoquinolinones as rock inhibitors - Google Patents

Phthalazinones and isoquinolinones as rock inhibitors Download PDF

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Publication number
WO2014113620A2
WO2014113620A2 PCT/US2014/011957 US2014011957W WO2014113620A2 WO 2014113620 A2 WO2014113620 A2 WO 2014113620A2 US 2014011957 W US2014011957 W US 2014011957W WO 2014113620 A2 WO2014113620 A2 WO 2014113620A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
heterocycle
carbocycle
occurrence
independently selected
Prior art date
Application number
PCT/US2014/011957
Other languages
French (fr)
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WO2014113620A3 (en
Inventor
Peter W. Glunz
Yan Zou
Mimi L. Quan
Vladimir Ladziata
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to US14/759,495 priority Critical patent/US9926282B2/en
Priority to ES14702408.7T priority patent/ES2684776T3/en
Priority to MX2015008741A priority patent/MX2015008741A/en
Priority to JP2015553839A priority patent/JP6488239B2/en
Priority to CN201480016485.1A priority patent/CN105073741B/en
Priority to EP14702408.7A priority patent/EP2945943B1/en
Priority to EA201591296A priority patent/EA027138B1/en
Priority to CA2898440A priority patent/CA2898440A1/en
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to EP17176983.9A priority patent/EP3252050B1/en
Priority to BR112015017008A priority patent/BR112015017008A2/en
Publication of WO2014113620A2 publication Critical patent/WO2014113620A2/en
Publication of WO2014113620A3 publication Critical patent/WO2014113620A3/en
Priority to HK16100934.1A priority patent/HK1212979A1/en
Priority to US15/890,436 priority patent/US10385026B2/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to novel phthalazinone and isoquinolinone compounds, and their analogues thereof, which are inhibitors of Rho kinases, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.
  • Rho-Kinase is a member of the serine-threonine protein kinase family.
  • ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. et al, EMBO J., 15: 1885-1893 (1996)).
  • ROCK has been identified as an effector molecule of RhoA, a small GTP-binding protein (G protein) that plays a key role in multiple cellular signaling pathways.
  • RhoA a small GTP-binding protein
  • ROCK and RhoA are ubiquitously expressed across tissues.
  • the RhoA/ROCK signaling pathway is involved in a number of cellular functions, such as ACTIN® organization, cell adhesion, cell migration, and cytokinesis (Riento, K. et al, Nat. Rev. Mol. Cell Biol, 4:446-456 (2003)).
  • RhoA Upon activation of its receptor, RhoA is activated, and, in turn, it activates ROCK. Activated ROCK phosphorylates the myosin-binding subunit of myosin light chain phosphatase, which inhibits activity of the phosphatase and leads to contraction. Contraction of the smooth muscle in the vasculature increases blood pressure, leading to hypertension.
  • Rho A/ROCK signaling pathway plays an important role in signal transduction initiated by several vasoactive factors, for example angiotensin II (Yamakawa, T. et al, Hypertension, 35:313-318
  • ROCK inhibitors 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)).
  • 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.
  • ROCK inhibitor Y-27632 also inhibited neointimal formation in rats (Sawada, N. et al, Circulation, 101 :2030-2033 (2000)).
  • ROCK inhibitor would be useful in treating other cardiovascular diseases.
  • fasudil was shown to reduce both the infarct size and neurologic deficit (Toshima, Y., Stroke, 31:2245-2250 (2000)).
  • the ROCK inhibitor Y-27632 was shown to improve ventricular hypertrophy, fibrosis and function in a model of congestive heart failure in Dahl salt- sensitive rats (Kobayashi, N. et al, Cardiovascular Res., 55:757-767 (2002)).
  • ROCK ROCK-related diseases
  • coronary vasospasm Shiokawa, H. et al, Cardiovasc. Res., 43: 1029-1039 (1999)
  • cerebral vasospasm Sato, M. et al, Circ. Res., 87: 195-200 (2000)
  • ischemia/reperfusion injury Yada, T. et al, J. Am. Coll. Cardiol, 45:599-607 (2005)
  • pulmonary hypertension Fukumoto, Y. et al, Heart, 91 :391-392 (2005)
  • angina Shiokawa, H. et al, J. Cardiovasc. Pharmacol, 39:319-327 (2002)
  • renal disease Satoh, S. et al, Eur. J. Pharmacol, 455: 169-174 (2002)
  • erectile dysfunction Gonzalez-Cadavid, N.F. et al., Endocrine, 23: 167-176 (2004)).
  • RhoA/ROCK signaling pathway allows formation of multiple competing lamellipodia that disrupt the productive migration of monocytes (Worthylake, R.A. et al, J. Biol. Chem., 278: 13578- 13584 (2003)). It has also been reported that small molecule inhibitors of Rho Kinase are capable of inhibiting MCP-1 mediated chemotaxis in vitro (Iijima, H., Bioorg. Med. Chem., 15: 1022-1033 (2007)). Due to the dependence of immune cell migration upon the RhoA/ROCK signaling pathway one would anticipate inhibition of Rho Kinase should also provide benefit for diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
  • ROCK inhibitors may also be useful in other diseases involving smooth muscle hyper-reactivity, including asthma and glaucoma (Shimokawa, H. et al, Arterioscler. Thromb. Vase. Biol, 25: 1767-1775 (2005)).
  • Rho- kinase has been indicated as a drug target for the treatment of various other diseases, including airway inflammation and hyperresponsiveness (Henry, P.J. et al., Pulm.
  • CVD cardiovascular diseases
  • ROCK inhibitors Although there are many reports of ROCK inhibitors under investigation (see, for example, US 2012/0122842 Al, US 2010/0041645 Al, US 2008/0161297 Al, and Hu, E. et al, Exp. Opin. Ther. Targets, 9:715-736 (2005)), 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 phthalazinone and isoquinolinone compounds, their analogues, 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
  • M is selected from N and CR 10 ;
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, -NR 6 C(0)-, and -NR 6 -;
  • R 1 is selected from R 5 R 5 , C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R 7 ;
  • R 2 is independently selected from halogen, Ci_6 alkyl, C 1-4 alkoxy, Ci_ 4 alkylthio, Ci_ 4 haloalkyl, -OH, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF 3 , CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci-4 alkyl), -NHC0 2 (Ci- 4 alkyl), -NHS0 2 (Ci- 4 alkyl),
  • R 3 is independently selected from halogen, Ci_6 alkyl, C 1-4 alkoxy, Ci_ 4 alkylthio, Ci_ 4 haloalkyl, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF 3 , CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci_ 4 alkyl), -NHC0 2 (Ci_ 4 alkyl), -NHS0 2 (Ci_ 4 alkyl), -S0 2 (Ci_
  • R 4 is independently selected from H, OH, NH 2 , CH 2 NH 2 , C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , Ci_ 4 alkoxy, CH 2 OH, CH 2 0(Ci_ 4 alkyl), CH 2 C0 2 H, CH 2 C0 2 (Ci_ 4 alkyl), Ci_ 4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, -(CH 2 ) n -C(0)Ci_ 4 alkyl, -(CH 2 ) n -C(0)carbocycle, -(CH 2 ) n -C(0)heterocycle, -(CH 2 ) n -C(0)NR a R a , -(CH 2 ) n -C(0)0-alkyl, -(CH 2 ) n -C(0)0-carbocycle,
  • R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ;
  • R 9 at each occurrence, is independently selected from halogen, OH, N0 2 , CHF 2 ,
  • Ci_ 4 alkyl Ci_ 4 alkoxy, CH 2 OH, CO(Ci_ 4 alkyl), C0 2 H, C0 2 (Ci_ 4 alkyl),
  • R 10 is selected from H and C 1-4 alkyl
  • R a at each occurrence, is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c is independently selected from -(CH 2 ) n -C3_6 cycloalkyl, -(CH 2 ) n -phenyl, and -(CH 2 ) n -5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • NHC(O) is other than
  • the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • M is CR 10 ;
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-;
  • R 1 is selected from R 5 R 5 , C 3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ;
  • alkyl, carbocycle, and heterocycle are substituted with 1-4 R 7 ;
  • R 3 at each occurrence, is independently selected from halogen, Ci_6 alkyl, C 1-4 alkoxy;
  • R 4 is H
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R 7 ;
  • R 7 is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, -NR 8 R 8 , -(CH 2 ) n -carbocycle, and -(CH 2 ) n -heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p , wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • R 8 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 9 at each occurrence, is independently selected from halogen, OH, C 1-4 alkyl, Ci-4 alkoxy;
  • R 10 is selected from H and C 1-4 alkyl
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
  • M is selected from N and CR 10 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • C(0)Ci- 4 alkyl, C(0)carbocycle, C(0)heterocycle, -(CH 2 ) taken C(0)NR a R a , C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S0 2 alkyl, S0 2 carbocycle, S0 2 heterocycle, S0 2 R a R a , -(CH 2 ) n -carbocycle, and -(CH 2 ) n -heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • R 9 is independently selected from halogen, OH, NO2, CHF 2 , CF 3 , Ci_4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
  • R 10 is selected from H and C 1-4 alkyl
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_ 4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c at each occurrence, is independently selected from -(CH 2 ) n -C3-6 cycloalkyl, -(CH 2 ) n -phenyl, and -(CH 2 ) n -5- to 6- membered heterocycle containing carbon atoms and
  • heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 5 is selected from H, C 1-4 alkyl, -(CH 2 ) n -C3 -1 o carbocycle, -(CH 2 ) n -aryl,
  • alkyl, cycloalkyl, aryl are substituted with 1 -4 R 7 ;
  • the present invention provides compounds of Formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ;
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a ,
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 R b ;
  • R c is independently selected from -(CH 2 ) n -C3_6 cycloalkyl, -(CH 2 ) n -phenyl, and -(CH 2 ) n -5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci_ 4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ; and
  • the present invention provides compounds of Formula (III):
  • M is selected from N and CR 1U ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a ,
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • L is -NR 6 -;
  • R 1 is heteroaryl substituted with 1-4 R 7 ;
  • R 7 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, OH, -(CH 2 ) n -carbocycle, and -(CH 2 ) n -heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • the present invention provides compounds of Formula (IV):
  • R 1 is selected from R 5 R 5 , C 3-10 carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R 7 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl, C 2 -4 alkenyl, C(0)Ci_ 4 alkyl, C(0)carbocycle, C(0)heterocycle, -(CH 2 ) n -C(0)NR a R a , C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle
  • R 9 is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 - 4) NR a R a , -(CR 10 R 10 ) favor- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 1 is selected from
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 9 is independently selected from halogen, OH, O2, CHF 2 , CF 3 , Ci_4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_ 4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c at each occurrence, is independently selected from -(CH 2 ) n -C3_6 cycloalkyl
  • heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ; and
  • the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein: R 1 is NR 5 R 5 ;
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 8 at each occurrence, is independently selected from H, Ci_ 4 alkyl,
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ; and
  • the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • M is selected from N and CR 10 ;
  • L is selected from Ci_ 2 alkylene substituted with 1-2 R 4 , wherein one or both carbon atoms and the groups attached thereto are replaced by O, NR 6 , and C(O);
  • R 1 is selected from NR 5 R 5 , C3-1 0 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R 7 ;
  • R 2 is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_ 4 alkylthio, Ci_ 4 haloalkyl, -OH, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF3, CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci_ 4 alkyl), -NHC0 2 (Ci_ 4 alkyl), -NHS0 2 (Ci_ 4 alkyl), -NHCO(Ci_
  • R 3 is independently selected from halogen, Ci_6 alkyl, Ci_ 4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF3, CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci_ 4 alkyl), -NHC0 2 (Ci_ 4 alkyl), -NHS0 2 (Ci_ 4 alkyl), -S0 2 (Ci_ 4 al
  • R 4 is independently selected from H, OH, NH 2 , CH 2 NH 2 , C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , Ci_ 4 alkoxy, CH 2 OH, CH 2 0(Ci_ 4 alkyl), CH 2 C0 2 H, CH 2 C0 2 (Ci_ 4 alkyl), Ci_ 4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, -(CH 2 ) n -C(0)Ci_ 4 alkyl, -(CH 2 ) n -C(0)carbocycle, -(CH 2 ) n -C(0)heterocycle, -(CH 2 ) n -C(0)NR a R a , -(CH 2 ) n -C(0)0-alkyl, -(CH 2 ) n -C(0)0-carbocycle,
  • R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ;
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, CO(Ci_ 4 alkyl), C0 2 H, C0 2 (Ci_ 4 alkyl),
  • R 10 is selected from H and Ci_ 4 alkyl
  • R a is independently selected from H, Ci_ 4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_ 4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c is independently selected from -(CH 2 ) n -C3_6 cycloalkyl, -(CH 2 ) n -phenyl, and -(CH 2 ) n -5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (V):
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, -NR 6 C(0)-, and -NR 6 -;
  • R 1 is selected from NR 5 R 5 , C 3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R 7 ;
  • R 2 is independently selected from halogen, Ci_6 alkyl, C 1-4 alkoxy, Ci_ 4 alkylthio, Ci_ 4 haloalkyl, -OH, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF 3 , CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci_ 4 alkyl), -NHC0 2 (Ci_ 4 alkyl), -NHS0 2 (Ci_ 4 alkyl), -NHC0
  • R 3 is independently selected from halogen, Ci_6 alkyl, C 1-4 alkoxy, Ci_ 4 alkylthio, Ci_ 4 haloalkyl, -CH 2 OH, -OCH 2 F, -OCHF 2 , -OCF 3 , CN, -NH 2 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , -C0 2 H, -CH 2 C0 2 H, -C0 2 (Ci_ 4 alkyl), -CO(Ci_ 4 alkyl), -CH 2 NH 2 , -CONH 2 , -CONH(Ci_ 4 alkyl), -CON(Ci_ 4 alkyl) 2 , -OCH 2 C0 2 H, -NHCO(Ci_ 4 alkyl), -NHC0 2 (Ci_ 4 alkyl), -NHS0 2 (Ci_ 4 alkyl), -S0 2 (Ci_
  • R 4 is independently selected from H, OH, NH 2 , CH 2 NH 2 , C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , -NH(Ci_ 4 alkyl), -N(C 1-4 alkyl) 2 , Ci_ 4 alkoxy, CH 2 OH, CH 2 0(Ci_ 4 alkyl), CH 2 C0 2 H, CH 2 C0 2 (Ci_ 4 alkyl), Ci_ 4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, -(CH 2 ) n -C(0)Ci_ 4 alkyl, -(CH 2 ) n -C(0)carbocycle, -(CH 2 ) n -C(0)heterocycle, -(CH 2 ) n -C(0)NR a R a , -(CH 2 ) n -C(0)0-alkyl, -(CH 2 ) n -C(0)0-carbocycle,
  • R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ;
  • R 9 at each occurrence, is independently selected from halogen, OH, N0 2 , CHF 2 ,
  • Ci_ 4 alkyl Ci_ 4 alkoxy, CH 2 OH, CO(Ci_ 4 alkyl), C0 2 H, C0 2 (Ci_ 4 alkyl),
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_ 4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c at each occurrence, is independently selected from -(CH 2 ) n -C3_6 cycloalkyl
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • R 1 is heteroaryl substituted with 1-4 R 7 .
  • the present invention provides compounds of Formula (VI):
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 9 is independently selected from halogen, OH, NO2, CHF 2 , CF 3 , Ci_4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
  • R a at each occurrence, is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c at each occurrence, is independently selected from -(CH 2 ) n -C3_6 cycloalkyl
  • heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (VI) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 5 is selected from H, C 1-4 alkyl, -(CH 2 ) n -C3 -1 o carbocycle, -(CH 2 ) n -aryl,
  • alkyl, cycloalkyl, aryl are substituted with 1 -4 R 7 ;
  • the present invention provides compounds of Formula (VI) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 8 and R 8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ;
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a ,
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 R b ;
  • R c is independently selected from -(CH 2 ) n -C3_6 cycloalkyl, -(CH 2 ) n -phenyl, and -(CH 2 ) n -5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci_ 4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ; and
  • the present invention provides compounds of Formula (VII):
  • R 5 at each occurrence, is independently selected from H, Ci_ 4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (V) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • L is -NR 6 -;
  • R 7 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, OH, -(CH 2 ) n -carbocycle, and -(CH 2 ) n -heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;
  • the present invention provides compounds of Formula (V) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • the present invention provides compounds of Formula (VIII):
  • R 1 is selected from R 5 R 5 , C 3-10 carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R 7 ;
  • R 5 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 6 at each occurrence, is independently selected from H and C 1-4 alkyl
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl, C 2 -4 alkenyl, C(0)Ci_ 4 alkyl, C(0)carbocycle, C(0)heterocycle, -(CH 2 ) n -C(0)NR a R a , C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle
  • R 9 is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 - 4) NR a R a , -(CR 10 R 10 ) favor- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ;
  • n at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
  • p at each occurrence, is independently selected from 0, 1, and 2;
  • the present invention provides compounds of Formula (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
  • R 1 is selected from
  • R 8 at each occurrence, is independently selected from H, C 1-4 alkyl,
  • R 9 is independently selected from halogen, OH, O2, CHF 2 , CF 3 , Ci_4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
  • R a is independently selected from H, C 1-4 alkyl, -(CH 2 ) n OH, CO(Ci_ 4 alkyl), COCF 3 , C0 2 (Ci_ 4 alkyl), -CONH 2 , -CONH-Ci_ 4 alkylene-C0 2 (Ci_ 4 alkyl), Ci_ 4 alkylene-C0 2 (Ci_4 alkyl), R c , C0 2 R c , and CONHR c ; alternatively, R a and R a are taken together with the nitrogen atom to which they are attached to form 4- to
  • R c at each occurrence, is independently selected from -(CH 2 ) n -C3_6 cycloalkyl
  • heteroatoms selected from the group consisting of: N, NH, N(C 1-4 alkyl), O, and S(0) p ; wherein each ring moiety is substituted with 0-2 R d ; and
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;
  • R 8 at each occurrence, is independently selected from H, Ci_ 4 alkyl,
  • R 9 is independently selected from halogen, OH, N0 2 , CHF 2 , CF 3 , Ci_ 4 alkyl, Ci_ 4 alkoxy, CH 2 OH, C0 2 H, C0 2 (Ci_ 4 alkyl), CONH 2 , -(CH 2 ) n NR a R a , -(CH 2 ) n CONR a R a , -0(CH 2 ) n heterocycle, -0(CH 2 ) (2 _ 4) NR a R a , -(CR 10 R 10 ) favor- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
  • M is N or CR 10 ;
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0-;
  • R 1 is selected from R 5 R 5 , C 3-10 carbocycle and 4- to
  • the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-; R 1 is selected from NR 5 R 5 , C 3-10 carbocycle and 4- to
  • 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ; wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R 7 .
  • the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR 6 C(0)-, and -NR 6 -; R 1 is 4- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p and substituted with 1-4 R 7 .
  • the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR 6 C(0)- or NR 6 -; R 1 is selected fro
  • the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is -NR 6 C(0)-; R 1 is C 3-10 carbocycle substituted with 1-4 R 7 .
  • -NHCOCF 3 -NHC0 2 (Ci_ 4 alkyl), -NHC0 2 (CH 2 ) 2 0(Ci_ 4 alkyl), -NHC0 2 (CH 2 ) 3 0(Ci_ 4 alkyl), -NHC0 2 (CH 2 ) 2 OH, -NHC0 2 (CH 2 ) 2 NH 2 , -NHC0 2 (CH 2 ) 2 N(C 1 _ 4 alkyl) 2 ,
  • the present invention provides compounds of Formulae (I),
  • L is selected from -NR 6 C(0)-;
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each substituted with 1-4 R 7 ;
  • the present invention provides compounds of Formulae (I),
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-;
  • R 1 is NR 5 R 5 ;
  • R 5 at each occurrence, is independently selected from H, Ci_ 4 alkyl, -(CR 6 R 6 ) n -C 3 -io carbocycle, and -(CR 6 R 6 ) n -4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p , wherein said carbocycle and heterocycle are substituted with 1-4 R 7 .
  • the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-; R 1 is NR 5 R 5 ; R 5 , at each occurrence, is independently selected from H, Ci-4 alkyl, -(CH 2 ) n -C3_io carbocycle, -(CH 2 ) n -aryl, -(CH 2 ) n -4-10 membered heterocycle selected from
  • the present invention provides compounds of Formulae (I),
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-;
  • R 1 is NR 5 R 5 ;
  • R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p , wherein said heterocycle is substituted with 1-4 R 7 .
  • the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-; R 1 is NR 5 R 5 ; R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
  • the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof selected from -CR 4 R 4 C(0)-,
  • R 1 is selected from
  • the present invention provides compounds of Formulae (I),
  • L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-;
  • R 1 is selected from NR 5 R 5 , C 3-10 carbocycle and 4- to
  • the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR 4 R 4 C(0)-, -OC(O)-, and -NR 6 C(0)-; R 1 is selected from C 3- io carbocycle and 4- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(0) p ; wherein said carbocycle and heterocycle are substituted with 1-4 R 7 ; R 5 , at each occurrence, is independently selected from H, C 1-4 alkyl, -(CR 6 R 6 ) n -C 3 _io carbocycle substituted with 1-4 R 7 and -(CR 6 R 6 ) n -4-10 membered heterocycle selected from
  • R 5 and R 5 are taken together with the nitrogen atom to which they attached to form a heterocycle selected from
  • the present invention provides a compound selected from any subset list of compounds exemplified in the present application.
  • the compounds of the present invention have ROCK IC5 0 values ⁇ 10 ⁇ .
  • the compounds of the present invention have ROCK IC50 values ⁇ 1 ⁇ .
  • the compounds of the present invention have ROCK IC5 0 values ⁇ 0.1 ⁇ .
  • the compounds of the present invention have ROCK IC5 0 values ⁇ 0.05 ⁇ .
  • the compounds of the present invention have ROCK IC5 0 values ⁇ 0.01 ⁇ .
  • the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate, thereof.
  • the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable 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.
  • 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.
  • 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).
  • the isomeric descriptors “R” and “S” are used as described herein for indicating atom configuration(s) relative to a core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).
  • chiral refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image.
  • homochiral refers to a state of enantiomeric purity.
  • optical activity refers to the degree to which a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci to Cio alkyl or “Ci_io alkyl” (or alkylene) is intended to include Ci, C 2 , C3, C 4 , C5, Ce, C7, C 8 , C9, and Cio 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, ?-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
  • Me methyl
  • Et ethyl
  • propyl e.g., n-propyl and isopropyl
  • butyl e.g., n-butyl, isobutyl, ?-butyl
  • pentyl e.g., n-pentyl, isopentyl, neopentyl.
  • Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain.
  • C2 to Ce alkenyl or “C2-6 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.
  • C2 to Ce alkynyl or “C2-6 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”
  • Ce haloalkoxy is intended to include Ci, C 2 , C3, 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
  • 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, 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".
  • carrier 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, [4.3.0]bicyclononane,
  • bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
  • Preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
  • a bridged ring occurs when one or more carbon atoms link two non- adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • bicyclic carbocycle or "bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated.
  • the bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure.
  • the bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable.
  • bicyclic carbocyclic group examples include, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
  • Aryl groups refer to monocyclic or 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).
  • heterocycle or “heterocyclic group” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic 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.
  • heterocycle it is intended to include heteroaryl.
  • heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
  • 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.
  • 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. 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.
  • 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:
  • 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, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo- l,3-dioxolen-4-yl)-methyl
  • esters may be prepared by conventional techniques known in the art.
  • 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”.
  • 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
  • the effectiveness of compounds of the present invention as ROCK inhibitors can be determined in a 30 ⁇ ⁇ assay containing 20 mM HEPES, pH 7.5, 20 mM MgCi 2 , 0.015% Brij-35, 4 mM DTT, 5 ⁇ ATP and 1.5 ⁇ 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 IC 50 ; i.e., the concentration of compound required to inhibit 50% of kinase activity.

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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

PHTHALAZI ONES AND ISOQUINOLINONES AS ROCK INHIBITORS
FIELD OF THE INVENTION
The present invention relates generally to novel phthalazinone and isoquinolinone compounds, and their analogues thereof, which are inhibitors of Rho kinases, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.
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 Rho A/ROCK signaling pathway plays an important role in signal transduction initiated by several vasoactive factors, for example angiotensin II (Yamakawa, T. et al, Hypertension, 35:313-318
(2000)), urotension II (Sauzeau, V. et al, Circ. Res., 88: 1102-1104 (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, Cardiovascular 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, Cardiovascular 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, H., Bioorg. Med. Chem., 15: 1022-1033 (2007)). Due to the dependence of immune cell migration upon the RhoA/ROCK signaling pathway one would anticipate inhibition of Rho Kinase should also provide benefit for diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
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. Set, 13:8293-8307 (2012); Zhou, L. et al, Am. J. Nephrol, 34:468- 475 (201 1)), as well as neurological disorders, such as spinal-cord injury, Alzheimer's 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 U.S., with coronary heart disease accounting for ~1 in 6 deaths overall in the U.S.. Contributing to these numbers, it was found that -33.5% of the adult U.S. population was hypertensive, and it was estimated that in 2010 ~6.6 million U.S. 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, US 2012/0122842 Al, US 2010/0041645 Al, US 2008/0161297 Al, and Hu, E. et al, Exp. Opin. Ther. Targets, 9:715-736 (2005)), 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 phthalazinone and isoquinolinone compounds, their analogues, 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 imgf000008_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
M is selected from N and CR10;
L is selected from -CR4R4C(0)-, -OC(O)-, -NR6C(0)-, and -NR6-;
R1 is selected from R5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R2, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -OH, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci-4 alkyl), -NHC02(Ci-4 alkyl), -NHS02(Ci-4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4, at each occurrence, is independently selected from H, OH, NH2, CH2NH2, C1-4 haloalkyl, OCH2F, OCHF2, OCF3, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, Ci_4 alkoxy, CH2OH, CH20(Ci_4 alkyl), CH2C02H, CH2C02(Ci_4 alkyl), Ci_4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and -(CR6R6)n- 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)„-NR8R8, -NHCO(Ci-4 alkyl), -NHCOCF3, -NHC02(Ci-4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)n-C(0)Ci_4alkyl, -(CH2)n-C(0)carbocycle, -(CH2)n-C(0)heterocycle, -(CH2)n -C(0)NRaRa, -(CH2)n-C(0)0-alkyl, -(CH2)n-C(0)0-carbocycle,
-(CH2)n-C(0)0-heterocycle, -(CH2)n-S02alkyl, -(CH2)n S02carbocycle,
-(CH2)n-S02heterocycle, -(CH2)n-S02NRaRa, -(CH2)n-carbocycle, and
-(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2,
CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, CO(Ci_4 alkyl), C02H, C02(Ci_4 alkyl),
-(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)ncarbocycle, -0(CH2)nheterocycle, -0(CH2)nNRaRa, -(CR10R10)n- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
R10 is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, OH, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci-4 alkyl), CONH2, -CONH(Ci-4 alkyl), -CON(C1-4 alkyl)2, -CONH-C1-4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, H(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and -NHCO(Ci-4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
provided is NHC(O), R is other than
Figure imgf000010_0001
and
Figure imgf000010_0002
, wherein X is N or a substituted or unsubstituted carbon atom;
2) when L is NR6, R1 is heterocycle substituted with 1-4 R7. In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
M is CR10;
L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-;
R1 is selected from R5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p;
wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy;
R4 is H;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, C1-4 alkyl, C1-4 alkoxy, -NR8R8, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H and C1-4 alkyl;
R9, at each occurrence, is independently selected from halogen, OH, C1-4 alkyl, Ci-4 alkoxy;
R10 is selected from H and C1-4 alkyl;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (I) above. In another aspect, the present invention provides compounds of Formula (II):
Figure imgf000012_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
M is selected from N and CR10;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci-4 alkyl), -S02NH2, -S02NH(Ci-4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci-4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)„ C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
R10 is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl,
Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3-6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (I) above. In another aspect, the present invention provides compounds of Formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5 is selected from H, C1-4 alkyl, -(CH2)n-C3-1o carbocycle, -(CH2)n-aryl,
-(CH2)n-4- 10 membered heterocycle selected from
Figure imgf000014_0001
wherein said alkyl, cycloalkyl, aryl are substituted with 1 -4 R7; and
other variables are as defined in Formula (II) above.
In another aspect, the present invention provides compounds of Formula (II) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5 and R5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
Figure imgf000014_0002
Figure imgf000015_0001
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -CH2NH2, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC(0)NH2,
-NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci_4 alkyl), -(CH2)n-CONR8R8, -0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa,
-(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, Ci_4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
other variables are as defined in Formula (II) above.
In another aspect, the present invention provides compounds of Formula (III):
Figure imgf000016_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
M is selected from N and CR1U; R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(C!_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci-4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci-4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(d_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa,
-(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (I) above. In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
L is -NR6-;
R1 is heteroaryl substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
other variables are as defined in Formula (I) above.
In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
-NR6-;
Figure imgf000018_0001
other variables are as defined in Formula (I) above.
In still another aspect, the present invention provides compounds of Formula (IV):
Figure imgf000019_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R1 is selected from R5R5, C3-10 carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R7;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3-io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, NO2, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci-4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(d_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9; R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, SC^heterocycle, S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkenyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2-4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (I) above.
In still another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R1 is selected from
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0001
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci-4 alkyl), -S02NH2, -S02NH(Ci-4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci-4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)„-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9; alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, O2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl,
-(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
other variables are as defined in Formula (IV) above. In still another aspect, the present invention provides compounds of Formula (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein: R1 is NR5R5;
R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(d_4 alkyl)2, -S02NH(CH2)2OH, -SO. K H^OCd^ alkyl), -CONH2,
-CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CH2CONH2, -(CH2)n-carbocycle,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, Ci_4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle,
S02NRaRa, -(CH2)n-cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb; and
other variables are as defined in Formula (IV) above.
In another aspect, the present invention provides compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
M is selected from N and CR10;
L is selected from Ci_2 alkylene substituted with 1-2 R4, wherein one or both carbon atoms and the groups attached thereto are replaced by O, NR6, and C(O); R1 is selected from NR5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R2, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -OH, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, Ci_4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4, at each occurrence, is independently selected from H, OH, NH2, CH2NH2, C1-4 haloalkyl, OCH2F, OCHF2, OCF3, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, Ci_4 alkoxy, CH2OH, CH20(Ci_4 alkyl), CH2C02H, CH2C02(Ci_4 alkyl), Ci_4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and -(CR6R6)n- 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, N02, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC02(CH2)20(C1_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(d_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, Ci_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)n-C(0)Ci_4alkyl, -(CH2)n-C(0)carbocycle, -(CH2)n-C(0)heterocycle, -(CH2)n -C(0)NRaRa, -(CH2)n-C(0)0-alkyl, -(CH2)n-C(0)0-carbocycle,
-(CH2)n-C(0)0-heterocycle, -(CH2)n-S02alkyl, -(CH2)n S02carbocycle,
-(CH2)n-S02heterocycle, -(CH2)n-S02NRaRa, -(CH2)n-carbocycle, and
-(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, CO(Ci_4 alkyl), C02H, C02(Ci_4 alkyl),
-(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)ncarbocycle, -0(CH2)nheterocycle,
-0(CH2)nNRaRa, -(CR10R10)n- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
R10 is selected from H and Ci_4 alkyl;
Ra, at each occurrence, is independently selected from H, Ci_4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, OH, halogen, Ci_4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, Ci_4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
provided
(1) when L is NHC(O), R is other than
Figure imgf000026_0001
and carbon atom;
Figure imgf000026_0002
w en s , s ot er t an
In another aspect, the present invention provides compounds of Formula (V):
Figure imgf000027_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
L is selected from -CR4R4C(0)-, -OC(O)-, -NR6C(0)-, and -NR6-;
R1 is selected from NR5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R2, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -OH, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4, at each occurrence, is independently selected from H, OH, NH2, CH2NH2, C1-4 haloalkyl, OCH2F, OCHF2, OCF3, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, Ci_4 alkoxy, CH2OH, CH20(Ci_4 alkyl), CH2C02H, CH2C02(Ci_4 alkyl), Ci_4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and -(CR6R6)n- 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)„-NR8R8, -NHCO(Ci-4 alkyl), -NHCOCF3, -NHC02(Ci-4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)n-C(0)Ci_4alkyl, -(CH2)n-C(0)carbocycle, -(CH2)n-C(0)heterocycle, -(CH2)n -C(0)NRaRa, -(CH2)n-C(0)0-alkyl, -(CH2)n-C(0)0-carbocycle,
-(CH2)n-C(0)0-heterocycle, -(CH2)n-S02alkyl, -(CH2)n S02carbocycle,
-(CH2)n-S02heterocycle, -(CH2)n-S02NRaRa, -(CH2)n-carbocycle, and
-(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2,
CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, CO(Ci_4 alkyl), C02H, C02(Ci_4 alkyl),
-(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)ncarbocycle, -0(CH2)nheterocycle, -0(CH2)nNRaRa, -(CR10R10)n- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, OH, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci-4 alkyl), -CONH-C1-4 alkylene-N(Ci-4 alkyl)2, -CONH-C1-4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl,
-(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
provided en L is NHC(O), R is other than
Figure imgf000029_0001
Figure imgf000029_0002
, wherein X is N or a substituted or unsubstituted carbon atom;
(2) when L is NR6, R1 is heteroaryl substituted with 1-4 R7.
In another aspect, the present invention provides compounds of Formula (VI):
Figure imgf000030_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, NO2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci-4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl,
-(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (V) above. In another aspect, the present invention provides compounds of Formula (VI) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5 is selected from H, C1-4 alkyl, -(CH2)n-C3-1o carbocycle, -(CH2)n-aryl,
-(CH2)n-4- 10 membered heterocycle selected from
Figure imgf000032_0001
wherein said alkyl, cycloalkyl, aryl are substituted with 1 -4 R7; and
other variables are as defined in Formula (V) above.
In another aspect, the present invention provides compounds of Formula (VI) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5 and R5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
Figure imgf000032_0002
Figure imgf000033_0001
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -CH2NH2, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC(0)NH2,
-NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci_4 alkyl), -(CH2)n-CONR8R8, -0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa,
-(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, Ci_4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
other variables are as defined in Formula (VI) above.
In another aspect, the present invention provides compounds of Formula (VII):
Figure imgf000034_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R5, at each occurrence, is independently selected from H, Ci_4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(C!_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci-4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (V) 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 -NR6-;
R7, at each occurrence, is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
other variables are as defined in Formula (V) above.
In another aspect, the present invention provides compounds of Formula (V) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
-NR6-; and
Figure imgf000036_0001
other variables are as defined in Formula (V) above.
In still another aspect, the present invention provides compounds of Formula (VIII):
Figure imgf000037_0001
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R1 is selected from R5R5, C3-10 carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R7;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, NO2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(d_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci-4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9; R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, SC^heterocycle, S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkenyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2-4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
other variables are as defined in Formula (V) above.
In still another aspect, the present invention provides compounds of Formula (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein:
R1 is selected from
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000039_0001
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci-4 alkyl), -S02NH2, -S02NH(Ci-4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci-4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)„-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9; alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, O2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl,
-(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
other variables are as defined in Formula (VIII) above. In still another aspect, the present invention provides compounds of Formula
(VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein: R1 is NR5R5;
R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(d_4 alkyl)2, -S02NH(CH2)2OH, -SO. HCCH^.OCd^ alkyl), -CONH2,
-CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CH2CONH2, -(CH2)n-carbocycle,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, Ci_4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle,
S02NRaRa, -(CH2)n-cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb; and
other variables are as defined in Formula (VIII) above. In one embodiment, the present invention provides compounds of Formulae (I),
(II), (III), and (IV), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein M is N or CR10; L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0-; R1 is selected from R5R5, C3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle and heterocycle are substituted with
1- 4 R7. In one embodiment, the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is selected from NR5R5, C3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR6C(0)-, and -NR6-; R1 is 4- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p and substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR6C(0)- or NR6-; R1 is selected fro
Figure imgf000042_0001
In one embodiment, the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is -NR6C(0)-; R1 is C3-10 carbocycle substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR6C(0)-; R1 is C3_6 cycloalkyl substituted with 1-4 R7 or aryl substituted with 1-4 R7; R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -NHCO(d_4 alkyl),
-NHCOCF3, -NHC02(Ci_4 alkyl), -NHC02(CH2)20(Ci_4 alkyl), -NHC02(CH2)30(Ci_4 alkyl), -NHC02(CH2)2OH, -NHC02(CH2)2NH2, -NHC02(CH2)2N(C1_4 alkyl)2,
-NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl) 2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci_4 alkyl), -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CH2CONH2, -(CH2)n-carbocycle, -0(CH2)n-carbocycle,
-0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9.
In one embodiment, the present invention provides compounds of Formulae (I),
(IV), (V), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -NR6C(0)-; R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, each substituted with 1-4 R7; R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -NHCO(d_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC02(CH2)20(Ci_4 alkyl), -NHC02(CH2)30(Ci_4 alkyl), -NHC02(CH2)2OH, -NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci-4 alkyl)2,
-NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl) 2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci_4 alkyl), -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CH2CONH2, -(CH2)n-carbocycle, -0(CH2)n-carbocycle,
-0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9.
In one embodiment, the present invention provides compounds of Formulae (I),
(II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is NR5R5; R5, at each occurrence, is independently selected from H, Ci_4 alkyl, -(CR6R6)n-C3-io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said carbocycle and heterocycle are substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is NR5R5; R5, at each occurrence, is independently selected from H, Ci-4 alkyl, -(CH2)n-C3_io carbocycle, -(CH2)n-aryl, -(CH2)n-4-10 membered heterocycle selected from
Figure imgf000044_0001
In one embodiment, the present invention provides compounds of Formulae (I),
(II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is NR5R5; R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said heterocycle is substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is NR5R5; R5 and R5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
Figure imgf000044_0002
Figure imgf000045_0001
R7, at each occurrence, is independently selected from H, =0, halogen, Ci_4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl), -(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(C!_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci-4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH,
-S02NH(CH2)20(Ci_4 alkyl), -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2,
-CH2CONH2, -(CH2)n-carbocycle, -0(CH2)n-carbocycle, -0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9.
In one embodiment, the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof selected from -CR4R4C(0)-,
-OC(O)-, and -NR6C(0)-; R1 is selected from
Figure imgf000045_0002
Figure imgf000045_0003
embodiment, the present invention provides compounds of Formulae (I),
(II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is selected from NR5R5, C3-10 carbocycle and 4- to
12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7; R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7; alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle substituted with 1-4 R7.
In one embodiment, the present invention provides compounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein L is selected from -CR4R4C(0)-, -OC(O)-, and -NR6C(0)-; R1 is selected from C3-io carbocycle and 4- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said carbocycle and heterocycle are substituted with 1-4 R7; R5, at each occurrence, is independently selected from H, C1-4 alkyl, -(CR6R6)n-C3_io carbocycle substituted with 1-4 R7 and -(CR6R6)n-4-10 membered heterocycle selected from
Figure imgf000046_0001
alternatively, R5 and R5 are taken together with the nitrogen atom to which they attached to form a heterocycle selected from
Figure imgf000046_0002
Figure imgf000047_0001
In another aspect, the present invention provides a compound selected from any subset list of compounds exemplified in the present application.
In another embodiment, the compounds of the present invention have ROCK IC50 values < 10 μΜ.
In another embodiment, the compounds of the present invention have ROCK IC50 values < 1 μΜ.
In another embodiment, the compounds of the present invention have ROCK IC50 values < 0.1 μΜ.
In another embodiment, the compounds of the present invention have ROCK IC50 values < 0.05 μΜ.
In another embodiment, the compounds of the present invention have ROCK 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.
II. 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 "Ci_io alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, C5, Ce, C7, C8, C9, and Cio 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, ?-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "Co alkyl" or "Co alkylene" is used, it is intended to denote a direct bond.
"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" 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 "carbocycle" 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 carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable 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 Cio aryl" or "C6-io 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" or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic 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", Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 1 13- 191, Harwood Academic Publishers (1991);
c) Bundgaard, PL, 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- l,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared 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, "μΕ" 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
AICI3 aluminum chloride
AIBN Azobisisobutyronitrile
BBr3 boron tribromide
BCI3 boron trichloride
BEMP 2-tert-butylimino-2-diethylamino- 1 ,3 -dimethylperhydro- 1,3,2- 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(T) (+)-l ,2-bis((2S,5S)-2,5-diethylphospholano)benzene(l,5- cyclooctadiene)rhodium(I) trifluoromethanesulfonate
Et3 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- l-ethanesulfonic acid
Hex Hexane
HOBt or HOBT 1 -hydroxybenzotriazole
H2SO4 sulfuric acid
K2CO3 potassium carbonate
KOAc potassium acetate
K3PO4 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
NH4C1 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)Cl2 [1,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
Ph3PCl2 triphenylphosphine dichloride
PG protecting group
POCl3 phosphorus oxychloride
i-PrOH or IPA isopropanol
PS polystyrene
SEM-C1 2-(trimethysilyl)ethoxymethyl chloride
Si02 silica oxide
SnCl2 tin(II) chloride
TBAI tetra-M-butylammonium iodide
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TMSCHN2 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 ROCK IC50 values measured for the following examples. IC50 ranges against ROCKs are as follows: + + + = 0.1 - 100 nM; ++ = 101 - 1000 nM; + = 1001 -50000 nM.
Table A
Figure imgf000064_0001
Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
4 - ++
5 - ++
6 - ++
7 - +++
8 - +
9 + +++
10 ++ +++
11 + ++
12 + +
13 + +
14 + +
15 + +
16 + +
17 + +++
18 + +
19 + +
20 + ++
21 ++ +++
22 + +
23 ++ +++
24 ++ +++
25 ++ +++
26 + +++
27 + +++
28 + ++
29 + +++
30 - -
31 + +++
32 - -
33 +++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
34 + ++
35 ++ +++
36 + +++
37 ++ +++
38 ++ +++
39 ++ +++
40 ++ +++
41 +++ +++
42 + +++
43 + ++
44 + +++
45 - +++
46 + +++
47 ++ +++
48 ++ +++
49 - +++
50 +++ +++
51 + +++
52 ++ ++
53 +++ +++
54 ++ +++
55 + +
56 + +
57 + +
58 +++ +++
59 + +
60 +++ +++
61 +++ +++
62 +++ +++
63 ++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
64 ++ +++
65 +++ +++
66 +++ +++
67 ++ +++
68 - +++
69 + ++
70 + +++
71 + +++
72 ++ +++
73 ++ +++
73 - -
74 + +++
75 +++ +++
76 +++ +++
77 +++ +++
78 ++ +++
79 +++ +++
80 +++ +++
81 + ++
82 + ++
83 +++
84 ++
85 +++
86 ++
87 ++
88 +
89 ++
90 ++
91 +
92 ++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
93 +++ +++
94 +++ +++
95 +++ +++
96 ++ +++
97 ++ ++
98 +++ +++
99 +++ +++
100 +++ +++
101 +++ +++
102 +++ +++
103 +++ +++
104 +++ +++
105 ++ +++
106 + +++
107 +++ +++
108 ++ +++
109 +++ +++
110 +++ +++
111 ++ ++
112 + ++
113 ++ ++
114 ++ +++
115 +++ +++
116 +++ +++
117 +++ +++
118 ++ +++
119 ++ +++
120 +++ +++
121 ++ +++
122 +++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
123 ++ +++
124 ++ +++
125 +++ +++
126 ++ +++
127 +++ +++
128 +++ +++
129 +++ +++
130 +++ +++
131 +++ +++
132 +++ +++
133 ++ +++
134 ++ +++
135 ++ +++
136 + +++
137 +++ +++
138 +++ +++
139 +++ +++
140 +++ +++
141 +++ +++
142 +++ +++
143 + +
144 +++ +++
145 +++ +++
146 +++ +++
147 +++ +++
148 +++ +++
149 +++ +++
150 +++ +++
151 +++ +++
152 +++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
153 +++
154 +++
155 +++
156 +++
157 +++
158 +++
159 +++
160 +++
161 +++
162 +++
163 +++
164 +++
165 +++
166 ++
167 +++
168 +++
169 +++
170 +++
171 +++
172 +++
173 +++
174 +++
175 +++
176 +++
177 +++
178 ++
179 +++
180 +++
181 ++
182 +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
183 +++ +++
184 +++ +++
185 +++ +++
186 ++ +++
187 +++ +++
188 +++ +++
189 +++ +++
190 +++ +++
191 +++ +++
192 ++ +++
193 + ++
194 ++ +++
195 +++ +++
196 + ++
197 +++ +++
198 +++ +++
199 +++ +++
200 +++ +++
201 +++ +++
202 +++ +++
203 ++ +++
204 ++ +++
205 ++ +++
206 +++ +++
207 +++ +++
208 +++ +++
209 ++ ++
210 ++ ++
211 + ++
212 ++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
213 +++ +++
214 +++ +++
215 ++ ++
216 + ++
217 + ++
218 + ++
219 +++ +++
220 +++ +++
221 ++ ++
222 +++ +++
223 +++ +++
224 +++ +++
225 +++ +++
226 +++ +++
227 ++ +++
228 +++ +++
229 +++ +++
230 +++ +++
231 ++ +++
232 ++ +++
233 ++ ++
234 ++ +++
235 +++ +++
236 ++ +++
237 ++ +++
238 ++ +++
239 ++ +++
240 ++ +++
241 +++ +++
242 ++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
243 - -
244 +++
245 +++
246 +++
247 +++
248 ++
249 +++
250 ++
251 ++
252 + ++
253 + ++
254 ++ +++
255 + ++
256 ++
257 +
258 +++
259 ++
260 ++
261 +++
262 ++
263 ++
264 +++
265 +++
266 +++
267 ++
268 +++
269 +
270 +++
271 +++
272 +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
273 ++
274 +++
275 +++
276 +
277 ++
278 ++
279 ++
280 ++
281 ++
282 ++
283 +++
284 +++
285 +++
286 ++
287 +++
288 +++
289 +++
290 +++
291 ++
292 ++
293 ++
294 ++
295 ++
296 ++
297 +++
298 +++
299 ++
300 +++
301 +++
302 +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
303 ++ +++
304 ++ +++
305 + +
306 ++ +++
307 ++ +++
308 +++ +++
309 +++ +++
310 ++ +++
311 +++ +++
312 ++ +++
313 +++ +++
314 +++ +++
315 +++ +++
316 ++ +++
317 +++ +++
318 +++ +++
319 +++ +++
320 +++ +++
321 +++ ++
322 +++ ++
323 +++ +++
324 +++ +++
325 ++ +++
326 +++ ++
327 +++ +++
328 ++ +++
329 +++ +++
330 +++ ++
331 ++ +++
332 +++ +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
333 +++
334 +++
335 +++
336 +++
337 +++
338 ++
339 +++
340 +++
341 +++
342 +++
343 +++
344 +++
345 ++ +++
346 + ++
347 + ++
348 ++ +++
349 +++ +++
350 +++ +++
351 +++ +++
352 + ++
353 ++ +++
354 +++ +++
355 + +++
356 +++ ++
357 + ++
358 ++ +++
359 + +++
360 + +++
361 ++ +++
362 + +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
363 + +++
364 ++ +++
365 + 221.80
366 ++ +++
367 + +++
368 + +++
369 ++ +++
370 + +++
371 ++ ++
372 ++ ++
373 +++
374 +++
375 +++
376 ++
377 +
378 +++
379 ++
380 ++
381 +++
382 +++
383 ++
384 ++
385 +++
386 ++
387 +
388 ++
389 ++
390 ++
391 ++
392 +++ Example No. ROCK1 IC50 (nM) ROCK2 IC50 (nM)
393 +++ +++
394 ++ +++
395 +++ +++
396 ++ +++
397 + ++
398 ++ +++
399 ++ ++
400 +++ +++
401 +++ +++
402 ++ +++
403 +++ +++
404 +++ +++
405 +++ +++
406 +++ +++
407 +++ +++
408 ++ +++
409 - -
410 - -
411 - -
412 - -
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 methods available to those skilled in the art of organic chemistry (Maffrand, J.P. et al, Heterocycle , 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 effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
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)).
Figure imgf000085_0001
"if ig Scheme 1 shows the synthesis of generic compounds le, If, lg, from the common intermediate Id. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (lb) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords intermediate lc. Cleavage of the protecting group, such as using TFA or HC1 in dioxane when PG = Boc, affords the arylamine intermediate Id. Intermediate Id is converted to the urea target le by treatment with an isocyanate or a carbamic chloride. Intermediate Id is converted to the amide target If by treatment with an acid chloride in the presence of a base such as pyridine or DIEA. Alternatively, Target If is prepared by coupling of intermediate Id with a carboxylic acid in the presence of a coupling reagent, such as HATU or BOP, and a base such as DIEA. Intermediate Id is converted to the carbamate target lg by treatment with a chloroformate in the presence of a base such as DIEA or TEA.
Scheme 2
Figure imgf000086_0001
Alternatively, targets le-g can be prepared as shown in Scheme 2. Aryl halide 2a (commercially available or prepared by literature methods) is converted to the aryl boronic acid or boronate ester 2b by coupling with bis(pinacolato)diboron in the presence of a base such a potassium acetate and a catalyst such as PdCl2(dppf) in dioxane or
DMSO. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (2b) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords target compounds le-g.
Scheme 3
Figure imgf000087_0001
Alternatively, target le can be prepared as shown in Scheme 3 beginning from isocyanate 3a, which is either commercially available or can be prepared from the aniline precursor upon treatment with phosgene (or equivalent) and an appropriate base such as TEA. Intermediate 3a is reacted with amine (3b) to afford urea 3c. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (3c) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords target compounds le. Scheme 4
Figure imgf000087_0002
4e
Scheme 4 shows the synthesis of carbamate target 4e, beginning from
chloroformate 4a (either commercially available or prepared by treatment of an appropriate halophenol with phosgene or a phosgene equivalent). Intermediate 4a is reacted with an amine (4b) in the presence of a base such as TEA to afford carbamate 4c. Aryl halide 4c is converted to the aryl boronic acid or boronate ester 4d by coupling with bis(pinacolato)diboron in the presence of a base such a potassium acetate and a catalyst such as PdCl2(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (4d) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords target compound 4e.
Scheme 5
Figure imgf000088_0001
Scheme 5 shows the synthesis of amide target 5e, beginning with boronic acid/ester 5a, which is either commercially available or is prepared from the aryl halide precursor. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (5a) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords intermediate 5b. Cleavage of the protecting group (PG) by alkaline hydrolysis (or other reagents as appropriate) affords carboxylic acid 5c. Coupling of intermediate 5c with amine 5d in the presence of a coupling reagent, such as HATU or BOP, and a base such as DIEA affords target 5e.
Scheme 6
Figure imgf000088_0002
5e
Scheme 6 shows an alternate synthesis to target 5e beginning from acid 6a. Coupling of intermediate 6a with amine 6b in the presence of a coupling reagent, such as HATU or BOP, and a base such as DIEA affords intermediate amide 6c. Aryl halide 6c is converted to the aryl boronic acid or boronate ester 6d by coupling with
bis(pinacolato)diboron in the presence of a base such a potassium acetate and a catalyst such as PdCl2(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling between aryl halide la and boronic acid or boronate ester (6d) in the presence of a base such as K3PO4 and a catalyst such as Pd(PPh3)4 affords target compound 5e.
Scheme 7
Figure imgf000089_0001
Scheme 7 shows the synthesis of target 7b beginning with intermediate aniline Id. Aniline Id is coupled with heteroaryl halide 7a under thermal SNAr conditions in the presence of a base such as DIEA in a solvent such as DMF to afford 7b. Alternatively, Id and 7a may be coupled under Buchwald-Hartwig N-arylation conditions using a base such as CS2CO3, a catalyst such as Pd2(dba)3 and an appropriate ligand to afford 7b.
Figure imgf000089_0002
Scheme 8 shows an alternative synthesis of target 7b, beginning from
intermediate 8a, which is either commercially available or can be prepared by literature methods. An appropriate protecting group is introduced by treatment with a base such as potassium carbonate and a protecting group reagent such as para-methoxybenzyl chloride to afford 8b. Treatment of aryl bromide 8b with sodium azide, (¾0 and a ligand such as proline affords aniline 8c. Aniline 8c is coupled with heteroaryl halide 7 a under thermal SNAr conditions in the presence of a base such as DIEA in a solvent such as DMF to afford intermediate 8d. Alternatively, 8c and 7a may be coupled under Buchwald- Hartwig N-arylation conditions using a base such as CS2CO3, a catalyst such as Pd2(dba)3 and an appropriate ligand to afford intermediate 8d. Cleavage of the protecting group under appropriate conditions (TFA in the case of a para-methoxybenzyl protecting group) affords target 7b.
Scheme 9
Figure imgf000090_0001
Scheme 9 shows an alternative synthesis of target 7b, starting from aryl bromide 8b. Coupling of intermediate 8b with heteroaryl amine 9a under Buchwald-Hartwig N- arylation conditions using a base such as CS2CO3, a catalyst such as Pd2(dba)3 and an appropriate ligand affords intermediate 8d. Cleavage of the protecting group under appropriate conditions (TFA in the case of a para-methoxybenzyl protecting group) affords target 7b.
Scheme 10
Figure imgf000090_0002
10a 10b 10c 1a (X = N) Scheme 10 shows the synthesis of intermediate la, where X = N. Furan-2,5-dione 10a can be converted to intermediate 10b by treatment with a reagent such as hydrazine. Intermediate 10b is chlorinated by treatment with a reagent such as POCI3 to afford dichloro intermediate 10c. Partial hydrolysis of 10c with a reagent such as AcOH affords intermediate la.
Figure imgf000091_0001
Scheme 11 shows the synthesis of intermediate la, where X = CR. Intermediate brominated with a reagent such as NBS to afford intermediate la.
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 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.
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 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: 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 CI 8, 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 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: 50 °C; Gradient: 0-100% B over 3 minutes; Flow: 1.1 1 mL/min.
Method F: Waters BEH C 18, 2.1 x 50 mm, 1.7-μιη 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.
Intermediate 1: 2-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)acetic acid
Figure imgf000093_0001
Intermediate 1A: Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate
Figure imgf000093_0002
To a vial containing a degassed (3x vacuurn/Ar) mixture of ethyl 2-(4- bromophenyl)acetate (1 g, 4.1 1 mmol), bis(pinacolato)diboron (1.25 g, 4.94 mmol), and potassium acetate (1.21 g, 12.3 mmol) in dioxane (10 mL), was added PdCi2(dppf) CH2CI2 adduct (0.090 g, 0.123 mmol). The reaction mixture was degassed, sealed and heated at 1 10 °C for 16 h. The mixture was diluted with water, then extracted with EtOAc. The organic phase was concentrated and purified via flash chromatography (EtOAc/hexane) to afford 1.1 g (92%) of Intermediate 1A. MS(ESI) m/z: 291.2 (M+H)+; XH NMR (500MHz, CDC13) δ 7.84 - 7.71 (m, 2H), 7.34 - 7.28 (m, J=8.0 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.27 (s, 12H), 1.26 - 1.22 (m, 3H). Intermedia -(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)acetate
Figure imgf000093_0003
To 4-chlorophthalazin- 1 (2H)-one (200 mg, 1.11 mmol), Intermediate 1A (386 mg, 1.33 mmol) and K3PO4 (588 mg, 2.77 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (64.0 mg, 0.055 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was concentrated and purified via flash chromatography (EtOAc/hexane) to afford 218 mg (46%) of Intermediate IB. MS(ESI) m/z: 309.1 (M+H)+; 'H NMR (500MHZ, DMSO- d6) δ 12.84 (s, 1H), 8.46 - 8.28 (m, 1H), 7.99 - 7.82 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.45 (d, J=6.6 Hz, 2H), 4.12 (qd, J=7.1, 1.8 Hz, 2H), 3.79 (s, 2H), 1.22 (td, J=7.0, 1.9 Hz, 3H).
Intermediate 1
Figure imgf000094_0001
To a solution of Intermediate IB (210 mg, 0.681 mmol) in MeOH (5 mL) and THF (5 mL), was added 1M aq. lithium hydroxide (3.41 mL, 3.41 mmol). The mixture was stirred rt overnight, then was concentrated. The residue was acidified with TFA, then was dissolved in DMSO/MeOH, and purified preparative HPLC to afford 170 mg (89%) of Intermediate 1. MS(ESI) m/z: 281.0 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.42 - 8.21 (m, 1H), 7.99 - 7.82 (m, 2H), 7.77 - 7.62 (m, 1H), 7.59 - 7.50 (m, 2H), 7.49 - 7.37 (m, J=8.3 Hz, 2H), 3.69 (s, 2H).
Intermediate 2: 5-((4-Methylpiperazin-l-yl)methyl)isoindoline, 3 TFA
Figure imgf000094_0002
Intermediate 2A: tert-Butyl di(prop-2-yn-l-yl)carbamate
Figure imgf000095_0001
To a solution of 2-propyn-l -amine and N-2-propynyl- (1.110 mL, 10.74 mmol) in THF (20 mL) at rt, was added BOC2O (2.58 g, 11.81 mmol). To this mixture was added TEA (0.150 mL, 1.074 mmol). The mixture was stirred at rt for 14 h. The reaction mixture was concentrated to an oil. The oil was partitioned between 0.2 Ν HC1 and EtOAc. The organic phase was washed with H20, sat. NaHCCh and brine, dried (Na2S04), filtered through a 1" pad of Si02 and concentrated to afford 2.40 g (100%) of Intermediate 2A as a yellow oil. MS(ESI) m/z: 216.1 (M+H)+; XH NMR (400MHz, CDCI3) δ 4.17 (br. s., 4H), 2.22 (t, J=2.4 Hz, 2H), 1.48 (s, 9H).
Intermediate 2B: tert-Butyl 5-(hydroxymethyl)isoindoline-2-carboxylate
Figure imgf000095_0002
To a degassed (evacuated and flushed with Ar (5x)) solution of prop-2-yn-l-ol (0.961 mL, 16.11 mmol) in toluene (5 mL) at 50 °C, were added in 5 portions at 10 minute intervals Intermediate 2A (1.20 g, 5.37 mmol) in degassed toluene (5 mL) and Tris(triphenylphosphine)rhodium(I) chloride (0.124 g, 0.134 mmol). Following the last addition, the brown mixture was stirred at 50 °C for 1.25 h. The reaction mixture was concentrated, then was co-evaporated with CHCI3 (2x). The crude product was purified by flash chromatography (0 to 100% ethyl acetate/hexanes, eluted at 75% EtOAc) to afford 1.15 g (86% yield) of Intermediate 2B as a white solid. MS(ESI) m/z:
521.3(M+H)+; 'H NMR (400MHZ, CD3OD) δ 7.33 - 7.21 (m, 3H), 4.63 (dd, J=5.6, 3.2 Hz, 4H), 4.60 (s, 2H), 1.52 (s, 9H).
Figure imgf000095_0003
To a solution of Intermediate 2B (500 mg, 2.006 mmol) in DCM (10 mL) at 0 °C, were added DIEA (0.420 mL, 2.407 mmol) and Ms-Cl (0.172 mL, 2.206 mmol). The mixture was stirred at 0 °C for 1.5 h. The mixture was diluted with DCM, then was washed with half sat. NH4C1 and brine. The organic phase was dried ( a2S04) and concentrated to afford 655 mg (100%) of Intermediate 2C as a brown oil. The material was used in the following step without further purification. MS(ESI) m/z: 272.0 (M-t- Bu+2H)+.
Intermediate 2D: tert-Butyl 5-((4-methylpiperazin-l-yl)methyl)isoindoline-2- carboxylate
Figure imgf000096_0001
To a solution of Intermediate 2C (657 mg, 2.007 mmol) in acetone (10 mL) at rt, were added K2CO3 (416 mg, 3.01 mmol) and 1-methyl piperazine (0.556 mL, 5.02 mmol). The mixture was stirred at rt for 2.5 h, then 1 h at 50 °C. The mixture was concentrated, then was partitioned between EtOAc and H20. The aqueous phase was extracted with EtOAc (2x). The combined organic phase was dried (Na2S04) and concentrated to afford Intermediate 2D as a brown oil. MS(ESI) m/z: 332.2(M+H)+; XH NMR (400MHz, CD3OD) δ 7.30 - 7.21 (m, 3H), 4.63 (dd, J=5.5, 2.0 Hz, 4H), 3.53 (s, 2H), 2.50 (br. s., 8H), 2.27 (s, 3H), 1.52 (s, 9H).
Intermediat 2:
Figure imgf000096_0002
Intermediate 2D was treated with 4N HC1 in dioxane (5 mL, 20.00 mmol) and the resultant suspension was stirred for 1 h, then was concentrated. The mixture was redissolved in TFA (10 mL) and was stirred at rt for 20 min. The mixture was concentrated. The brown oil was coevaporated with DCM (2x), ether, MeOH and CH3CN to afford 1.36 g (100% yield, -85% purity) of Intermediate 2 as a brown semisolid, which was used as is without further purification. MS(ESI) m/z: 232.2 (M+H)+; XH NMR (400MHz, CD3OD) δ 7.49 - 7.40 (m, 3H), 4.62 (s, 4H), 3.82 (s, 2H), 3.34 (br. s., 4H), 2.89 (s, 3H), 2.90 (br. s, 4H).
Intermediate 3: 4-(4-Aminophenyl)phthalazin- 1 (2H)-one, TFA salt
Inte
Figure imgf000097_0001
To 4-chlorophthalazin-l(2H)-one (118 mg, 0.653 mmol), (4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (170 mg, 0.719 mmol) and potassium phosphate (347 mg, 1.634 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (37.8 mg, 0.033 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 35 min. The reaction mixture was concentrated and purified via flash chromatography to afford 150 mg (68%) of
Intermediate 3A. MS(ESI) m/z: 338.1 (M+H)+.
Figure imgf000097_0002
To Intermediate 3A (150 mg, 0.445 mmol) in CH2C12 (3 mL), was added TFA (2 mL). The mixture was stirred rt for 2h, then was concentrated. The crude product was purified via flash chromatography, then preparative HPLC to afford 62 mg (59%) of Intermediate 3. MS(ESI) m/z: 238.1 (M+H)+; ¾ NMR (500MHz, CD3OD) δ 8.44 (dt, J=4.7, 2.3 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.81 - 7.75 (m, 1H), 7.71 - 7.61 (m, 2H), 7.41 - 7.30 (m, 2H).
Intermediate 4: 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phi
(isoindolin-2-yl)ethanone
Figure imgf000098_0001
To 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol), isoindoline (0.161 mL, 1.416 mmol), and HATU (587 mg, 1.545 mmol) in DMF (5 mL), was added DIEA (0.450 mL, 2.57 mmol). The mixture was stirred at rt for 1 h. The resultant heterogeneous mixture was diluted with EtOAc, then was washed with H20, 1 N HC1, H20, sat. aHC03 and brine. The organic phase was dried (Na2S04), filtered and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford 147 mg (34%) of Intermediate 4A as a white solid. MS(ESI) m/z: 333.9 (M+H)+; XH NMR (400MHz, CDC13) δ 7.34 - 7.30 (m, 3H), 7.30 - 7.22 (m, 4H), 4.89 (s, 2H), 4.83 (s, 2H), 3.73 (s, 2H)
Intermediate 4:
Figure imgf000099_0001
To a mixture of Intermediate 4A (146 mg, 0.437 mmol), bis(pinacolato)diboron (133 mg, 0.524 mmol), and potassium acetate (129 mg, 1.31 mmol) in a reaction vial, was added dioxane (3 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). PdCl2(dppf) (¾(¾ adduct (9.6 mg, 0.013 mmol) was added, then reaction mixture was degassed (3x vacuum/Ar). The vial was sealed, then was heated at 110 °C for 2 h. The reaction mixture was diluted with EtOAc, then was washed with ¾0 and brine. The organic phase was dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 50% ethyl acetate/hexanes) to afford 120 mg (72%) of Intermediate 4 as a yellow solid. MS(ESI) m/z: 386.1 (M+H)+; XH NMR
(400MHz, CDC13) δ 7.55 (dd, J=7.5, 0.9 Hz, IH), 7.50 (d, J=10.1 Hz, IH), 7.39 (t, J=7.4 Hz, IH), 7.32 - 7.22 (m, 4H), 4.84 (s, 4H), 3.80 (s, 2H), 1.33 (s, 12H).
Intermediate 5: 2-(3-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phi
(isoindolin-2-yl)ethanone
Figure imgf000099_0002
Intermediate 5A: 2-(4-Bromo-3 -fluorophenyl)- l-(isoindolin-2-yl)ethanone
Figure imgf000100_0001
To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (300 mg, 1.287 mmol),isoindoline (0.161 mL, 1.416 mmol), and HATU (734 mg, 1.931 mmol) in DMF (5 mL), was add DIEA (0.450 mL, 2.6 mmol). The mixture was stirred rt for 18 h. The reaction mixture was diluted with EtOAc, then was washed with H20, 1 N HC1, H20, sat. a2C03 and brine. The organic phase was dried (Na2S04), filtered through a 1 " pad of Si02 and concentrated. The crude product was purified by flash chromatography
(gradient from 0 to 100% ethyl acetate/hexanes) to afford 379 mg (88%) of Intermediate 5A as an off-white solid. MS(ESI) m/z: 333.9 (M+H)+; 'H NMR (400MHZ, CDCI3) δ 7.50 (dd, J=8.0, 7.4 Hz, 1H), 7.33 - 7.22 (m, 4H), 7.14 (dd, J=9.2, 2.0 Hz, 1H), 7.01 (dd, J=8.5, 1.9 Hz, 1H), 4.83 (s, 4H), 3.72 (s, 2H).
Intermediate 5:
Figure imgf000100_0002
To a mixture of Intermediate 5A (200 mg, 0.598 mmol), bis(pinacolato)diboron
(182 mg, 0.718 mmol), and potassium acetate (176 mg, 1.80 mmol) in a reaction vial, was added dioxane (5 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). PdCl2(dppf) CH2C12 adduct (13 mg, 0.018 mmol) was added, then the reaction mixture was degassed (3x vacuum/Ar). The vial was sealed, then was heated at 110 °C for 2 h. Additional catalyst (13 mg) was added and the reaction mixture was stirred at 110 °C for 2 more hours. The reaction mixture was cooled to room temperature, then was filtered and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford 208 mg (91%) of Intermediate 5 as a yellow solid. MS(ESI) m/z: 386.1 (M+H)+; 'H NMR (400MHZ, CDCI3) δ 7.71 (t, J=6.9 Hz, 1H), 7.35 - 7.20 (m, 4H), 7.13 (d, J=7.5 Hz, 1H), 7.04 (d, J=10.1 Hz, 1H), 4.83 (s, 2H), 4.77 (s, 2H), 3.78 (s, 2H), 1.35 (s, 12H).
Figure imgf000101_0001
To a solution of isoquinolin-l(2H)-one (105 mg, 0.723 mmol) in DMF (2 mL), was added NBS (142 mg, 0.796 mmol). The mixture was stirred at rt for 2h, then was concentrated. The crude product was purified via preparative HPLC to afford 110 mg (68%) of Intermediate 6. MS(ESI) m/z: 223.9 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 11.57 (br. s., 1H), 8.24 (dd, J=8.0, 0.8 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.79 - 7.75 (m, 1H), 7.61 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 7.55 (s, 1H).
Figure imgf000101_0002
To a mixture of 2-(4-bromophenyl)acetic acid (300 mg, 1.395 mmol), isoindoline
(183 mg, 1.535 mmol), and HATU (796 mg, 2.093 mmol) in DMF (5 mL), was add DIEA (0.487 mL, 2.79 mmol). The mixture was stirred at rt overnight. The reaction mixture was quenched with water, then extracted with EtOAc. The organic phase was washed with 10% LiCl, brine, and concentrated. The residue was purified via flash chromatography (EtOAc/hexane) to afford 390 mg (88%) of Intermediate 7. MS(ESI) m/z: 316.0 (M+H)+. (Isoindolin-2-yl)acetyl)phenyl)boronic acid
Figure imgf000101_0003
A mixture of Intermediate 7 (30 mg, 0.095 mmol), bis(pinacolato)diboron (24 mg, 0.095 mmol), and potassium acetate (27.9 mg, 0.285 mmol) in dioxane (1 mL) was degassed (3x vacuum/Ar). Then PdCi2(dppf) (¾(¾ adduct (2.083 mg, 2.85 μιηοΐ) was added, the reaction mixture was degassed again (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction was purified via preparative HPLC to afford 14 mg (53%) of Intermediate 8. MS(ESI) m/z: 282.1 (M+H)+.
Intermediate 9: l-(Isoindolin-2-yl)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethanone
Figure imgf000102_0001
According to a procedure similar to the preparation of Intermediate 8,
Intermediate 7 (400 mg, 1.27 mmol) afforded after flash chromatography (0 to 60% EtOAc/hexane gradient) 406 mg (88%) of Intermediate 9. MS(ESI) m/z: 364.1 (M+H)" XH NMR (500MHz, CDC13) δ 7.82 - 7.77 (m, J=8.3 Hz, 2H), 7.39 - 7.33 (m, J=8.0 Hz, 2H), 7.27 (d, J=0.6 Hz, 3H), 7.27 - 7.24 (m, 1H), 7.20 (d, J=6.6 Hz, 1H), 4.84 (s, 2H), 4.77 (s, 2H), 3.81 (s, 2H), 1.38 - 1.31 (m, 12H).
Intermediate 10: N-(4-(4,4,5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)indoline- 1 carboxamide
Figure imgf000102_0002
Inter -(4-Bromophenyl)indoline-l -carboxamide
Figure imgf000102_0003
A mixture of l-bromo-4-isocyanatobenzene (300 mg, 1.515 mmol) and indoline (199 mg, 1.667 mmol) in (¾(¾ (5 mL) was stirred at rt lh. The reaction mixture was diluted with EtOAc (100 mL), then was washed with 1 N HC1, sat. Na2C03, and brine. The organic phase was dried over Na2S04, then concentrated. The residue was purified by flash chromatography (0-60% EtOAc/hexane gradient) to afford 470 mg (98%) of Intermediate 10A as a yellow foam. MS(ESI) m/z: 317.0 (M+H)+; XH NMR (500MHz, CDC13) δ 7.88 (d, J=8.0 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.41 - 7.35 (m, 2H), 7.22 - 7.17 (m, 2H), 6.99 (td, J=7.4, 1.1 Hz, 1H), 6.47 (br. s., 1H), 4.15 - 4.05 (m, 2H), 3.25 (t, J=8.5 Hz, 2H).
Intermediate 10:
Figure imgf000103_0001
dioxane, 1 10 °C
To a mixture of Intermediate 10A (470 mg, 1.482 mmol), bis(pinacolato)diboron (452 mg, 1.778 mmol), and potassium acetate (436 mg, 4.45 mmol) in dioxane (20 mL), was added PdCi2(dppf) CH2CI2 adduct (32.5 mg, 0.044 mmol). The reaction mixture was degassed (3x vacuum/ Ar), sealed in a vial and heated at 110 °C for 3 h. The reaction was quenched with water, extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine, dried ( a2S04) and concentrated. The residue was purified by flash chromatography (0-60% EtOAc/hexane gradient) to afford 430 mg (80%) of
Intermediate 10 as a white solid. MS(ESI) m/z: 365.1 (M+H)+; XH NMR (500MHz,
CDCI3) δ 7.89 (d, J=8.0 Hz, 1H), 7.81 - 7.77 (m, J=8.3 Hz, 2H), 7.52 - 7.48 (m, 2H), 7.23 - 7.18 (m, 2H), 7.01 - 6.94 (m, 1H), 6.56 (s, 1H), 4.17 - 4.04 (m, 2H), 3.25 (t, J=8.5 Hz, 2H), 1.39 - 1.32 (m, 12H).
Intermediate 11: 2-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)propanoic acid
Figure imgf000104_0001
Intermediate 11A: Ethyl 2-(4-bromophenyl)propanoate
Figure imgf000104_0002
To a solution of ethyl 2-(4-bromophenyl)acetate (150 mg, 0.617 mmol) in THF (3 mL) at -78 °C, was added 1.5M LDA (0.514 mL, 0.926 mmol). The mixture was stirred at -78 °C for 20 min, then iodomethane (175 mg, 1.23 mmol) was added. The solution was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-20% EtOAc/hexane gradient) to afford 120 mg (76%) of Intermediate 11A as a yellow oil. MS(ESI) m/z: 257.0 (M+H)+; XH NMR (500MHz, CDC13) δ 7.47 - 7.42 (m, 2H), 7.21 - 7.16 (m, 2H), 4.12 (dddd, J=17.6, 10.4, 7.1, 3.7 Hz, 2H), 3.67 (q, J=7.3 Hz, 1H), 1.48 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H). Intermediate 11B: Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propanoate
Figure imgf000104_0003
To a mixture of Intermediate 11A (120 mg, 0.467 mmol), bis(pinacolato)diboron (142 mg, 0.56 mmol), and potassium acetate (137 mg, 1.40 mmol) in dioxane (4 mL), was added PdCi2(dppf) CH2CI2 adduct (10 mg, 0.014 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed and heated at 110 °C for 16 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-30%
EtOAc/hexane gradient) to afford 120 mg (85%) of Intermediate 11B as a yellow oil. MS(ESI) m/z: 327.2 (M+H)+; ¾ NMR (500MHz, CDC13) δ 7.81 - 7.75 (m, J=8.3 Hz, 2H), 7.35 - 7.29 (m, J=8.0 Hz, 2H), 4.11 (dddd, J=17.8, 10.6, 7.1, 3.6 Hz, 2H), 3.77 - 3.66 (m, 1H), 1.49 (d, J=7.2 Hz, 3H), 1.37 - 1.30 (m, 12H), 1.19 (t, J=7.2 Hz, 3H).
Interm -(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)propanoate
Figure imgf000105_0001
To 4-chlorophthalazin-l(2H)-one (70 mg, 0.388 mmol), Intermediate 11B (118 mg, 0.388 mmol) and potassium phosphate (206 mg, 0.969 mmol), were added dioxane (3 mL) and water (0.333 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (22.40 mg, 0.019 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-80% EtOAc/hexane gradient) to afford 100 mg (80%) of Intermediate 11C as a yellow foam. MS(ESI) m/z: 323.1 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.84 (s, 1H), 8.41 - 8.31 (m, 1H), 7.98 - 7.84 (m, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.20 - 4.02 (m, 2H), 3.91 (d, J=6.9 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).
Intermediate 11:
Figure imgf000106_0001
To a solution of Intermediate 11C (100 mg, 0.310 mmol) in THF (3 mL), was added 1M LiOH (0.620 mL, 0.620 mmol). The mixture was stirred at rt for 3h, then was concentrated. The residue was purified via preparative HPLC to afford 90 mg (99%) of Intermediate 11 as a white solid. MS(ESI) m/z: 295.1 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.42 - 8.23 (m, 1H), 7.99 - 7.82 (m, 2H), 7.78 - 7.66 (m, 1H), 7.61 - 7.52 (m, J=8.0 Hz, 2H), 7.50 - 7.40 (m, J=8.0 Hz, 2H), 3.80 (q, J=7.2 Hz, 1H), 1.44 (d, J=6.9 Hz, 3H).
Intermediate 12: 6-Methoxy-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)indoline- 1 -carboxamide
Figure imgf000106_0002
1 -Bromo-4-isocyanatobenzene (146 mg, 0.737 mmol) was mixed with 6- methoxyindoline (110 mg, 0.737 mmol) in DCM (3 mL), and stirred rt 2h. The reaction mixture was diluted with EtO Ac (100 mL), then was washed with 1 Ν HC1, sat a2C03, and brine, dried (Na2S04), and concentrated. The residue was purified by flash chromatography (gradient 0-50% EtO Ac/Hex) to afford Intermediate 12A (230 mg, 0.662 mmol, 90% yield) as a purple solid. MS(ESI) m/z: 346.9 (M+H)+; ¾ NMR (500MHz, chloroform-d) δ 7.58 (d, J=2.2 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.34 - 7.28 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.60 (br. s., 1H), 6.50 (dd, J=8.1, 2.3 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H), 3.82 - 3.72 (m, 3H), 3.07 (t, J=8.4 Hz, 2H).
Intermediate 12:
Figure imgf000107_0001
To a mixture of Intermediate 12A (230 mg, 0.662 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (202 mg, 0.795 mmol), and potassium acetate (195 mg, 1.99 mmol) in dioxane (20 mL), was added PdCl2(dppf) CH2C12 adduct (14.5 mg, 0.020 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 3 h. The mixture was diluted with water, extracted with EtO Ac (2 x 30 mL). The combined organic layer was washed with brine, dried (Na2S04) and concentrated. The residue was by flash chromatography (gradient 0-60% EtO Ac/Hex) to afford Intermediate 12 (230 mg, 88% yield) as a white solid. MS(ESI) m/z 395.1 (M+H)+.
Intermediate 13 : 4-(4-Bromophenyl)-2-(4-methoxybenzyl)phthalazin- 1 (2H)-one
Figure imgf000107_0002
4-(4-Bromophenyl)phthalazin-l(2H)-one (1.50 g, 4.98 mmol), K2C03 (1.38 g, 9.96 mmol) and dry DMF (25 mL) were added into a round bottom flask. To the above mixture, l-(chloromethyl)-4-methoxybenzene (1.35 mL, 9.96 mmol) was added dropwise with stirring at rt over 5 min. Then, the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to rt, diluted with water (150 mL) and EtO Ac (250 mL). The organic phase was separated, washed with water (3x100 rnL), brine (1x50 mL), and dried ( a2S04). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-50% EtO Ac/Hex). The material was recrystallized from hexanes/EtOAc (7:3; -100 mL), washed with hexanes and dried to afford Intermediate 13 (1.39 g, 66.2% yield) as a white solid. MS(ESI) m/z: 421.0 (M+H)+; XH-NMR (400 MHz, CDC13) δ ppm 8.56 - 8.49 (m, 1H), 7.75 (quind, J=7.4, 1.3 Hz, 2H), 7.69 - 7.62 (m, 3H), 7.47 (t, J=7.9 Hz, 4H), 6.85 (d, J=8.6 Hz, 2H), 5.39 (s, 2H), 3.77 (s, 3H).
Inte -one
Figure imgf000108_0001
Intermediate 13 (0.500 g, 1.187 mmol), L-proline (0.178 g, 1.543 mmol), and cuprous oxide (0.170 g, 1.19 mmol) were placed into a 20 mL pressure vial, and DMSO (8 mL) was added. The reaction mixture was degassed with stirring (3x vacuum/Ar), and sodium azide (0.154 g, 2.37 mmol) was added. The reaction mixture was degassed again (2x vacuum/Ar), and stirred under Ar at 100 °C for 5 h. The reaction mixture was quenched with sat. NH4C1, diluted with EtOAc (200 mL) and water (100 mL). Organic phase was washed with sat. a2C03 (2x), water, brine, dried ( a2S04) and concentrated. The product was purified via flash chromatography (0-80% EtO Ac/Hex) to afford
Intermediate 14 (0.386 g, 91% yield) as an off-white solid. MS(ESI) m/z: 421.0 (M+H)+; XH-NMR (400 MHz, CDC13) δ ppm 8.54 - 8.46 (m, 1H), 7.84 - 7.77 (m, 1H), 7.77 - 7.66 (m, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.41 - 7.35 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 5.40 (s, 2H), 5.30 (s, 2H), 3.77 (s, 3H)
Intermediate 15: l-(2-Hydroxy-2-methylpropyl)-lH-indazole-3-carboxylic acid
Figure imgf000109_0001
Intermediate 15A: Ethyl l-(2-hydroxy-2-methylpropyl)-lH-indazole-3-carboxylate
Figure imgf000109_0002
To a vial containing ethyl lH-indazole-3-carboxylate (75 mg, 0.39 mmol) and
2,2-dimethyloxirane (0.088 mL, 0.99 mmol), was added acetonitrile (1.5 mL). To this mixture was added CS2CO3 (193 mg, 0.591 mmol). The vial was sealed and the mixture was stirred at 90 °C for 2.5 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford
Intermediate 15A (45 mg, 43.5% yield) as a colorless oil. MS(ESI) m/z: 263.1 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 8.24 (dt, J=8.3, 0.9 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.50 - 7.43 (m, 1H), 7.32 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.45 (s, 2H), 2.73 (s, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.26 (s, 6H).
Intermedia
Figure imgf000109_0003
To a solution of Intermediate 15A (45 mg, 0.17 mmol) in THF (1 mL), was added 1M aq. LiOH (0.20 mL, 0.20 mmol), followed by MeOH (0.3 mL). The homogeneous mixture was stirred at rt for 1.5 h. Additional 1M aq. LiOH (0.1 mL, 0.1 mmol) was added and the mixture was stirred at rt for 14 h. The reaction mixture was partially evaporated to remove volatile solvents. The solution was diluted with ¾0, then was acidified with 1 N HC1 (-0.3 mL). The aqueous phase was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried ( a2S04) and concentrated to afford Intermediate 15 (40 mg, 100% yield) as an off-white solid. MS(ESI) m/z: 235.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 8.27 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.41 - 7.31 (m, 1H), 4.48 (s, 2H), 1.30 (s, 6H).
Intermediate 16: 1 -(2 -Hydrox -2-methylpropyl)-lH-indole-3-carboxylic acid
Figure imgf000110_0001
Intermediate 16A: Methyl l-(2-hydroxy-2-methylpropyl)-lH-indole-3-carboxylate
Figure imgf000110_0002
To a vial containing methyl lH-indole-3-carboxylate (200 mg, 1.14 mmol) and 2,2-dimethyloxirane (0.254 mL, 2.85 mmol), was added acetonitrile (3 mL). To this mixture was added CS2CO3 (558 mg, 1.71 mmol). The vial was sealed and the mixture was stirred at 90 °C for 2.5 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford
Intermediate 16A (274 mg, 1.108 mmol, 97% yield) white solid. MS(ESI) m/z: 248.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.26 - 8.11 (m, 1H), 7.91 (s, 1H), 7.49 - 7.38 (m, 1H), 7.31 - 7.23 (m, 2H), 4.13 (s, 2H), 3.91 (s, 3H), 1.48 (s, 1H), 1.29 (s, 6H). Intermediate 16:
Figure imgf000111_0001
To a solution of Intermediate 16A (272 mg, 1.10 mmol) in THF (5 mL), was added 1M aq. LiOH (1.2 mL, 1.2 mmol), followed by MeOH (1 mL). The homogeneous mixture was stirred at rt for 1.5 h. Additional 1M aq. LiOH (1.0 mL, 1.0 mmol) was added and the mixture was stirred at rt for 14 h. The reaction mixture was heated at 50 °C for 24 h, then at 60 °C for 9 h. The reaction mixture was partially concentrated to remove the organic solvent. The partially insoluble mixture was diluted with H20 and was washed with Et20. The organic phase was extracted with H20 (2x). The combined aqueous phase was acidified to pH 3 with 1 N HC1, then was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried ( a2S04) and concentrated to afford Intermediate 16 (255 mg, 99% yield) as an off-white solid. MS(ESI) m/z: 234.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.27 - 8.20 (m, 1H), 8.01 (s, 1H), 7.49 - 7.42 (m, 1H), 7.34 - 7.26 (m, 2H), 4.15 (s, 2H), 1.30 (s, 6H).
Intermediate 17: l-(2-(Dimethylamino)ethyl)-lH-indazole-3-carboxylic acid
Figure imgf000111_0002
Intermediate 18: 2-(2-(Dimethylamino)ethyl)-2H-indazole-3-carboxylic acid
Figure imgf000111_0003
Intermediate 17A: Methyl l-(2-(dimethylamino)ethyl)-lH-indazole-3-carboxylate Intermediate 17B: Methyl 2-(2-(dimethylamino)ethyl)-2H-indazole-3-carboxylate
Figure imgf000112_0001
17a 17b
In a sealed tube, ethyl lH-indazole-3-carboxylate (50 mg, 0.263 mmol) mixed with 2-bromo-N,N-dimethylethanamine (120 mg, 0.789 mmol), K2C03 (182 mg, 1.314 mmol) in DMF (5 mL), stirred 80 °C o/n. Concentrated and purified by prep HPLC. Two fractions were collected, 1st fraction concentrated to afford Intermediate 17A (29 mg, 45% yield) as a white solid. MS(ESI) m/z: 248.1 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.21 (d, J=8.4 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.58 - 7.52 (m, 1H), 7.43 - 7.36 (m, 1H), 4.96 (t, J=6.4 Hz, 2H), 4.06 (s, 3H), 3.81 (t, J=6.4 Hz, 2H), 2.88 (s, 6H).
2nd fraction concentrated to afford Intermediate 17B (19 mg, 29% yield) as a white solid. MS(ESI) m/z: 248.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.00 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.38 - 7.29 (m, 1H), 5.35 (t, J=6.1 Hz, 2H), 4.06 (s, 3H), 3.80 (t, J=6.1 Hz, 2H), 3.00 (s, 6H).
Intermedia
Figure imgf000112_0002
Intermediate 17A (28 mg, 0.113 mmol), dissolved in THF (2 mL), add 1M lithium hydroxide (0.283 mL, 0.283 mmol), stirred rt o/n. Concentrated and acidified with TFA, dissolved in ACN, purified via prep HPLC to afford Intermediate 17 (23 mg 87% yield). MS(ESI) m/z: 234.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.20 (dt, J=8.3, 0.9 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.57 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.40 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 4.97 - 4.91 (m, 2H), 3.89 - 3.81 (m, 2H), 3.04 (s, 6H).
Intermediate 18:
Figure imgf000113_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 17b (19 mg) with lithium hydroxide afforded Intermediate 18 (16 mg, 89%). MS(ESI) m/z: 234.1; 'H NMR (400MHZ, methanol-d4) δ 8.10 (dt, J=8.5, 1.0 Hz, 1H), 7.76 (dt, J=8.7, 0.9 Hz, 1H), 7.41 (ddd, J=8.6, 6.7, 1.2 Hz, 1H), 7.34 - 7.28 (m, 1H), 5.38 - 5.32 (m, 2H), 3.89 - 3.81 (m, 2H), 3.02 (s, 6H).
Intermediate 19: 2-(Oxetan- -ylmethyl)-2H-indazole-3-carboxylic acid
Figure imgf000113_0002
Intermediate 20: l-(Oxetan- -ylmethyl)-lH-indazole-3-carboxylic acid
Figure imgf000113_0003
Intermediate 19A: Ethyl 2-(oxetan-3-ylmethyl)-2H-indazole-3-carboxylate
Intermediate 19B: Ethyl l-(oxetan-3-ylmethyl)-lH-indazole-3-carboxylate
Figure imgf000113_0004
19a 19b To a vial containing ethyl lH-indazole-3-carboxylate (50 mg, 0.263 mmol) in acetonitrile (2 mL), were added 3-(bromomethyl)oxetane (59.5 mg, 0.394 mmol) and CS2CO3 (128 mg, 0.394 mmol). The vial was sealed and the mixture was stirred at 90 °C for 3h. Add DCM, filtered, concentrated and the residue was loaded onto 10 g column, eluted with EtO Ac/Hex (0-60%); collected 1st peak at 20% EtOAc, concentrated to afford Intermediate 19A (27 mg, 40% yield). MS(ESI) m/z: 261.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 8.03 (dt, J=8.4, 1.2 Hz, IH), 7.77 (dt, J=8.5, 1.0 Hz, IH), 7.40 - 7.33 (m, IH), 7.33 - 7.28 (m, IH), 5.24 (d, J=7.3 Hz, 2H), 4.81 (dd, J=7.9, 6.4 Hz, 2H), 4.67 (t, J=6.3 Hz, 2H), 4.50 (q, J=7.0 Hz, 2H), 3.80 - 3.64 (m, IH), 1.51 (t, J=7.0 Hz, 3H).
Collected 2nd peak at 35% EtOAc was concentrated to afford Intermediate 19B.
(30 mg, 44% yield). MS(ESI) 261.1 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 8.23 (dt, J=8.3, 0.9 Hz, IH), 7.54 - 7.44 (m, 2H), 7.33 (ddd, J=8.1, 6.7, 1.2 Hz, IH), 4.85 - 4.76 (m, 4H), 4.59 - 4.55 (m, 2H), 4.54 - 4.48 (m, 2H), 3.70 (tt, J=7.5, 5.8 Hz, IH), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 19:
Figure imgf000114_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 19a (27 mg) with lithium hydroxide afforded Intermediate 19 (24 mg,
99%). MS(ESI) 233.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) d 8.39 (dt, J=8.6, 1.0 Hz, IH), 7.91 - 7.87 (m, 2H), 7.65 (ddd, J=8.5, 5.4, 2.3 Hz, IH), 5.18 (dd, J=14.1 , 8.4 Hz, IH), 4.97 (dd, J=13.9, 5.3 Hz, IH), 4.90 (dd, J=1 1.6, 8.3 Hz, IH), 4.69 (dd, J=1 1.6, 5.2 Hz, IH), 3.86 (d, J=5.3 Hz, 2H), 3.69 (tt, J=8.3, 5.3 Hz, IH).
Intermediate 20:
Figure imgf000115_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 19b (30 mg) with lithium hydroxide afforded Intermediate 20 (22 mg, 82%). MS(ESI) 233.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.15 (dt, J=8.2, 1.0 Hz, IH), 7.71 (dt, J=8.5, 0.8 Hz, IH), 7.49 (ddd, J=8.5, 7.2, 1.1 Hz, IH), 7.32 (ddd,
J=8.1, 7.1, 0.9 Hz, IH), 4.93 - 4.85 (m, 2H), 4.61 (t, J=6.2 Hz, 2H), 3.76 - 3.60 (m, IH).
Intermediate 21 : 1 -(( 1 -((Benzyloxy)carbonyl)piperidin-4-yl)methyl)- 1 H-indazole-3 - carboxylic acid
Figure imgf000115_0002
Intermediate 21A: Methyl l-((l-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-lH- indazole-3-carboxylate
Figure imgf000115_0003
21a
To a vial containing ethyl 1 H-indazole-3 -carboxylate (100 mg, 0.526 mmol) in acetonitrile (5 mL), were added benzyl 4-(bromomethyl)piperidine- 1 -carboxylate (246 mg, 0.789 mmol) and CS2CO3 (257 mg, 0.789 mmol). The vial was sealed and the mixture was stirred at 90 °C for 12h. Concentrated and purified by prep HPLC. Two fractions were collected, 1st fraction concentrated to afford Intermediate 21a (80 mg, 37% yield) as a white solid. MS(ESI) 408.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 9.62 (br. s., IH), 8.24 (dt, J=8.1, 0.9 Hz, IH), 7.51 - 7.43 (m, 2H), 7.40 - 7.30 (m, 6H), 5.17 - 5.10 (m, 2H), 4.36 (d, J=7.3 Hz, 2H), 4.30 - 4.15 (m, 2H), 4.06 (s, 3H), 2.86 - 2.66 (m, 2H), 2.30 (ddt, J=15.4, 7.8, 3.8 Hz, IH), 1.67 - 1.50 (m, 2H), 1.30 (qd, J=12.4, 4.1 Hz, 2H).
Intermediate 21:
Figure imgf000116_0001
According to the procedure for preparation of Intermediate 17, saponification of
Intermediate 21A (80 mg) with lithium hydroxide afforded Intermediate 21 (46 mg, 60%). MS(ESI) 394.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.15 (dt, J=8.2, 1.0 Hz, IH), 7.65 (d, J=8.6 Hz, IH), 7.46 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.34 - 7.24 (m, 6H), 4.87 (br. s., 2H), 4.38 (d, J=7.3 Hz, 2H), 4.11 (d, J=13.6 Hz, 2H), 2.76 (br. s., 2H), 2.25 (ddt, J=15.2, 7.7, 3.9 Hz, IH), 1.52 (d, J=11.4 Hz, 2H), 1.25 (qd, J=12.4, 4.4 Hz, 2H).
Intermediate 22: l-((Tetrahydro-2H-pyran-4-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000116_0002
Intermediate 22A: Methyl l-((tetrahydro-2H-pyran-4-yl)methyl)-lH-indazole-3- carboxylate
Figure imgf000117_0001
22a
To a vial containing ethyl lH-indazole-3-carboxylate (150 mg, 0.789 mmol) in DMF (2 mL), were added 4-(bromomethyl)tetrahydro-2H-pyran (212 mg, 1.18 mmol) and CS2CO3 (385 mg, 1.18 mmol). The vial was sealed and the mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated and purified by prep HPLC. Two fractions were collected, 1 st fraction was concentrated to afford Intermediate 22A (76 mg, 35% yield) as a white solid. MS(ESI) 275.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.23 (dt, J=8.3, 0.9 Hz, 1H), 7.50 - 7.47 (m, 2H), 7.34 (ddd, J=8.1, 4.6, 3.2 Hz, 1H), 4.37 (d, J=7.5 Hz, 2H), 4.09 - 3.99 (m, 5H), 3.47 - 3.33 (m, 2H), 2.46 - 2.30 (m, 1H), 1.55 - 1.45 (m, 4H).
Intermediate 22:
Figure imgf000117_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 22A (78 mg) with lithium hydroxide afforded Intermediate 22 (66 mg, 89%). MS(ESI) 261.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.21 - 8.11 (m, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (td, J=7.7, 0.9 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, 1H), 4.37 (d, J=7.3 Hz, 2H), 3.88 (dt, J=l 1.3, 3.2 Hz, 2H), 3.39 - 3.33 (m, 2H), 2.29 (dt, J=15.1, 7.6 Hz, 1H), 1.48 - 1.36 (m, 4H).
Intermediate 23: l-((3-Methyloxetan-3-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000118_0001
Intermed -((3-methyloxetan-3-yl)methyl)-lH-indazole-3-carboxylate
Figure imgf000118_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (200 mg) with 3-(bromomethyl)-3-methyloxetane afforded Intermediate 23A (183 mg, 63%). MS(ESI) 275.1 (M+H)+; 'H NMR
(400MHz, chloroform-d) δ 8.26 - 8.20 (m, IH), 7.49 - 7.44 (m, 2H), 7.35 - 7.28 (m, IH), 4.80 (d, J=6.2 Hz, 2H), 4.65 (s, 2H), 4.56 - 4.47 (m, 2H), 4.45 - 4.36 (m, 2H), 1.48 (t, J=7.2 Hz, 3H), 1.30 (s, 3H).
Intermediate 23:
Figure imgf000118_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 23A (183 mg) with lithium hydroxide to afforded Intermediate 23 (145 mg, 88%). MS(ESI) 247.1 (M+H)+; ¾ NMR (400MHz, methanol^) δ 8.16 (dt, J=8.3, 1.0 Hz, IH), 7.66 (d, J=8.6 Hz, IH), 7.46 (ddd, J=8.4, 7.1, 1.0 Hz, IH), 7.30 (ddd, J=8.1, 7.1, 0.9 Hz, IH), 4.83 (d, J=6.2 Hz, 2H), 4.69 (s, 2H), 4.38 (d, J=6.2 Hz, 2H), 1.22 (s, 3H).
Intermediate 24: l-((Tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000119_0001
Intermedia -((tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylate
Figure imgf000119_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (200 mg) 3-(bromomethyl)tetrahydrofuran afforded Intermediate 24A (140 mg, 49%). MS(ESI) 275.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.23 (dt, J=8.2, 1.0 Hz, IH), 7.52 - 7.41 (m, 2H), 7.35 - 7.28 (m, IH), 4.53 (q, J=7.1 Hz, 2H), 4.45 (d, J=7.7 Hz, 2H), 3.97 (td, J=8.4, 5.5 Hz, IH), 3.80 - 3.70 (m, 2H), 3.67 - 3.58 (m, IH), 3.14 - 3.00 (m, IH), 2.01 (dtd, J=12.9, 7.9, 5.6 Hz, IH), 1.80 - 1.67 (m, IH), 1.49 (t, J=7.2 Hz, 3H).
Intermediate 24:
Figure imgf000119_0003
According to the procedure for preparation of Intermediate 17, saponification of
Intermediate 24A (140 mg) with lithium hydroxide afforded Intermediate 24 (120 mg, 95%). MS(ESI) 247.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.11 (d, J=8.4 Hz, IH), 7.57 (d, J=8.6 Hz, IH), 7.39 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.28 - 7.19 (m, IH), 4.40 (d, J=7.5 Hz, 2H), 3.86 (td, J=8.1, 5.5 Hz, IH), 3.70 - 3.61 (m, 2H), 3.56 (dd, J=8.9, 5.4 Hz, IH), 2.94 - 2.82 (m, IH), 2.00 - 1.84 (m, IH), 1.75 - 1.58 (m, IH). Intermediate 25: l-((Tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylic acid
(enantiomer 1)
Figure imgf000120_0001
Intermediate 26: l-((Tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylic acid
(enantiomer 2)
Figure imgf000120_0002
The enantiomers of Intermediate 24 (64 mg) were separated via the following conditions:
Column: CHIRALPAK® AD-H, 4.6 x 250 mm, 5 μ
Mobile Phase: 15% MeOH / 85% C02
Flow Conditions: 2.0 mL/min, 150 Bar, 35 °C
Detector Wavelength: 220 nm
Injection Details: 10 μϊ^ of ~1 mg/mL in MeOH
1st isomer: Intermediate 25 (24 mg, 38%). MS(ESI) 247.2 (M+H)+; XH NMR
(400MHz, methanol-d4) δ 8.16 (d, J=8.1 Hz, IH), 7.68 (d, J=8.6 Hz, IH), 7.48 (t, J=7.5 Hz, IH), 7.32 (t, J=7.4 Hz, IH), 4.49 (d, J=7.7 Hz, 2H), 3.93 (td, J=8.1, 5.5 Hz, IH), 3.82
- 3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2 Hz, IH), 3.05 - 2.86 (m, IH), 2.12 - 1.90 (m, IH), 1.87 - 1.66 (m, IH).
2nd isomer: Intermediate 26 (25 mg, 39%). MS(ESI) 247.2 (M+H)+; XH NMR
(400MHz, methanol-d4) δ 8.16 (d, J=8.1 Hz, IH), 7.68 (d, J=8.6 Hz, IH), 7.48 (t, J=7.5 Hz, IH), 7.32 (t, J=7.4 Hz, IH), 4.49 (d, J=7.7 Hz, 2H), 3.93 (td, J=8.1, 5.5 Hz, IH), 3.82
- 3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2 Hz, IH), 3.05 - 2.86 (m, IH), 2.12 - 1.90 (m, IH), 1.87 - 1.66 (m, IH). Intermediate 27: l-(Oxetan- -ylmethyl)-lH-indazole-3-carboxylic acid
Figure imgf000121_0001
Interme iate 27A: Ethyl l-(oxetan-2-ylmethyl)-lH-indazole-3-carboxylate
Figure imgf000121_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (160 mg) with 2-(bromomethyl)oxetane afforded
Intermediate 27A (100 mg, 46%). MS(ESI) 247.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.21 (dt, J=8.3, 0.9 Hz, IH), 7.66 (dt, J=8.5, 0.8 Hz, IH), 7.43 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.36 - 7.27 (m, IH), 5.33 - 5.21 (m, IH), 4.82 - 4.66 (m, 2H), 4.64 - 4.48 (m, 3H), 4.23 (dt, J=9.1, 6.0 Hz, IH), 2.80 - 2.64 (m, IH), 2.64 - 2.46 (m, IH), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 27:
Figure imgf000121_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 27A (100 mg) with lithium hydroxide afforded Intermediate 27 (90 mg, 99%). MS(ESI) 233.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.14 (dt, J=8.3, 1.0 Hz, IH), 7.80 - 7.69 (m, IH), 7.44 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.37 - 7.25 (m, IH), 5.25 (dtd, J=7.7, 6.4, 3.7 Hz, IH), 4.81 - 4.64 (m, 2H), 4.55 (ddd, J=8.6, 7.3, 5.7 Hz, IH), 4.28 (dt, J=9.1, 6.0 Hz, IH), 2.74 (dtd, J=11.4, 8.2, 6.3 Hz, IH), 2.61 - 2.51 (m, IH). Intermediate 28: l-(2-Methoxyethyl)-lH-indazole-3-carboxylic acid
Figure imgf000122_0001
Intermediate 28A: Ethyl l-(2-methoxyethyl)-lH-indazole-3-carboxylate
Figure imgf000122_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (150 mg) with 1 -bromo-2-methoxy ethane afforded
Intermediate 28A (104 mg, 53%). MS(ESI) 249.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.20 (dt, J=8.2, 1.0 Hz, IH), 7.55 (d, J=8.6 Hz, IH), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.29 (ddd, J=8.0, 7.0, 0.8 Hz, IH), 4.63 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.0 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 3.26 (s, 3H), 1.48 (t, J=7.0 Hz, 3H).
Intermediate 28:
Figure imgf000122_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 28A (104 mg) with lithium hydroxide afforded Intermediate 28 (90 mg, 98%). MS(ESI) 221.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.14 (dt, J=8.3, 0.9 Hz, IH), 7.67 (dt, J=8.6, 0.9 Hz, IH), 7.45 (ddd, J=8.5, 7.2, 1.1 Hz, IH), 7.30 (ddd, J=8.1, 7.0, 0.8 Hz, IH), 4.64 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.27 - 3.20 (m, 3H). Intermediate 29: l-(2-Hydroxypropyl)-lH-indazole-3-carboxylic acid
Figure imgf000123_0001
Intermediate 29A: Methyl l-(2-hydroxypropyl)-lH-indazole-3-carboxylate
Figure imgf000123_0002
To a vial containing ethyl lH-indazole-3-carboxylate (200 mg, 1.052 mmol) in DMF (3 mL), was added 2-methyloxirane (122 mg, 2.103 mmol) and CS2CO3 (411 mg, 1.262 mmol). The vial was sealed and the mixture was stirred at 80 °C o/n. LC/MS showed reaction completed. Quenched with water, extracted with EtOAc, washed organic layer with 10% LiCl, brine, concentrated and the residue was purified by prep HPLC to afford Intermediate 29A (35 mg, 14%). MS(ESI) 235.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 8.19 (dt, J=8.2, 1.0 Hz, 1H), 7.95 (s, 1H), 7.58 - 7.52 (m, 1H), 7.43 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.50 - 4.35 (m, 3H), 4.03 - 3.94 (m, 3H), 2.93 (s, 2H), 2.85 (d, J=0.4 Hz, 2H), 1.37 - 1.24 (m, 3H).
Intermediate 29:
Figure imgf000123_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 29A (35 mg) with lithium hydroxide afforded Intermediate 29 (25mg, 81%). MS(ESI) 221.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.15 (dt, J=8.2, 1.0 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.46 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.48 - 4.42 (m, 2H), 4.29 (td, J=6.4, 5.4 Hz, 1H), 1.28 - 1.18 (m, 3H).
Intermediate 30: l-(3-(Benzyloxy)-2-hydroxypropyl)-lH-indazole-3-carboxylic acid
Figure imgf000124_0001
To a vial containing ethyl lH-indazole-3-carboxylate (200 mg, 1.052 mmol) in DMF (3 mL), was added 2-((benzyloxy)methyl)oxirane (345 mg, 2.103 mmol) and CS2CO3 (514 mg, 1.577 mmol). The vial was sealed and the mixture was stirred at 80 °C o/n. LC/MS showed reaction completed. Quenched with water, extracted with EtOAc, washed organic layer with 10% LiCl, brine, concentrated and the residue was purified by prep HPLC. 1st fraction concentrated to afford Intermediate 30 (120mg, 35% yield) as a white solid. MS(ESI) 327.1 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 8.19 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.36 - 7.27 (m, 6H), 4.63 - 4.57 (m, 2H), 4.51 - 4.48 (m, 2H), 4.45 - 4.36 (m, 1H), 3.59 - 3.41 (m, 4H).
Intermediate 31: l-(2,3-Dihydroxypropyl)-lH-indazole-3-carboxylic acid
Figure imgf000125_0001
Intermediate 30 (90 mg, 0.276 mmol) was dissolved in MeOH (3 mL), degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon for 3h, filtered and concentrated under vacuum to afford Intermediate 31 as a colorless oil (58 mg, 89%). MS(ESI) 237.1 (M+H)+; XH NMR (400MHz, methanol^) δ 8.17 - 8.10 (m, IH), 7.70 (d, J=8.6 Hz, IH), 7.45 (ddd, J=8.4, 7.1, 1.0 Hz, IH), 7.29 (ddd, J=8.0, 7.0, 0.8 Hz, IH), 4.62 (dd, J=14.3, 4.4 Hz, IH), 4.51 (dd, J=14.3, 7.3 Hz, IH), 4.16 (dq, J=7.3, 5.0 Hz, IH), 3.66 - 3.53 (m, 2H).
Intermediate 32: l-(2-(2-Methoxyethoxy)ethyl)-lH-indazole-3-carboxylic acid
Figure imgf000125_0002
Intermediate 32A: Ethyl l-(2-(2-methoxyethoxy)ethyl)-lH-indazole-3-carboxylate
Figure imgf000126_0001
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (150 mg) with l-bromo-2-(2-methoxyethoxy)ethane afforded Intermediate 32A (105 mg, 46%). MS(ESI) 293.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.20 (dt, J=8.2, 1.0 Hz, IH), 7.63 - 7.57 (m, IH), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.30 (ddd, J=8.1, 7.0, 0.9 Hz, IH), 4.67 (t, J=5.6 Hz, 2H), 4.53 (q, J=7.3 Hz, 2H), 3.97 (t, J=5.7 Hz, 2H), 3.56 - 3.48 (m, 2H), 3.43 - 3.37 (m, 2H), 3.28 (s, 3H), 1.48 (t, J=7.2 Hz, 3H). Intermediate 32:
Figure imgf000126_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 32A (105 mg)) with lithium hydroxide afforded Intermediate 32 (93 mg, 98%). MS(ESI) 265.1 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 8.12 (dt, J=8.2, 0.9 Hz, IH), 7.72 - 7.62 (m, IH), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.27 (ddd, J=8.1, 7.0, 0.8 Hz, IH), 4.62 (t, J=5.4 Hz, 2H), 3.93 (t, J=5.4 Hz, 2H), 3.49 - 3.43 (m, 2H), 3.37 - 3.32 (m, 2H), 3.17 (s, 3H).
Intermediate 33: l-((l-(tert-Butoxycarbonyl)azetidin-3-yl)methyl)-lH-indazole-3- carboxylic acid
Figure imgf000127_0001
Intermediate 33A: Ethyl l-((l-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-lH-indazole- 3-carboxylate
Figure imgf000127_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (150 mg) with tert-butyl 3-(bromomethyl)azetidine-l- carboxylate afforded Intermediate 33A (180 mg, 48%). MS(ESI) 360.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 8.22 (d, J=8.4 Hz, IH), 7.56 - 7.43 (m, 2H), 7.32 (ddd, J=8.0, 6.8, 1.1 Hz, IH), 4.67 (d, J=7.7 Hz, 2H), 4.57 - 4.44 (m, 2H), 4.02 (t, J=8.5 Hz, 2H), 3.80 (dd, J=8.9, 5.2 Hz, 2H), 3.24 (ddd, J=7.9, 5.1, 2.6 Hz, IH), 1.48 (t, J=7.0 Hz, 3H), 1.44 (s, 9H).
Intermediate 33:
Figure imgf000127_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 33A (180 mg) with lithium hydroxide afforded Intermediate 33 (155 mg, 93%). MS(ESI) 332.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.16 (dt, J=8.2, 1.0 Hz, IH), 7.73 (d, J=8.6 Hz, IH), 7.50 (ddd, J=8.5, 7.2, 1.1 Hz, IH), 7.33 (ddd, J=8.0, 7.0, 0.8 Hz, IH), 4.72 (d, J=7.3 Hz, 2H), 4.06 - 3.96 (m, 2H), 3.84 (br. s., 2H), 3.27 - 3.17 (m, IH), 1.41 (s, 9H).
Intermediate 34: l-(2-(Benzyloxy)ethyl)-lH-indazole-3-carboxylic acid
Figure imgf000128_0001
Intermediate 34A: Ethyl l-(2-(benzyloxy)ethyl)-lH-indazole-3-carboxylate
Figure imgf000128_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (120 mg) with ((2-bromoethoxy)methyl)benzene afforded Intermediate 34A (120 mg, 59%). MS(ESI) 325.2 (M+H)+; XH NMR (500MHz, chloroform-d) d 8.21 (d, J=8.3 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 7.40 (d, J=1.4 Hz, IH), 7.32 - 7.27 (m, IH), 7.25 - 7.20 (m, 3H), 7.11 - 7.06 (m, 2H), 4.66 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.2 Hz, 2H), 4.40 (s, 2H), 3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Intermediate 34:
Figure imgf000128_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 34A (120 mg) with lithium hydroxide afforded Intermediate 34 (100 mg, 91%). MS(ESI) 297.2 (M+H)+; 'H NMR (500MHZ, methanol-d4) d 8.15 (dt, J=8.1, 1.0 Hz, IH), 7.65 (d, J=8.5 Hz, IH), 7.42 (ddd, J=8.5, 7.1, 1.0 Hz, IH), 7.33 - 7.25 (m, IH), 7.20 - 7.13 (m, 3H), 7.05 - 6.90 (m, 2H), 4.65 (t, J=5.2 Hz, 2H), 4.37 (s, 2H), 3.91 (t, J=5.1 Hz, 2H).
Intermed -(2-Hydroxyethyl)-lH-indazole-3-carboxylic acid
Figure imgf000129_0001
Intermediate 34 (84 mg, 0.283 mmol) was dissolved in MeOH (2 niL), degassed and add 10% Pd/C (15 mg), stirred under ¾ balloon for 2h. Filtered and concentrated to afford Intermediate 35 (55 mg, 94%) as a white solid. MS(ESI) 207.1 (M+H)+; ¾ NMR (400MHz, methanol-d4) d 8.14 (dt, J=8.3, 1.0 Hz, IH), 7.72 - 7.62 (m, IH), 7.45 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.29 (ddd, J=8.1, 7.1, 0.9 Hz, IH), 4.64 - 4.53 (m, 2H), 4.07 - 3.97 (m, 2H).
Intermediate 36: l-(2-(Tetrahydro- -pyran-4-yl)ethyl)-lH-indazole-3-carboxylic acid
Figure imgf000129_0002
Intermediate 36A: Ethyl l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-lH-indazole-3- carboxylate
Figure imgf000129_0003
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (120 mg) with 4-(2-bromoethyl)tetrahydro-2H-pyran afforded Intermediate 36A (90 mg, 47%). MS(ESI) 303.2 (M+H)+; 'H NMR (500MHZ, chloroform-d) d 8.23 (dt, J=8.3, 1.0 Hz, IH), 7.54 - 7.42 (m, 2H), 7.31 (ddd, J=8.0, 5.9, 1.8 Hz, IH), 4.62 - 4.43 (m, 4H), 4.01 - 3.87 (m, 2H), 3.34 (td, J=l 1.8, 2.1 Hz, 2H), 1.98 - 1.85 (m, 2H), 1.65 (dd, J=12.9, 1.9 Hz, 2H), 1.54 (dd, J=7.4, 3.6 Hz, IH), 1.48 (t, J=7.2 Hz, 3H), 1.41 - 1.29 (m, 2H).
Intermediate 36:
Figure imgf000130_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 36A (90 mg) with lithium hydroxide afforded Intermediate 36 (80 mg, 98%). MS(ESI) 275.2 (M+H)+; 'H NMR (400MHZ, methanol-d4) d 8.22 - 8.12 (m, IH), 7.62 (d, J=8.6 Hz, IH), 7.45 (ddd, J=8.4, 7.0, 0.9 Hz, IH), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, IH), 4.51 (t, J=7.3 Hz, 2H), 3.96 - 3.81 (m, 2H), 3.38 - 3.24 (m, 2H), 1.86 (q, J=7.0 Hz, 2H), 1.72 - 1.60 (m, 2H), 1.54 - 1.42 (m, IH), 1.37 - 1.24 (m, 2H).
Intermediate 37: l-(3-(Benzyloxy)propyl)-lH-indazole-3-carboxylic acid
Figure imgf000130_0002
Intermediate 37A: Ethyl l-(3-(benzyloxy)propyl)-lH-indazole-3-carboxylate
Figure imgf000131_0001
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (120 mg) with ((3-bromopropoxy)methyl)benzene afforded Intermediate 37A (105 mg, 49%). MS(ESI) 339.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.22 (dt, J=8.1, 1.0 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.43 - 7.37 (m, 1H), 7.37 - 7.25 (m, 6H), 4.66 - 4.60 (m, 2H), 4.56 - 4.48 (m, 2H), 4.43 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 2.35 - 2.21 (m, 2H), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 37:
Figure imgf000131_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 37A (105 mg) with lithium hydroxide afforded Intermediate 37 (88 mg, 91%). MS(ESI) 339.2 (M+H)+; ¾ NMR (400MHz, methanol-d4) d 8.15 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.38 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.31 - 7.20 (m, 7H), 4.54 (t, j=6.7 Hz, 2H), 4.34 (s, 2H), 3.41 - 3.36 (m, 2H), 2.25 - 2.10 (m, 2H).
Interme lic acid
Figure imgf000131_0003
Intermediate 37 (80 mg, 0.258 mmol) was dissolved in MeOH (3 mL), degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon for 3h, filtered and concentrated under vacuum to afford Intermediate 38 as a colorless oil (50 mg, 75%). MS(ESI) 221.1 (M+H)+; XH NMR (500MHz, methanol^) d 8.17 - 8.13 (m, IH), 7.68 (d, J=8.5 Hz, IH), 7.46 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.30 (ddd, J=8.0, 7.1, 0.8 Hz, IH), 4.60 (t, J=6.9 Hz, 2H), 3.55 (t, J=6.1 Hz, 2H), 2.14 (t, J=6.3 Hz, 2H).
Intermediate 39: l-(3-Methoxypropyl)-lH-indazole-3-carboxylic acid
Figure imgf000132_0001
Intermediate 39A: Ethyl l-(3-methoxypropyl)-lH-indazole-3-carboxylate
Figure imgf000132_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (80 mg) with l-bromo-3-methoxypropane afforded Intermediate 39A (50 mg, 45%). MS(ESI) 263.2 (M+H)+; XH NMR (500MHz, chloroform-d) d 8.21 (d, J=8.3 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 7.40 (d, J=1.4 Hz, IH), 7.32 - 7.27 (m, IH), 7.25 - 7.20 (m, 3H), 7.11 - 7.06 (m, 2H), 4.66 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.2 Hz, 2H), 4.40 (s, 2H), 3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Intermediate 39:
Figure imgf000132_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 39A (50 mg) with lithium hydroxide afforded Intermediate 39 (44 mg, 99%). MS(ESI) 235.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) d 8.14 (dt, J=8.3, 0.9 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.49 - 7.41 (m, 1H), 7.29 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.61 - 4.54 (m, 2H), 3.28 (t, J=5.9 Hz, 2H), 3.25 (s, 3H), 2.16 (t, J=6.1 Hz, 2H).
Intermediate 40: l-(Pyridin- -ylmethyl)-lH-indazole-3-carboxylic acid
Figure imgf000133_0001
Interme -(pyridin-4-ylmethyl)-lH-indazole-3-carboxylate
Figure imgf000133_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (70 mg) with 4-(bromomethyl)pyridine afforded
Intermediate 40A (50 mg, 48%). MS(ESI) 282.1 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.61 - 8.42 (m, 2H), 8.26 (dt, J=8.2, 1.1 Hz, 1H), 7.47 - 7.37 (m, 1H), 7.35 - 7.31 (m, 1H), 7.31 (d, J=0.7 Hz, 1H), 7.06 - 6.99 (m, 2H), 5.70 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H).
Intermediate 40:
Figure imgf000134_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 40A (50 mg) with lithium hydroxide afforded Intermediate 40 (45 mg, 95%). MS(ESI) 254.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) d 8.56 - 8.44 (m, 2H), 8.28 - 8.13 (m, 1H), 7.70 - 7.57 (m, 1H), 7.48 (d, J=1.3 Hz, 1H), 7.36 (dd, J=8.3, 1.0 Hz, 1H), 7.26 - 7.15 (m, 2H), 5.84 (s, 2H).
Intermediate 41: l-(Pyridin- -ylmethyl)-lH-indazole-3-carboxylic acid
Figure imgf000134_0002
Intermediate 41A: Ethyl l-(pyridin-2-ylmethyl)-lH-indazole-3-carboxylate
Figure imgf000134_0003
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (70 mg) with 2-(bromomethyl)pyridine afforded
Intermediate 41A (88 mg, 85%). MS(ESI) 282.1 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.61 - 8.54 (m, 1H), 8.24 (dt, J=8.1, 1.0 Hz, 1H), 7.55 (td, J=7.7, 1.8 Hz, 1H), 7.45 (dt, J=8.5, 0.9 Hz, 1H), 7.38 (ddd, J=8.4, 6.9, 1.2 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.20 - 7.14 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 5.84 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H). Intermediate 41:
Figure imgf000135_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 41A (88 mg) with lithium hydroxide afforded Intermediate 41 (105 mg, 91%). MS(ESI) 254.1 (M+H)+; XH NMR (400MHz, methanol-d4) d 8.67 (dd, J=5.4, 0.8 Hz, IH), 8.21 (dt, J=8.1, 1.0 Hz, IH), 8.12 (td, J=7.8, 1.8 Hz, IH), 7.74 - 7.61 (m, 2H), 7.51 (ddd, J=8.4, 7.1, 1.0 Hz, IH), 7.42 (d, J=7.9 Hz, IH), 7.37 (ddd, J=8.1, 7.1, 0.9 Hz, IH), 5.99 (s, 2H). Intermediate 42: l-(Pyridin- -ylmethyl)-lH-indazole-3-carboxylic acid
Figure imgf000135_0002
Intermedi -(pyridin-3-ylmethyl)-lH-indazole-3-carboxylate
Figure imgf000135_0003
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (70 mg) with 3-(bromomethyl)pyridine afforded
Intermediate 42A (18 mg, 18%). MS(ESI) 282.1 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.61 (d, J=1.8 Hz, IH), 8.54 (dd, J=4.8, 1.5 Hz, IH), 8.25 (dt, J=8.1, 1.0 Hz, IH), 7.54 - 7.47 (m, IH), 7.45 - 7.30 (m, 3H), 7.22 (ddd, J=7.9, 4.8, 0.8 Hz, IH), 5.73 (s, 2H), 4.55 (q, J=7.0 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H). Intermediate 42:
Figure imgf000136_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 42A (18 mg) with lithium hydroxide afforded Intermediate 42 (23 mg, 98%). MS(ESI) 254.1 (M+H)+; 'H NMR (500MHZ, methanol-d4) d 8.94 - 8.84 (m, IH), 8.78 (d, J=5.5 Hz, IH), 8.49 - 8.37 (m, IH), 8.18 (dt, J=8.3, 0.8 Hz, IH), 8.02 - 7.92 (m, IH), 7.77 (d, J=8.5 Hz, IH), 7.52 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.36 (ddd, J=8.1, 7.2, 0.7 Hz, IH), 5.98 (s, 2H).
Intermediate 43: 6-Fluoro-l-(2-methylprop-l-en-l-yl)-lH-indazole-3-carboxylic acid
propyl)-lH-indazole-3-carboxylic
Figure imgf000136_0002
Figure imgf000137_0001
Intermediate 43 Intermediate 44
To a vial containing methyl 6-fluoro-lH-indazole-3-carboxylate (200 mg, 1.030 mmol) in DMF (3 mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15 mmol) and CS2CO3 (403 mg, 1.236 mmol). The vial was sealed and the mixture was stirred at 80 °C for 3h. Quenched with water, acidified with 1 N HCl. Extracted with EtOAc, the organic layer was concentrated and loaded on 10 g column, eluted with MeOH/DCM. Collected two fractions: 1st fraction: 5% MeOH; 2nd fraction: 8% MeOH.
1st fraction afforded Intermediate 43 (26 mg, 11%). MS(ESI) 235.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 13.78 (br. s., 1H), 8.05 (dd, J=9.1, 5.5 Hz, 1H), 7.55 (dt, J=9.9, 1.1 Hz, 1H), 7.44 - 7.32 (m, 1H), 7.21 (td, J=9.3, 2.3 Hz, 1H), 1.93 (d, J=l. l Hz, 3H), 1.79 (d, J=1.4 Hz, 3H).
2nd fraction afforded Intermediate 44 (90 mg, 36%). MS(ESI) 253.1 (M+H)+; XH NMR (400MHz, methanol-d4) d 8.10 (dd, J=9.0, 5.3 Hz, 1H), 7.44 (dd, J=9.5, 2.0 Hz, 1H), 7.08 (td, J=9.1, 2.1 Hz, 1H), 4.39 (s, 2H), 1.24 (s, 6H).
Intermediate 45: 5-Fluoro-l-(2-methylprop-l-en-l-yl)-lH-indazole-3-carboxylic acid
Figure imgf000137_0002
Intermediate 46: 5-Fluoro-l-(2-hydroxy-2-methylpropyl)-lH-indazole-3-carboxylic acid
Figure imgf000137_0003
Figure imgf000138_0001
Intermediate 45 Intermediate 46A
To a vial containing methyl 5-fluoro-lH-indazole-3-carboxylate (200 mg, 1.03 mmol) in ACN (3 mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15 mmol) and CS2CO3 (403 mg, 1.24 mmol). The vial was sealed and the mixture was stirred at 80 °C for 3h. Filtered, concentrated and the residue was loaded onto lOg column, eluted with EtO Ac/Hex (0-60%); collected a 1st fraction at 40% EtOAc. Then eluted with
MeOH/DCM (0-10%); collected a 2nd fraction at 10% MeOH.
2nd fraction concentrated to afford Intermediate 45 (20 mg, 8%). MS(ESI) 235.1 (M+H)+; XH NMR (400MHz, methanol-cU) d 7.84 - 7.70 (m, IH), 7.63 (ddd, J=9.4, 2.5, 0.7 Hz, IH), 7.29 (dt, J=3.1, 1.5 Hz, IH), 7.21 (td, J=9.2, 2.4 Hz, IH), 1.98 (d, J=1.3 Hz, 3H), 1.76 (d, J=1.3 Hz, 3H).
1st fraction concentrated to afford Intermediate 46A (130 mg, 48%). MS(ESI) 267.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) d 7.81 - 7.76 (m, IH), 7.58 - 7.52 (m, IH), 7.18 (td, J=8.9, 2.4 Hz, IH), 4.42 (s, 2H), 4.02 - 3.97 (m, 3H), 1.26 (s, 6H).
Intermediate
Figure imgf000138_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 46A (130 mg) with lithium hydroxide afforded Intermediate 46 (1 15 mg,
93%) as a white solid. MS(ESI) 253. 1 (M+H)+; 'H NMR (500MHZ, methanol-cU) d 7.77 - 7.68 (m, 2H), 7.32 - 7.20 (m, IH), 4.43 (s, 2H), 1.30 - 1.21 (m, 6H). Intermediate 47: l-((Tetrahydro-2H-pyran-2-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000139_0001
Intermediate 47A: Ethyl l-((tetrahydro-2H-pyran-2-yl)methyl)-lH-indazole-3- carboxylate
Figure imgf000139_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3 -carboxylate (150 mg) with 2-(bromomethyl)tetrahydro-2H-pyran afforded Intermediate 47A (163 mg, 72%). MS(ESI) 267.1 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.20 (dt, J=8.2, 1.0 Hz, IH), 7.63 - 7.57 (m, IH), 7.43 (ddd, J=8.4, 7.1, 1.2 Hz, IH), 7.31 (ddd, J=8.0, 6.9, 0.9 Hz, IH), 4.62 - 4.45 (m, 4H), 4.00 - 3.81 (m, 2H), 3.33 (td, J=11.6, 2.5 Hz, IH), 1.91 - 1.80 (m, IH), 1.68 - 1.59 (m, IH), 1.57 - 1.44 (m, 6H), 1.42 - 1.28 (m, IH). Intermediate 47:
Figure imgf000139_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 47A (46 mg) with lithium hydroxide afforded Intermediate 47 (30 mg,
72%) as a white solid. MS(ESI) 261.2 (M+H)+; XH NMR (400MHz, methanol^) d 8.13 (dd, J=8.1, 0.9 Hz, IH), 7.75 - 7.62 (m, IH), 7.52 - 7.40 (m, IH), 7.40 - 7.25 (m, IH), 59 - 4.41 (m, 2H), 3.94 - 3.80 (m, 2H), 1.93 - 1.78 (m, IH), 1.65 (d, J=11.7 Hz, IH), 59 - 1.42 (m, 3H), 1.41 - 1.26 (m, IH).
Intermediate 48 : 1 -(2 -Hydroxy -2 -methy lpropy 1)- 1 H-pyrrolo [2 , 3 -b]pyridine-3 - carboxylic acid
Figure imgf000140_0001
Intermediate 48A: Methyl l-(2-hydroxy-2-methylpropyl)-lH-pyrrolo[2,3-b]pyridine-3- carbox late
Figure imgf000140_0002
To a vial containing methyl lH-pyrrolo[2,3-b]pyridine-3-carboxylate (120 mg, 0.681 mmol) in DMF (3 mL), were added 2,2-dimethyloxirane (0.303 mL, 3.41 mmol) and CS2CO3 (266 mg, 0.817 mmol). The vial was sealed and the mixture was stirred at 80 °C for 3h. Quenched with water, extracted with EtOAc, concentrated and the residue was loaded onto lOg column, eluted with EtO Ac/Hex (0-60%); collected a fraction at 40% EtOAc. Concentrated to afford Intermediate 48A (134 mg, 79%). MS(ESI) 249.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) d 8.45 (dd, J=7.9, 1.5 Hz, IH), 8.33 (dd, J=4.7, 1.7 Hz, IH), 7.99 (s, IH), 7.24 (dd, J=7.9, 4.6 Hz, IH), 4.44 (s, IH), 4.33 (s, 2H), 3.92 (s, 3H), 1.24 (s, 6H).
Intermediate 48
Figure imgf000140_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 48A (134 mg) with lithium hydroxide afforded Intermediate 48 (127 mg, 99%) as a white solid. MS(ESI) 235.2 (M+H)+; XH NMR (400MHz, methanol^) d 8.47 (dd, J=7.9, 1.5 Hz, IH), 8.29 (d, J=4.0 Hz, IH), 8.14 (s, IH), 7.23 (dd, J=7.9, 4.8 Hz, IH), 4.33 (s, 2H), 1.17 (s, 6H).
Intermediate 49: 5-Fluoro-l-((tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000141_0001
Intermediate 49A: Methyl 5-fluoro-l-((tetrahydrofuran-3-yl)methyl)-lH-indazole-3- carboxylate
Figure imgf000141_0002
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (100 mg) with 3-(bromomethyl)tetrahydrofuran afforded Intermediate 49A (66 mg, 46%). MS(ESI) 279.2 (M+H)+; XH NMR (400MHz, chloroform-d) d 7.87 - 7.81 (m, IH), 7.46 - 7.41 (m, IH), 7.22 (td, J=8.9, 2.4 Hz, IH), 4.41 (d, J=7.7 Hz, 2H), 4.06 - 4.00 (m, 3H), 3.97 - 3.92 (m, IH), 3.80 - 3.67 (m, 2H), 3.60 (dd, J=9.1, 4.7 Hz, IH), 3.11 - 2.95 (m, IH), 2.08 - 1.96 (m, IH), 1.74 - 1.64 (m, IH).
Intermediate 49:
Figure imgf000142_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 49A (68 mg) with lithium hydroxide afforded Intermediate 49 (63 mg,
98%) as a white solid. MS(ESI) 265.2 (M+H)+; XH NMR (500MHz, methanol^) d 7.74 - 7.67 (m, 2H), 7.26 (td, J=8.9, 2.5 Hz, 1H), 4.47 (d, J=7.7 Hz, 2H), 3.92 (td, J=8.3, 5.5 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.60 (dd, J=8.8, 5.2 Hz, 1H), 3.01 - 2.87 (m, 1H), 2.08 - 1.95 (m, 1H), 1.80 - 1.69 (m, 1H).
Intermediate 50: 6-Fluoro-l-((tetrahydrofuran-3-yl)methyl)-lH-indazole-3-carboxylic acid
Figure imgf000142_0002
Intermediate 50A: Methyl 6-fluoro-l-((tetrahydrofuran-3-yl)methyl)-lH-indazole-3- carbox late
Figure imgf000142_0003
According to the procedure for preparation of Intermediate 19B, alkylation of ethyl lH-indazole-3-carboxylate (100 mg) with 3-(bromomethyl)tetrahydrofuran afforded Intermediate 50A (68 mg, 47%). MS(ESI) 279.2 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.22 - 8.15 (m, 1H), 7.18 - 7.04 (m, 2H), 4.37 (d, J=7.7 Hz, 2H), 4.03 (s, 3H), 3.96 (td, J=8.3, 5.4 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.61 (dd, J=9.0, 4.8 Hz, 1H), 3.09 - 2.95 (m, 1H), 2.02 (dtd, J=12.9, 8.0, 5.5 Hz, 1H), 1.74 - 1.63 (m, 1H).
Intermediat
Figure imgf000143_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 50A (68 mg) with lithium hydroxide afforded Intermediate 50 (50 mg,
77%) as a white solid. MS(ESI) 265.2 (M+H)+; XH NMR (500MHz, methanol^) d 8.12 (dd, J=8.7, 5.1 Hz, 1H), 7.44 (dd, J=9.4, 1.9 Hz, 1H), 7.10 (td, J=9.1, 2.2 Hz, 1H), 4.43 (d, J=7.7 Hz, 2H), 3.93 (td, J=8.2, 5.4 Hz, 1H), 3.84 - 3.71 (m, 2H), 3.61 (dd, J=8.8, 5.5 Hz, 1H), 3.04 - 2.83 (m, 1H), 2.12 - 1.93 (m, 1H), 1.84 - 1.65 (m, 1H).
Intermediate 51: 6-(2-Hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000143_0002
Intermedia -hydroxypyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000143_0003
Ethyl 6-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (130 mg, 0.59 mmol) was mixed with aluminum tribromide (787 mg, 2.95 mmol) in EtSH (2 ml) and stirred at rt for 2h. Cooled to 0 °C, add MeOH dropwise, concentrated, and the residue was loaded onto lOg column, eluted with EtO Ac/Hex (0-40%); collected fraction at 30% EtOAc, concentrated to afford Intermediate 51A (50 mg, 41%). MS(ESI) 207.1 (M+H)+; XH NMR (400MHz, methanol-d4) d 8.25 (s, 1H), 8.15 (dd, J=2.1, 0.8 Hz, 1H), 7.99 (dd, J=9.5, 0.7 Hz, 1H), 7.27 (dd, J=9.6, 2.1 Hz, 1H), 4.35 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). Intermediate 51B: Ethyl 6-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000144_0001
To a solution of Intermediate 51A (50 mg, 0.24 mmol) in acetonitrile (3 ml) and water (0.2 ml) was added K2CO3 (134 mg, 0.970 mmol) and 2,2-dimethyloxirane (0.646 ml, 7.27 mmol). The reaction mixture was heated to 120 °C by MW for 35min, LCMS shows the reaction was completed with formation of desired product. Filtered and purified through prep HPLC to afford Intermediate 51B (51 mg, 76%). MS(ESI) 279.2 (M+H)+; ¾ NMR (400MHz, chloroform-d) d 8.35 (s, 1H), 8.34 - 8.31 (m, 1H), 8.11 - 8.04 (m, 1H), 7.29 (dd, J=9.6, 2.1 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 1.45 - 1.39 (m, 9H)
Intermediate 51:
Figure imgf000144_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 51B (51 mg) with lithium hydroxide afforded Intermediate 51 (25 mg,
55%) as a white solid. MS(ESI) 251.2 (M+H)+; XH NMR (500MHz, methanol-cU) d 8.33 (dd, J=2.2, 0.6 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J=9.6, 0.6 Hz, 1H), 7.37 (dd, J=9.6, 1.9 Hz, 1H), 3.86 (s, 2H), 1.35 (s, 6H)
Intermediate 52: 6-(2-Methoxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000145_0001
Int rmediate 52A: Ethyl 6-(2-methoxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000145_0002
To a vial containing Intermediate 51A (30 mg, 0.145 mmol) in CH3CN (3 mL), were added l-bromo-2-methoxyethane (30.3 mg, 0.218 mmol) and CS2CO3 (95 mg, 0.29 mmol). The vial was sealed and the mixture was stirred at 70 °C for 3h. LC/MS showed reaction completed. Filtered and concentrated. The residue was loaded onto 10 g column, eluted with EtO Ac/Hex (0-50%); collected fraction at 30% EtO Ac, concentrated to afford Intermediate 52A (25 mg, 65%). MS(ESI) 265.2 (M+H)+; XH NMR (500MHz, methanol-cU) d 8.35 (dd, J=2.2, 0.5 Hz, 1H), 8.27 (s, 1H), 8.03 - 7.99 (m, 1H), 7.34 (dd, J=9.6, 2.2 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.22 - 4.15 (m, 2H), 3.82 - 3.74 (m, 2H), 3.50 - 3.41 (m, 3H), 1.40 (t, J=7.2 Hz, 3H). Intermediate 52:
Figure imgf000145_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 52A (25 mg) with lithium hydroxide afforded Intermediate 52 (12 mg,
54%) as a white solid. MS(ESI) 237.1 (M+H)+.
Intermediate 53: 6-(2-(Pyrr -a]pyridine-3-carboxylic acid
Figure imgf000145_0004
Intermediate 53A: Ethyl 6-(2-(pyrrolidin-l-yl)ethoxy)pyrazolo[l,5-a]pyridine-3- arboxylate
Figure imgf000146_0001
According to the procedure for preparation of Intermediate 52A, alkylation of
Intermediate 51A (36 mg) with l-(2-bromoethyl)pyrrolidine afforded Intermediate 53A
(29 mg, 55%) as a white solid. MS(ESI) 304.2 (M+H)+; 'H NMR (400MHZ, chloroform- d) d 8.39 - 8.25 (m, 3H), 8.07 (d, J=9.5 Hz, IH), 7.21 (dd, J=9.7, 2.2 Hz, IH), 4.44 - 4.38 (m, 3H), 4.38 - 4.33 (m, IH), 4.06 - 3.94 (m, 2H), 3.69 - 3.62 (m, 2H), 3.05 (d, J=9.7 Hz, 2H), 2.17 (d, J=4.0 Hz, 4H), 1.41 (t, J=7.2 Hz, 3H).
Intermediate 53:
Figure imgf000146_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 53A (29 mg) with lithium hydroxide afforded Intermediate 53 (16 mg,
61%) as a white solid. MS(ESI) 276.2 (M+H)+; XH NMR (400MHz, methanol^) d 8.41 (d, J=1.5 Hz, IH), 8.30 (s, IH), 8.04 (d, J=9.5 Hz, IH), 7.39 (dd, J=9.6, 2.1 Hz, IH), 4.47 - 4.40 (m, 2H), 3.80 (d, J=7.5 Hz, 2H), 3.76 - 3.68 (m, 2H), 3.25 (br. s., 2H), 2.21 - 2.12 (m, 2H), 2.09 (br. s., 2H).
Intermediate 54: 6-(2-(Dimethylamino)ethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000146_0003
Intermediate 54A: Ethyl 6-(2-(dimethylamino)ethoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000147_0001
According to the procedure for preparation of Intermediate 52A, alkylation of Intermediate 51A (35 mg) with 2-bromo-N,N-dimethylethanamine afforded
Intermediate 54A (20 mg, 43%) as a white solid. MS(ESI) 278.2 (M+H)+; XH NMR (500MHz, methanol-d4) d 8.47 (dd, J=2.2, 0.8 Hz, IH), 8.32 (s, IH), 8.07 (dd, J=9.6, 0.5 Hz, IH), 7.42 (dd, J=9.6, 2.2 Hz, IH), 4.52 - 4.42 (m, 2H), 4.36 (q, J=7.2 Hz, 2H), 3.70 - 3.61 (m, 2H), 3.06 - 2.99 (m, 6H), 1.45 - 1.35 (m, 3H).
Intermediate 54:
Figure imgf000147_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 54A (18 mg) with lithium hydroxide afforded Intermediate 54 (8 mg,
61%) as a white solid. MS(ESI) 250.2 (M+H)+; XH NMR (500MHz, methanol-cU) d 8.47 (dd, J=2.2, 0.6 Hz, IH), 8.32 (s, IH), 8.11 - 8.07 (m, IH), 7.41 (dd, J=9.6, 2.2 Hz, IH), 4.49 - 4.40 (m, 2H), 3.71 - 3.60 (m, 2H), 3.02 (s, 6H).
Intermediate 55: 6-(2-Morpholinoethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000147_0003
Intermediate 55A: Ethyl 6-(2-morpholinoethoxy)pyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000148_0001
According to the procedure for preparation of Intermediate 52A, alkylation of Intermediate 51A (40 mg) with 4-(2-bromoethyl)morpholine afforded Intermediate
55A (47 mg, 76%) as a white solid. MS(ESI) 320.3 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.30 (s, IH), 8.13 - 8.10 (m, IH), 8.02 (dd, J=9.7, 0.7 Hz, IH), 7.20 (dd, J=9.7, 2.2 Hz, IH), 4.36 (q, J=7.2 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 3.77 - 3.69 (m, 4H), 2.83 (t, J=5.6 Hz, 2H), 2.61 - 2.53 (m, 4H), 1.40 (t, J=7.2 Hz, 3H).
Intermediate 55:
Figure imgf000148_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 55A (47 mg) with lithium hydroxide afforded Intermediate 55 (58 mg,
97%) as a white solid. MS(ESI) 320.3 (M+H)+; XH NMR (400MHz, methanol^) d 8.38 (dd, J=2.2, 0.7 Hz, IH), 8.32 (s, IH), 8.09 (dd, J=9.7, 0.7 Hz, IH), 7.36 (dd, J=9.7, 2.2 Hz, IH), 4.51 - 4.43 (m, 2H), 3.97 (br. s., 4H), 3.72 - 3.64 (m, 2H), 3.61 - 3.35 (m, 4H).
Intermediate 56: 5-(2-Hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000148_0003
Intermediate -hydroxypyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000148_0004
Ethyl 5-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (300 mg, 1.36 mmol) was mixed with aluminum tribromide (1817 mg, 6.81 mmol) in EtSH (5 ml) and stirred at rt for 3h. Cooled to 0 °C, add MeOH dropwise, then water. Extracted with EtOAc.
Concentrated and the residue was loaded onto 24 g column, eluted with EtO Ac/Hex (0- 40%); collected fraction at 30% EtOAc, concentrated to afford Intermediate 56A (90 mg, 32%). MS(ESI) 207.2 (M+H)+; ¾ NMR (400MHz, methanol^) d 8.42 (dd, J=7.5, 0.4 Hz, 1H), 8.21 (s, 1H), 7.41 - 7.27 (m, 1H), 6.67 (dd, J=7.5, 2.6 Hz, 1H), 4.32 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). Intermediate 56B: Ethyl 5-(2-hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000149_0001
To a solution of Intermediate 56A (22 mg, 0.107 mmol) in acetonitrile (3 ml) and water (0.2 ml) was added K2CO3 (59.0 mg, 0.427 mmol) and 2,2-dimethyloxirane (0.142 ml, 1.600 mmol). The reaction mixture was heated to 120 °C by microwave for 30 min. Additional 2,2-dimethyloxirane (0.142 ml, 1.60 mmol) was added, and the mixture was stirred at 120 °C for 30 min. The mixture was concentrated and the residue was loaded onto lOg column, eluted with EtO Ac/Hex (0-40%); collected product at 30% EtOAc, concentrated to afford Intermediate 56B (27 mg, 91%). MS(ESI) 279.3 (M+H)+.
Intermediate 56:
Figure imgf000149_0002
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 56B (27 mg) with lithium hydroxide afforded Intermediate 56 (19 mg,
78%) as a white solid. MS(ESI) 251.1 (M+H)+; 'H NMR (400MHZ, methanol-cU) d 8.54 - 8.42 (m, 1H), 8.25 (s, 1H), 7.42 (d, J=2.6 Hz, 1H), 6.82 (dd, J=7.5, 2.6 Hz, 1H), 3.92 (s, 2H), 1.35 (s, 6H). Inte acid
Figure imgf000150_0001
According to the procedure for preparation of Intermediate 17, saponification of ethyl 5 -methoxypyrazolo [ 1 ,5 -a]pyridine-3 -carboxylate (19 mg) with lithium hydroxide afforded Intermediate 57 (16 mg, 97%) as a white solid. MS(ESI) 193.1 (M+H)+.
Intermediate 58: 5-(2-(Pyrro -a]pyridine-3-carboxylic acid
Figure imgf000150_0002
Intermediate 58A: Ethyl 5-(2-(pyrrolidin-l-yl)ethoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000150_0003
To a vial containing Intermediate 56A (45 mg, 0.22 mmol) in DMF (3 mL), were added l-(2-bromoethyl)pyrrolidine, hydrobromide (85 mg, 0.33 mmol) and CS2CO3 (213 mg, 0.655 mmol). The vial was sealed and the mixture was stirred at 70 °C for 16h. LC/MS showed reaction completed. Filtered and concentrated. Purified through prep HPLC to afford Intermediate 58A (48 mg, 73%). MS(ESI) 304.3 (M+H)+; ¾ NMR (500MHz, methanol-d4) d 8.55 (dd, J=7.4, 0.6 Hz, IH), 8.30 (s, IH), 7.52 (d, J=2.8 Hz, IH), 6.86 (dd, J=7.7, 2.8 Hz, IH), 4.55 - 4.47 (m, 2H), 4.36 (q, J=7.0 Hz, 2H), 3.84 - 3.73 (m, 4H), 3.29 - 3.19 (m, 2H), 2.21 (br. s., 2H), 2.08 (br. s., 2H), 1.46 - 1.33 (m, 3H).
Intermediate 58:
Figure imgf000151_0001
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 58A (48 mg) with lithium hydroxide afforded Intermediate 58 (34 mg,
55%) as a white solid. MS(ESI) 276.3 (M+H)+; XH NMR (500 MHz, methanol-d4) d ppm 8.54 (1 H, dd, J=7.57, 0.69 Hz), 8.29 (1 H, s), 7.5(1 H, d, J=2.75 Hz), 6.85 (1 H, dd, J=7.43, 2.75 Hz), 4.44 - 4.56 (2 H, m), 3.71 - 3.84 (4 H, m),3.26 - 3.28 (2 H, m), 2.21 (2 H, br. s.), 2.07 (2 H, br. s.).
Intermediate 59: 5-(2-Methoxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000151_0002
Intermediate 59A: Ethyl 5-(2-methoxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000151_0003
According to the procedure for preparation of Intermediate 58A, alkylation of Intermediate 56A (35 mg) with 1 -bromo-2-methoxy ethane afforded Intermediate 59A
(37 mg, 82%) as a white solid. MS(ESI) 265.3 (M+H)+; 'H NMR (500MHZ, chloroform- d) d 8.3 1 (dd, J=7.4, 0.5 Hz, IH), 8.27 (s, IH), 7.42 (d, J=2.8 Hz, IH), 6.66 (dd, J=7.4, 2.8 Hz, IH), 4.35 (q, J=7.0 Hz, 2H), 4.28 - 4.17 (m, 2H), 3.85 - 3.74 (m, 2H), 3.51 - 3.42 (m, 3H), 1.39 (t, J=7.2 Hz, 3H).
Intermediate 59:
Figure imgf000151_0004
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 59A (37 mg) with lithium hydroxide afforded Intermediate 59 (28 mg,
85%) as a white solid. MS(ESI) 237.3 (M+H)+; XH NMR (400MHz, methanol^) d 8.47 (dd, J=7.6, 0.5 Hz, IH), 8.26 (s, IH), 7.44 (d, J=2.6 Hz, IH), 6.77 (dd, J=7.5, 2.6 Hz, IH), 4.31 - 4.19 (m, 2H), 3.90 - 3.75 (m, 2H), 3.47 - 3.39 (m, 3H).
Intermediate 60: 5-(2-Morpholinoethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000152_0001
Intermediate 60A: Ethyl 5-(2-morpholinoethoxy)pyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000152_0002
According to the procedure for preparation of Intermediate 58A, alkylation of Intermediate 56A (40 mg) with 4-(2-bromoethyl)morpholine afforded Intermediate
60A (51 mg, 82%) as a white solid. MS(ESI) 320.3 (M+H)+; XH NMR (400MHz, chloroform-d) d 8.30 (dd, J=7.5, 0.7 Hz, IH), 8.25 (s, IH), 7.40 (d, J=2.6 Hz, IH), 6.60 (dd, J=7.5, 2.6 Hz, IH), 4.33 (q, J=7.0 Hz, 2H), 4.19 (t, J=5.6 Hz, 2H), 3.78 - 3.67 (m, 4H), 2.83 (t, J=5.6 Hz, 2H), 2.61 - 2.53 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).
Intermediate 60:
Figure imgf000152_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 60A (51 mg) with lithium hydroxide afforded Intermediate 60 (60 mg,
93%) as a white solid. MS(ESI) 292.3 (M+H)+; XH NMR (400MHz, methanol-cU) d 8.53 (dd, J=7.6, 0.5 Hz, IH), 8.29 (s, IH), 7.50 (d, J=2.6 Hz, IH), 6.83 (dd, J=7.5, 2.6 Hz, IH), 4.58 - 4.51 (m, 2H), 4.05 (br. s., 2H), 3.88 (br. s., 2H), 3.78 - 3.70 (m, 2H), 3.65 - 3.48 (m, 2H), 3.45 - 3.34 (m, 2H).
Intermediate 61: 5-(2-Hydroxypropoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000153_0001
Intermediate 61A: Ethyl 5-(2-hydroxypropoxy)pyrazolo[l,5-a]pyridine-3-carboxylate
Figure imgf000153_0002
To a solution of Intermediate 56A (41 mg, 0.20 mmol) in acetonitrile (3 ml) and water (0.2 ml) was added K2CO3 (137 mg, 0.994 mmol) and 2-methyloxirane (0.417 ml, 5.97 mmol). The reaction mixture was heated to 120 °C on MW for 30min. Reaction is completed. Concentrated and the residue was loaded onto 10 g column, eluted with EtO Ac/Hex (0-50%); collected fraction at 30% EtOAc, concentrated to afford
Intermediate 61A (26 mg, 50%). MS(ESI) 265.2 (M+H)+.
Intermediate 61:
Figure imgf000153_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 61A (26 mg) with lithium hydroxide afforded Intermediate 61 (21 mg,
82%) as a white solid. MS(ESI) 265.2 (M+H)+; XH NMR (400MHz, methanol-cU) d 8.46 (dd, J=7.6, 0.6 Hz, 1H), 8.27 - 8.23 (m, 1H), 7.41 (d, J=2.6 Hz, 1H), 6.84 - 6.75 (m, 1H), 4.17 (td, J=6.5, 4.0 Hz, 1H), 4.08 - 3.90 (m, 2H), 1.38 - 1.23 (m, 3H).
Intermediate 62: 5-(2-Hydroxyethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000154_0001
Intermediate 62A: Methyl 5-(2-(benzyloxy)ethoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000154_0002
According to the procedure for preparation of Intermediate 58A, alkylation of methyl 5-hydroxypyrazolo[l,5-a]pyridine-3-carboxylate (43 mg) with ((2- bromoethoxy)methyl)benzene afforded Intermediate 62A (71 mg, 99%). MS(ESI) 327.3 (M+H)+.
Inter -(2-(Benzyloxy)ethoxy)pyrazolo[l,5-a]pyridine-3-carboxylic acid
Figure imgf000154_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 62A (75 mg) with lithium hydroxide afforded Intermediate 62B (46 mg,
64%) as a white solid. MS(ESI) 313.2 (M+H)+.
Intermediate 62:
Figure imgf000154_0004
Intermediate 62B (43 mg, 0.138 mmol) was mixed with MeOH (5 mL), degassed, add 10% Pd/C (ca. 20 mg), stirred under H2 balloon o/n for 16h. Filtered and concentrated to afford Intermediate 62 (26 mg, 85%). MS(ESI) 223.2 (M+H)+; 'H NMR (400MHz, methanol-d4) d 8.46 (d, J=7.7 Hz, 1H), 8.25 (s, 1H), 7.42 (d, J=2.6 Hz, 1H), 6.78 (dd, J=7.6, 2.8 Hz, 1H), 4.25 - 4.14 (m, 2H), 3.97 - 3.87 (m, 2H). Intermediate 63 : 5 -(2-Hydroxy-3 -methoxypropoxy)pyrazolo [ 1 ,5 -a]pyridine-3 - carboxylic acid
Figure imgf000155_0001
Intermediate 63A: Ethyl 5-(2-hydroxy-3-methoxypropoxy)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000155_0002
To a solution of Intermediate 56A (38 mg, 0.184 mmol) in acetonitrile (3 ml) and water (0.2 ml) was added K2CO3 (102 mg, 0.737 mmol) and 2-
(methoxymethyl)oxirane (487 mg, 5.53 mmol). The reaction mixture was heated to 120 °C on MW for 35min, LCMS shows the reaction was complete with formation of desired product. Filtered and purified through prep HPLC to afford Intermediate 63A (30 mg, 55%). MS(ESI) 295.2 (M+H)+.
Intermediate 63:
Figure imgf000155_0003
According to the procedure for preparation of Intermediate 17, saponification of Intermediate 63A (60 mg) with lithium hydroxide afford Intermediate 63 (47 mg, 87%) as a white solid. MS(ESI) 267.1 (M+H)+; XH NMR (500MHz, methanol-d4) δ 8.48 - 8.45 (m, 1H), 8.26 (s, 1H), 7.43 (d, J=2.8 Hz, 1H), 6.78 (dd, J=7.4, 2.8 Hz, 1H), 4.24 - 4.06 (m, 3H), 3.60 - 3.53 (m, 2H), 3.46 - 3.38 (m, 3H).
Intermediate 66: 4-(4-Aminophenyl)isoquinolin-l(2H)-one, TFA
Figure imgf000156_0001
To 4-bromoisoquinolin-l(2H)-one (166 mg, 0.741 mmol), (4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (176 mg, 0.741 mmol) and K3PO4 (393 mg, 1.85 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (43 mg, 0.037 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 40 min. The reaction mixture was concentrated, then the residue was purified by flash chromatography (0-100% EtO Ac/Hex). The product was dissolved in DCM (2 mL), then was treated with TFA (1 mL). The mixture was stirred rt for lh, concentrated and purified via preparative HPLC to afford Intermediate 66 (117 mg, 45% yield). MS(ESI) m/z: 237.1 (M+H)+; XH NMR (500MHz, methanol-d4) δ 8.41 (dd, J=8.0, 0.8 Hz, 1H), 7.70 (ddd, J=8.3, 7.0, 1.5 Hz, 1H), 7.61 - 7.50 (m, 5H), 7.49 - 7.42 (m, 2H), 7.14 (s, 1H), 3.35 (s, 1H).
Intermediate 67: 2-(4-(l-Oxo-l,2-dihydroisoquinolin-4-yl)phenyl)acetic acid
Figure imgf000156_0002
Intermediate 67A: Ethyl 2-(4-(l-oxo-l,2-dihydroisoquinolin-4-yl)phenyl)acetate
Figure imgf000157_0001
To 4-bromoisoquinolin-l(2H)-one (166 mg, 0.741 mmol), Intermediate 1A (215 mg, 0.741 mmol) and K3PO4 (393 mg, 1.85 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (43 mg, 0.037 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 40 min. The reaction mixture was concentrated, then was purified via prep HPLC to afford Intermediate 67A (21 mg, 9.2% yield). MS(ESI) m/z: 308.1 (M+H)+.
Figure imgf000157_0002
A solution of Intermediate 67A (21 mg, 0.068 mmol) in THF, was treated with 1M lithium hydroxide (0.2 ml, 0.200 mmol). The mixture was stirred rt for 16h, then was concentrated. The residue was purified via preparative HPLC to afford Intermediate 67 (13 mg, 68% yield). MS(ESI) m/z: 280.1 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.40 (br. s., 1H), 1 1.43 (d, J=5.2 Hz, 1H), 8.30 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (ddd, J=8.1, 7.0, 1.4 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.42 - 7.33 (m, 5H), 7.08 (d, J=5.8 Hz, 1H), 3.31 (br. s., 2H).
Intermediate 68: 4-Bromo-6,7-dimethoxyisoquinolin-l(2H)-one
Figure imgf000158_0001
To a solution of 6,7-dimethoxyisoquinolin-l(2H)-one (205 mg, 1.00 mmol) in AcOH (2 mL), was add bromine (192 mg, 1.199 mmol) in AcOH (1 mL). The mixture was stirred rt for lh, then poured onto ice and extracted with EtO Ac. The organic phase was washed with brine, then was concentrated. The product was purified by flash chromatography (0-80% EtO Ac/Hex) to afford Intermediate 68 (230 mg, 0.81 mmol, 81% yield) as white form. MS(ESI) m/z: 283.9 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.42 (br. s., IH), 7.62 (s, IH), 7.44 (br. s., IH), 7.13 (s, IH), 3.94 (s, 3H), 3.89 (s, 3H).
Intermedi -Isopropoxyindoline
Figure imgf000158_0002
Intermediate 69A: 6-(Benzyloxy)indoline
Figure imgf000158_0003
To a solution of 6-(benzyloxy)-lH-indole (580 mg, 2.60 mmol) in EtOH (5 mL) at 0 °C, was added Sodium cyanoborohydride (326 mg, 5.20 mmol). The mixture was stirred rt for 16 h then was concentrated. The residue was purified via prep HPLC to afford Example 69A (280 mg; 32% yield) as a yellow oil. MS(ESI) m/z: 226.1 (M+H)+; 'H NMR (500MHZ, chloroform-d) δ 10.54 (br. s., 2H), 7.46 - 7.32 (m, 5H), 7.26 (d, J=8.5 Hz, IH), 7.13 (d, J=2.2 Hz, IH), 6.99 (dd, J=8.5, 2.2 Hz, IH), 4.99 (s, 2H), 3.97 - 3.84 (m, 2H), 3.23 (t, J=7.6 Hz, 2H).
Intermediate 69B: tert-Butyl 6-(benzyloxy)indoline-l-carboxylate
Figure imgf000158_0004
To a mixture of Intermediate 69 A (270 mg, 1.20 mmol) and B0C2O (0.334 mL, 1.44 mmol) in THF at rt, was added cat. DMAP. The resulting mixture was stirred rt for 16 h, then was concentrated and. The residue was purified via flash chromatography (0- 50% EtO Ac/Hex) to afford Intermediate 69B (150 mg; 39% yield). MS(ESI) m/z: 326.1 (M+H)+; XH NMR (500MHz, chloroform-d) δ 7.54 - 7.46 (m, 2H), 7.45 - 7.37 (m, 2H), 7.36 - 7.31 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.1, 2.3 Hz, 1H), 5.10 (s, 2H), 4.10 - 3.91 (m, 2H), 3.04 (t, J=8.7 Hz, 2H), 1.71 - 1.55 (m, 9H).
Intermediate 69C: tert-Butyl 6-hydroxyindoline-l-carboxylate
Figure imgf000159_0001
To a degassed solution of Intermediate 69B (140 mg, 0.43 mmol) in MeOH (5 mL) was added 10% Pd/C (30 mg). The mixture was stirred under ¾ (balloon) for 4h. The mixture was filtered and concentrated to afford Intermediate 69C (90 mg; 89% yield) as white solid. MS(ESI) m/z: 236.1 (M+H)+; XH NMR (500MHz, methanol-d4) δ 7.32 - 7.12 (m, 1H), 6.93 - 6.85 (m, 1H), 6.41 - 6.30 (m, 1H), 3.95 - 3.85 (m, 2H), 3.01 - 2.88 (m, 2H), 1.54 (br. s., 9H).
Intermediat
Figure imgf000159_0002
Intermediate 69C (45 mg, 0.19 mmol) was mixed with 2-iodopropane (163 mg,
0.956 mmol), CS2CO3 (93 mg, 0.287 mmol) in DMF (3 mL). The mixture was stirred at 80 °C for 16h, then was concentrated. The residue was purified via flash chromatography (0-40% EtO Ac/Hex) to afford Intermediate 69D (35 mg; 66% yield) as colorless foam. MS(ESI) m/z: 277.9 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 7.50 - 7.26 (m, 1H), 7.01 - 6.95 (m, 1H), 6.46 (dd, J=8.3, 2.5 Hz, 1H), 4.50 (dt, J=11.9, 6.0 Hz, 1H), 3.99 - 3.83 (m, 2H), 3.03 - 2.92 (m, 2H), 1.64 - 1.48 (m, 9H), 1.32 - 1.25 (m, 6H).
Intermediate 69:
Figure imgf000160_0001
Intermediate 69D (35 mg, 0.13 mmol) was mixed with TFA (0.5 mL) and DCM (1 mL), and stirred rt for 20 min. The mixture was concentrated to afford Intermediate 69 (36 mg; 99% yield) as a colorless foam. MS(ESI) m/z: 177.9 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 7.40 - 7.31 (m, 1H), 7.05 - 6.95 (m, 2H), 4.61 (dt, J=12.1, 6.1 Hz, 1H), 3.86 (t, J=7.7 Hz, 2H), 3.24 (t, J=7.7 Hz, 2H), 1.34 - 1.27 (m, 6H).
Intermediate 70: l-(Isoindolin-2-yl)-2-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)ethanone
Figure imgf000160_0002
Intermediate 70A: 2-(4-Bromo-3-methylphenyl)-l-(isoindolin-2-yl)ethanone
Figure imgf000160_0003
To a solution of 2-(4-bromo-3-methylphenyl)acetic acid (200 mg, 0.87 mmol), isoindoline (0.109 mL, 0.96 mmol), and DIEA (0.305 mL, 1.75 mmol) in DMF (3 mL), was add HATU (398 mg, 1.05 mmol). The mixture was stirred at rt for 19 h. The reaction mixture was diluted with EtOAc, then was washed with H20, sat. a2C03 and brine. The organic phase was dried (Na2S04) and concentrated. The crude product was purified by flash chromatography to afford Intermediate 70A (128 mg, 44% yield) as an off-white solid. MS(ESI) 329.9 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 7.48 (d, J=8.1 Hz,
1H), 7.32 - 7.27 (m, 3H), 7.25 - 7.20 (m, 2H), 7.01 (dd, J=8.1, 1.8 Hz, 1H), 4.82 (d, J=5.3 Hz, 4H), 3.69 (s, 2H), 2.38 (s, 3H). Intermediate 70:
Figure imgf000161_0001
To a degassed (evacuated and flushed with Ar (3x)) mixture of Intermediate 70A (128 mg, 0.388 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (118 mg, 0.465 mmol) and potassium acetate (1 14 mg, 1.16 mmol) in dioxane (2 mL), was added PdCi2(dppf) (¾(¾ adduct (15.8 mg, 0.019 mmol). The mixture was degassed (2x), then the vial was sealed and stirred at 1 10 °C for 2.5 h. The reaction mixture was diluted with EtOAc and was washed with H20 and brine. The organic phase was dried (Na2S04), filtered through a 1 " pad of S1O2 and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford Intermediate 70 (126 mg, 86% yield) as a yellow solid. MS(ESI) 378.1 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 7.73 (d, J=7.7 Hz, 1H), 7.32 - 7.23 (m, 3H), 7.21 - 7.10 (m, 3H), 4.82 (s, 2H), 4.75 (s, 2H), 3.75 (s, 2H), 2.52 (s, 3H), 1.32 (s, 12H).
Intermediate 71: 1 -(Indolin- 1 -yl)-2-(3 -methyl-4-(4,4,5 ,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)ethanone
Figure imgf000161_0002
According to the procedure the preparation of Intermediate 70, substituting indoline for isoindoline afforded Intermediate 71. MS(ESI) 378.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.26 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.23 - 7.07 (m, 4H), 7.04 - 6.96 (m, 1H), 4.01 (t, J=8.5 Hz, 2H), 3.78 (s, 2H), 3.13 (t, J=8.5 Hz, 2H), 2.52 (s, 3H), 1.33 (s, 12H).
Intermediate 72 : 2-(3 -Fluoro-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)- 1 - (i e
Figure imgf000162_0001
According to the procedure the preparation of Intermediate 5, substituting indoline for isoindoline afforded Intermediate 72. MS(ESI) 382.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.24 (d, J=8.1 Hz, 1H), 7.71 (dd, J=7.5, 6.6 Hz, 1H), 7.23 - 7.13 (m, 2H), 7.1 1 (d, J=7.7 Hz, 1H), 7.06 - 6.99 (m, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.82 (s 2H), 3.16 (t, J=8.5 Hz, 2H), 1.35 (s, 12H).
Intermediate 73: 4-Bromo-6-methoxyisoquinolin-l(2H)-one
Figure imgf000162_0002
To a solution of 6-methoxyisoquinolin-l(2H)-one (112 mg, 0.639 mmol) in DMF
(2 mL), was added NBS (137 mg, 0.767 mmol). The mixture was stirred at rt overnight, then was concentrated. The residue was purified via prep HPLC to afford Intermediate 73 (120 mg, 74% yield) as white solid. MS(ESI) m/z: 253.9 (M+H)+; ¾ NMR (400MHz, DMSO-d6) 5 1 1.41 (br. s., 1H), 8.16 (d, J=8.8 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.18 (dd, J=8.8, 2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 3.99 - 3.87 (m, 3H).
Intermediate 74: l-(Indolin-6-yloxy)-2-methylpropan-2-ol, TFA Inte
Figure imgf000163_0001
To a mixture of Intermediate 69C (12 mg, 0.051 mmol) and 2,2-dimethyloxirane
(37 mg, 0.51 mmol) in acetonitrile (1 mL), was added K2CO3 (35 mg, 0.26 mmol) in water (0.1 mL). The mixture was stirred in a sealed tube at 100 °C for 3h, then was concentrated. The residue was purified via flash chromatography (0-40% EtOAc/Hex) to afford Intermediate 74A (12 mg, 64% yield). MS(ESI) m/z: 308.2 (M+H)+. XH NMR (500MHz, chloroform-d) δ 7.61 - 7.46 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.50 (dd, J=8.1, 2.3 Hz, 1H), 3.99 (t, J=8.3 Hz, 2H), 3.80 (s, 2H), 3.07 - 2.96 (m, 2H), 1.59 (d, J=18.4 Hz, 9H), 1.33 (s, 6H).
Intermediat
Figure imgf000163_0002
Intermediate 74A (12 mg, 0.039 mmol) was stirred with TFA (0.5 mL) and DCM (0.5 mL) for 20 min, then was concentrated to afford Intermediate 74 (12 mg, 96% yield). MS(ESI) m/z: 208.2 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 7.41 - 7.32 (m, 1H), 7.07 - 6.97 (m, 2H), 3.84 (t, J=7.7 Hz, 2H), 3.81 (s, 2H), 3.24 (t, J=7.7 Hz, 2H), 1.32 (s, 6H).
Intermediate 75: -(Pyridin-3-ylmethoxy)indoline, 2TFA
Figure imgf000163_0003
Intermediate 75A: tert-Butyl 6-(pyridin-3-ylmethoxy)indoline-l-carboxylate
Figure imgf000164_0001
To a solution of pyridin-3-ylmethanol (26.4 mg, 0.242 mmol), Intermediate 69C (38 mg, 0.162 mmol), and triphenylphosphine (106 mg, 0.404 mmol) in THF (3 mL), was added DEAD (0.064 mL, 0.404 mmol). The reaction was stirred at rt overnight. The mixture was purified by preparative HPLC to afford Intermediate 75A (42 mg, 59% yield) as a white solid. MS(ESI) m/z: 327.1 (M+H)+; 'H NMR (500MHZ, chloroform-d) δ 15.42 (br. s., IH), 8.91 (s, IH), 8.81 (d, J=5.2 Hz, IH), 8.35 (d, J=8.0 Hz, IH), 7.82 (dd, J=8.0, 5.5 Hz, IH), 7.63 (br. s., IH), 7.05 (d, J=8.3 Hz, IH), 6.54 (d, J=7.2 Hz, IH), 5.23 (s, 2H), 4.00 (t, J=8.5 Hz, 2H), 3.04 (t, J=8.5 Hz, 2H), 1.56 (br. s., 9H).
Intermediate 75:
Figure imgf000164_0002
Intermediate 75A (45 mg, 0.102 mmol) was stirred with TFA (1 mL) and DCM (2 mL) at rt for 20 min, then was concentrated to afford Intermediate 75 (47 mg, 100% yield) as a yellow oil. MS(ESI) m/z: 227.1 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 9.01 (s, IH), 8.85 (d, J=5.5 Hz, IH), 8.70 (d, J=8.5 Hz, IH), 8.10 (dd, J=8.0, 5.8 Hz, IH), 7.45 (d, J=8.5 Hz, IH), 7.24 (d, J=2.2 Hz, IH), 7.21 (dd, J=8.5, 2.5 Hz, IH), 5.40 (s, 2H), 3.94 - 3.85 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).
Intermediate 76: -(Pyridin-2-ylmethoxy)indoline, 2TFA
Figure imgf000164_0003
According to the procedure for the preparation of Intermediate 75, substituting pyridin-2-ylmethanol for pyridin-3-ylmethanol afforded Intermediate 76. MS(ESI) m/z: 227.1 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 8.82 (dd, J=5.5, 0.8 Hz, IH), 8.48 (td, J=7.8, 1.7 Hz, IH), 8.07 (d, J=7.7 Hz, IH), 7.98 - 7.82 (m, IH), 7.46 (d, J=8.5 Hz, IH), 7.35 - 7.14 (m, 2H), 5.56 - 5.39 (m, 2H), 3.93 - 3.82 (m, 2H), 3.30 - 3.25 (m, 2H). Intermediate 77 -(Pyridin-4-ylmethoxy)indoline, 2TFA
Figure imgf000165_0001
According to the procedure for the preparation of Intermediate 75, substituting pyridin-4-ylmethanol for pyridin-3-ylmethanol afforded Intermediate 77. MS(ESI) m/z: 227 '.1 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 8.94 - 8.84 (m, 2H), 8.22 - 8.15 (m, 2H), 7.48 - 7.41 (m, IH), 7.25 (d, J=2.2 Hz, IH), 7.21 (dd, J=8.5, 2.5 Hz, IH), 5.51 (s, 2H), 3.93 - 3.87 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).
Intermediate 78: (R)- -((Tetrahydrofuran-3-yl)oxy)indoline, TFA
Figure imgf000165_0002
According to the procedure for the preparation of Intermediate 75, substituting (5)-tetrahydrofuran-3-ol for pyridin-3-ylmethanol afforded Intermediate 78. MS(ESI) m/z: 206.1 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 7.38 (d, J=8.3 Hz, IH), 7.05 (d, J=2.2 Hz, IH), 7.01 (dd, J=8.5, 2.2 Hz, IH), 5.03 (qd, J=4.0, 1.5 Hz, IH), 4.02 - 3.79 (m, 6H), 3.25 (t, J=7.7 Hz, 2H), 2.32 - 2.21 (m, IH), 2.12 - 2.04 (m, IH).
Intermediate 79: (5)- -((Tetrahydrofuran-3-yl)oxy)indoline, TFA
Figure imgf000165_0003
According to the procedure for the preparation of Intermediate 75, substituting (R)-tetrahydrofuran-3-ol for pyridin-3-ylmethanol afforded Intermediate 79. MS(ESI) m/z: 206.1 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 7.40 - 7.35 (m, IH), 7.08 - 6.97 (m, 2H), 4.05 - 3.81 (m, 6H), 3.25 (t, J=7.7 Hz, 2H), 2.38 - 2.23 (m, IH), 2.17 - 2.03 (m, IH).
Intermediate 80: (R)-6-((l-Methylpyrrolidin-3-yl)oxy)indoline, 2TFA According to the procedur6e for the prepar0ation- of Intermediate 75, substituting (5)-l-methylpyrrolidin-3-ol for pyridin-3-ylmethanol afforded Intermediate 80.
MS(ESI) m/z: 219.1 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 7.46 - 7.39 (m, 1H), 7.17 - 7.1 1 (m, 1H), 7.10 - 7.03 (m, 1H), 5.24 (br. s., 1H), 3.98 - 3.79 (m, 4H), 3.50 - 3.35 (m, 1H), 3.27 (t, J=7.7 Hz, 2H), 3.01 (br. s., 3H), 2.68 (br. s., 1H), 2.49 - 2.33 (m, 1H), 2.27 (br. s., 1H).
Intermediate 81: (5)-6-((l-Methylpyrrolidin-3-yl)oxy)indoline, 2TFA
According to the procedur te foor the pr°epxaration of Intermediate 75, substituting (R)-l-methylpyrrolidin-3-ol for pyridin-3-ylmethanol afforded Intermediate 81.
MS(ESI) m/z: 219.1 (M+H)+. Intermediate 82: 2-(Indolin-6-yloxy)-N,N-dimethylethanamine, 2TFA
Figure imgf000166_0001
According to the procedure for the preparation of Intermediate 75, substituting 2 (dimethylamino)ethanol for pyridin-3-ylmethanol afforded Intermediate 82. MS(ESI) m/z: 207.2 (M+H)+.
Intermediate 83: 6-( -Methylpiperidin-4-yl)oxy)indoline, 2TFA
Figure imgf000166_0002
According to the procedure for the preparation of Intermediate 75, substituting 1 methylpiperidin-4-ol for pyridin-3-ylmethanol afforded Intermediate 83. MS(ESI) m/z: 233.2 (M+H)+.
Intermediate 84: Methyl 2-(indolin-6-yloxy)acetate
Figure imgf000167_0001
According to the procedure for the preparation of Intermediate 69, substituting methyl 2-bromoacetate for 2-iodopropane afforded Intermediate 84. MS(ESI) m/z: 208.1 (M+H)+; XH NMR (500MHz, methanol-cU) δ 7.38 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.02 (dd, J=8.4, 2.3 Hz, 1H), 4.77 (s, 2H), 3.86 (t, J=7.7 Hz, 2H), 3.78 - 3.75 (m, 3H), 3.24 (t, J=7.7 Hz, 2H).
Intermediate 85 -(Oxetan-3-ylmethoxy)indoline, TFA
Figure imgf000167_0002
According to the procedure for the preparation of Intermediate 75, substituting 3- (bromomethyl)oxetane for pyridin-3-ylmethanol afforded Intermediate 85. MS(ESI) m/z: 206.1(M+H)+.
Intermediate 86: -(2-(Pyrrolidin-l-yl)ethoxy)indoline, 2TFA
Figure imgf000167_0003
According to the procedure for the preparation of Intermediate 69, substituting methyl l-(2-bromoethyl)pyrrolidine, hydrobromide for 2-iodopropane afforded
Intermediate 86. MS(ESI) m/z: 233.1 (M+H)+.
Intermediate 87: 1 -(6-(2-Hydroxy-2-methylpropoxy)indolin- 1 -yl)-2
tetrameth - 1 ,3 ,2-dioxaborolan-2-yl)phenyl)ethanone
Figure imgf000167_0004
Intermediate 87A: 2-(4-Bromophenyl)-l-(6-(2 -hydroxy -2-methylpropoxy)indolin-l- yl)ethanone
Figure imgf000168_0001
To a mixture of 2-(4-bromophenyl)acetic acid (92 mg, 0.43 mmol), Intermediate
74 (138 mg, 0.43 mmol), and HATU (245 mg, 0.644 mmol) in DMF (5 mL), was add DIEA (0.375 mL, 2.15 mmol). The mixture was stirred rt for 16h. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-80%
EtO Ac/Hex) to afford Intermediate 87A (162 mg, 93% yield) as a colorless foam.
MS(ESI) m/z: 404.0 (M+H)+; ¾ NMR (500MHz, chloroform-d) δ 7.93 (d, J=2.2 Hz,
IH), 7.49 - 7.44 (m, 2H), 7.20 - 7.14 (m, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, IH), 6.60 (dd, J=8.3, 2.2 Hz, IH), 4.11 - 4.02 (m, 2H), 3.77 (s, 2H), 3.72 (s, 2H), 3.10 (t, J=8.4 Hz, 2H), 1.36 - 1.28 (m, 6H). Intermediate 87:
Figure imgf000168_0002
To a mixture of Intermediate 87A (163 mg, 0.403 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (123 mg, 0.484 mmol), and potassium acetate (119 mg, 1.21 mmol) in dioxane (4 mL), was added PdCl2(dppf) (¾(¾ adduct (8.9 mg, 0.012 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 1 10 °C for 2 h. The reaction mixture was diluted with water, then was extracted with EtOAc. The organic phase was concentrated and the residue was purified by flash chromatography (0-80% EtO Ac/Hex) to afford Intermediate 87 (178 mg, 98% yield). MS(ESI) m/z: 452.2(M+H)+; 'H NMR (500MHZ, chloroform-d) δ 7.95 (d, J=2.2 Hz, 1H), 7.81 - 7.77 (m, J=8.3 Hz, 2H), 7.34 - 7.30 (m, J=8.0 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.59 (dd, J=8.1, 2.3 Hz, 1H), 4.05 (t, J=8.4 Hz, 2H), 3.80 (d, J=13.2 Hz, 4H), 3.07 (t, J=8.3 Hz, 2H), 1.34 (s, 12H), 1.24 - 1.22 (m, 6H).
Intermediate 88: N,N-Dimethylindoline-6-carboxamide, TFA
Figure imgf000169_0001
Intermediate 88A: N,N-Dimethyl-lH-indole-6-carboxamide
Figure imgf000169_0002
To a mixture of lH-indole-6-carboxylic acid (1 10 mg, 0.683 mmol),
dimethylamine, HCl (83 mg, 1.024 mmol), and HATU (389 mg, 1.024 mmol) in DMF (3 mL), was added DIEA (0.596 mL, 3.41 mmol). The mixture was stirred rt for 2h, then was concentrated. The mixture was purified by prep HPLC to afford Intermediate 88A (125 mg, 97% yield). MS(ESI) m/z: 189.0 (M+H)+; XH NMR (500MHz, chloroform-d) δ 9.56 (br. s., 1H), 7.61 (d, J=8.0 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.24 - 7.19 (m, 1H), 7.12 (dd, J=8.1, 1.5 Hz, 1H), 6.53 - 6.48 (m, 1H), 3.27 - 3.05 (m, 3H), 2.99 (br. s., 3H).
Intermediate 88:
Figure imgf000169_0003
To a solution of Intermediate 88A (125 mg, 0.664 mmol) in AcOH (3 mL) at 0 °C was added Sodium cyanoborohydride (83 mg, 1.328 mmol). The mixture was stirred at 0 °C for 5 min, warmed to rt and stirred for 5 h. The reaction mixture was made basic with 20% NaOH at 0 °C, then was extracted with DCM (3 x 70 mL). The organic layer was washed with brine, dried over Na2S04, concentrated and purified via preparative HPLC to afford Intermediate 88 (155 mg, 0.509 mmol, 77% yield) as a yellow oil. MS(ESI) m/z: 191.1 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 7.60 - 7.53 (m, 1H), 7.52 - 7.46 (m, 2H), 3.89 (t, J=7.8 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.11 (s, 3H), 3.00 (s, 3H). Intermediate 89: Indolin-6-yl(4-methylpiperazin- 1 -yl)methanone, 2TFA
Figure imgf000170_0001
According to the procedure for the preparation of Intermediate 88, substituting 1- methylpiperazine for dimethylamine, HCl afforded Intermediate 89. MS(ESI) m/z: 246 A (M+H)+.
Intermediate 90 : (4-Hydroxypiperidin- 1 -yl)(indolin-5 -yl)methanone
Figure imgf000170_0002
According to the procedure for the preparation of Intermediate 88, substituting piperidin-4-ol for dimethylamine, HCl and lH-indole-5-carboxylic acid for lH-indole-6 carboxylic acid afforded Intermediate 90. MS(ESI) m/z: 247.1 (M+H)+; 'H NMR (400MHz, chloroform-d) δ 7.16 - 7.12 (m, 1H), 7.03 (dd, J=8.0, 1.7 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 3.93 (br. s., 1H), 3.84 (tt, J=8.3, 4.0 Hz, 2H), 3.64 - 3.41 (m, 4H), 3.19 (ddd, J=13.2, 9.5, 3.3 Hz, 2H), 2.99 (t, J=8.5 Hz, 2H), 1.88 - 1.73 (m, 2H), 1.57 - 1.41 (m, 2H).
Intermediate 91: (4-Hydroxypiperidin- 1 -yl)(indolin-6-yl)methanone, TFA
Figure imgf000170_0003
According to the procedure for the preparation of Intermediate 88, substituting piperidin-4-ol for dimethylamine, HCl afforded Intermediate 91. MS(ESI) m/z: 247.1 (M+H)+; XH NMR (500MHz, methanol-cU) δ 7.57 (dd, J=7.7, 0.8 Hz, IH), 7.51 - 7.47 (m, 2H), 4.16 (br. s., IH), 3.95 - 3.88 (m, 3H), 3.60 (br. s., IH), 3.37 (t, J=7.8 Hz, 3H), 3.28 - 3.17 (m, IH), 2.02 - 1.88 (m, IH), 1.82 (br. s., IH), 1.57 (br. s., IH), 1.46 (br. s., IH). Intermediate 92: )methanone, TFA
Figure imgf000171_0001
According to the procedure for the preparation of Intermediate 88, substituting morpholine for dimethylamine, HCl afforded Intermediate 92. MS(ESI) m/z: 233.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 12.19 (br. s., 3H), 7.42 (d, J=7.9 Hz, IH), 7.35 (dd, J=7.8, 1.2 Hz, IH), 7.20 (s, IH), 3.93 (t, J=7.8 Hz, 2H), 3.77 (br. s., 4H), 3.60 (br. s., 2H), 3.42 - 3.24 (m, 4H).
Intermediate 93: holino)methanone
Figure imgf000171_0002
According to the procedure for the preparation of Intermediate 88, substituting morpholine for dimethylamine, HCl and lH-indole-5-carboxylic acid for lH-indole-6- carboxylic acid afforded Intermediate 93. MS(ESI) m/z: 233.1 (M+H)+; 'H NMR (400MHz, chloroform-d) δ 7.19 (d, J=l.l Hz, IH), 7.11 - 7.06 (m, IH), 6.53 (d, J=8.1 Hz, IH), 4.04 (br. s., IH), 3.76 - 3.54 (m, 10H), 3.02 (t, J=8.6 Hz, 2H).
Intermediate 94: 4-(4-Amino- -methylphenyl)phthalazin-l(2H)-one, TFA
Figure imgf000171_0003
Intermediate 94A: tert-Butyl (4-bromo-3-methylphenyl)carbamate
Figure imgf000172_0001
To a solution of 4-bromo-3-methylaniline (2.0 g, 10.8 mmol) and B0C2O (2.82 g, 12.9 mmol) in MeOH (20 mL), was added sodium carbonate (2.51 g, 23.7 mmol). The mixture was stirred at rt for 5 h. Additional B0C2O (0.28 g, 1.3 mmol) was added and the mixture was stirred at rt for 20 h. The reaction mixture was filtered to remove inorganic salt. The filtrate was concentrated to give a white solid, which was suspended in EtOAc (-100 mL). The suspension was filtered through a 1 " pad of Si02. The filtrate was concentrated to afford Intermediate 94A (3.03 g, 98% yield) as a white solid. MS(ESI) m/z: 307.9 (M+Na)+; 'H NMR (400MHZ, chloroform-d) δ 7.40 (d, J=8.6 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 7.02 (dd, J=8.6, 2.6 Hz, 1H), 6.38 (br. s., 1H), 2.36 (s, 3H), 1.51 (s, 9H).
Intermediate 94B: tert-Butyl (4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-3- methylphenyl)carbamate
Figure imgf000172_0002
To a vial containing Intermediate 94A (1.5 g, 5.24 mmol), 5,5,5',5'-tetramethyl- 2,2'-bi(l,3,2-dioxaborinane) (1.30 g, 5.77 mmol) and potassium acetate (1.54 g, 15.7 mmol), was added dioxane (15 ml). The mixture was degassed (evacuated and flushed with Ar (3x)), then PdCl2(dppf) CH2C12 adduct (0.214 g, 0.262 mmol) was added. The mixture was degassed (3x), then the vial was sealed and heated at 1 10 °C for 2.5 h. The reaction mixture was partitioned between EtOAc and H20. The organic phase was washed with H20 and brine, dried ( a2S04), filtered through a 1 " pad of S1O2 and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 50% ethyl acetate/hexanes) to afford Intermediate 94B (1.545 g, 4.84 mmol, 92% yield) as an orange foam. MS(ESI) m/z: 250.2 (M(boronic acid)-H)~; ¾ NMR (400MHz, chloroform-d) δ 7.67 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.11 (dd, J=8.1, 2.0 Hz, 1H), 6.41 (br. s., 1H), 3.75 (s, 4H), 2.49 (s, 3H), 1.51 (s, 9H), 1.02 (s, 6H).
Intermediate 94C: tert-Butyl (3-methyl-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate
Figure imgf000173_0001
To 4-chlorophthalazin- 1 (2H)-one (400 mg, 2.22 mmol), Intermediate 94B (778 mg, 2.44 mmol) and phosphoric acid, potassium salt (1175 mg, 5.54 mmol), were added dioxane (6 mL) and water (0.667 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (128 mg, 0.111 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 40 min. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with H20 and brine, dried ( a2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford Intermediate 94C (540 mg, 1.54 mmol, 69% yield) as a white solid. MS(ESI) m/z: 352.0 (M+H)+; XH NMR (400MHz, methanol-cU) δ 8.46 - 8.40 (m, 1H), 7.91 - 7.80 (m, 2H), 7.47 - 7.35 (m, 3H), 7.20 (d, J=8.1 Hz, 1H), 2.09 (s, 3H), 1.54 (s, 9H).
Intermediate 94:
Figure imgf000174_0001
To a suspension of Intermediate 94C (540 mg, 1.54 mmol) in DCM (5 mL), was added TFA (2 mL). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated, then was co-evaporated with DCM (3x) to afford Intermediate 94 (723 mg, 98% yield) as a solid. MS(ESI) m/z: 252.1 (M+H)+; XH NMR (400MHz, methanol- d4) δ 8.45 (dd, J=7.9, 1.1 Hz, 1H), 7.93 - 7.82 (m, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.38 - 7.27 (m, 3H), 2.19 (s, 3H)
Intermediate 95: 4-(Dimethylamino)-N-(indolin-6-yl)benzamide, 2TFA
Figure imgf000174_0002
I
Figure imgf000174_0003
To a mixture of 6-nitroindoline (300 mg, 1.83 mmol) and B0C2O (0.509 mL, 2.19 mmol) in THF at rt, was added cat. DMAP. The resulting mixture was stirred rt o/n. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-20% EtO Ac/Hex) to afford Intermediate 95A (480 mg, 99% yield). MS(ESI) m/z: 287.0 (M+Na)+; ¾ NMR (500MHz, methanol-d4) δ 8.51 (br. s., 1H), 7.81 (dd, J=8.3, 2.2 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 4.12 - 4.02 (m, 2H), 3.25 - 3.16 (m, 2H), 1.67 - 1.49 (m, 9H).
Intermediate 95B: tert-Butyl 6-Aminoindoline- 1 -carboxylate B
Figure imgf000175_0001
To a degassed mixture of Intermediate 95A (450 mg, 1.70 mmol) in MeOH (10 mL), was add 10% Pd/C. The mixture was stirred rt for 2 h under H2 (balloon). The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (0-40% EtOAc/Hex) to afford Intermediate 95B (300 mg, 75% yield). MS(ESI) m/z: 235.1 (M+H)+; ¾ NMR (500MHz, chloroform-d) δ 7.78 - 7.14 (m, 1H), 6.54 - 6.42 (m, 2H), 3.90 (br. s., 2H), 3.61 - 3.40 (m, 2H), 2.96 (t, J=8.5 Hz, 2H), 1.71 - 1.46 (m, 9H).
Figure imgf000175_0002
To a mixture of 4-(dimethylamino)benzoyl chloride (22 mg, 0.12 mmol) and Intermediate 95B (23 mg, 0.098 mmol) in DCM (2 mL) at 0 °C, was added DIEA (0.051 mL, 0.30 mmol). The mixture was stirred rt for lh, then was concentrated. The residue was purified by flash chromatography (0-60% EtOAc/Hex) to afford Intermediate 95C (17 mg, 45.4% yield). MS(ESI) m/z: 382.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.17 - 8.02 (m, 1H), 7.91 - 7.82 (m, 2H), 7.60 (br. s., 1H), 7.15 (d, J=8.6 Hz, 2H), 4.07 - 3.97 (m, 2H), 3.19 - 3.14 (m, 6H), 3.12 - 3.05 (m, 2H), 1.58 (br. s., 9H) Intermediate 95:
Figure imgf000175_0003
Intermediate 95C (17 mg, 0.045 mmol) stirred with TFA and DCM for 20 min, then was concentrated to afford Intermediate 95 (19 mg). MS(ESI) m/z: 282.1 (M+H)+: XH NMR (400MHz, methanol-d4) δ 7.94 - 7.85 (m, 3H), 7.76 - 7.67 (m, 1H), 7.44 (d, J=8.6 Hz, 1H), 6.90 - 6.81 (m, 2H), 3.93 - 3.87 (m, 2H), 3.35 (t, J=7.7 Hz, 2H), 3.07 (s, 6H).
Intermediate 96: 4-(4-Amino-2-chlorophenyl)phthalazin-l(2H)-one
Figure imgf000176_0001
Intermediate 96A: tert-But l 4-bromo-3-chloro hen l carbamate
Figure imgf000176_0002
To a solution of 4-bromo-3-chloroaniline (1.5 g, 7.3 mmol) and B0C2O (2.38 g, 10.9 mmol) in MeOH (20 mL), was added sodium carbonate (1.694 g, 15.98 mmol). The mixture was stirred at rt for 16h. The reaction mixture was concentrated. The residue was suspended in water, then extracted with DCM. The organic phase was concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford
Intermediate 96A (2.0 g, 6.52 mmol, 90% yield). 'H NMR (400MHZ, chloroform-d) δ 7.64 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.08 (dd, J=8.7, 2.5 Hz, 1H), 6.46 (br. s., 1H), 1.53 - 1.51 (m, 9H).
Intermediate 96B: tert-Butyl (3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamate
Figure imgf000176_0003
A mixture of Intermediate 96A (1.96 g, 6.39 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.79 g, 7.03 mmol), and potassium acetate (1.88 g, 19.2 mmol) in dioxane (10 mL). Then PdCl2(dppf) CH2C12 adduct (0.14 g, 0.19 mmol) was added, the reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 16 h. The reaction was quenched with water, extracted with EtOAc, concentrated and purified through via flash chromatography (0-40% EtO Ac/Hex) to Intermediate 96B (1.40 g, 62% yield). MS(ESI) m/z: 298.1 (M-(t-Bu)+2H)+; 'H NMR (400MHz, chloroform-d) δ 7.63 (d, J=8.1 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.18 (dd, J=8.1, 2.0 Hz, 1H), 6.50 (s, 1H), 1.52 (s, 9H), 1.40 - 1.33 (m, 12H).
Intermediate 96C: tert-Butyl (3-chloro-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate
c
Figure imgf000177_0001
To 4-chlorophthalazin- 1 (2H)-one (100 mg, 0.554 mmol), Intermediate 96B (206 mg, 0.581 mmol) and phosphoric acid, potassium salt (294 mg, 1.38 mmol), were added dioxane (5 mL) and water (0.556 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (32 mg, 0.028 mmol) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was concentrated, then purified by flash chromatography (0- 80% EtOAc/Hex) to afford Intermediate 96C (200 mg, 97% yield). (ESI) m/z: 372.0 (M+H)+.
Intermediate 96:
Figure imgf000178_0001
Intermediate 96C (200 mg, 0.538 mmol) was stirred with TFA (2 mL) and DCM (3 ml) at rt for 30 min. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-100% EtO Ac/Hex) to afford Intermediate 96 (120mg, 82% yield). MS(ESI) m/z 272.0 (M+H)+; XH NMR (400MHz, DMSO-d6) δ 12.73 (s, 1H), 8.36 - 8.22 (m, 1H), 7.93 - 7.78 (m, 2H), 7.41 - 7.24 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 6.64 (dd, J=8.4, 2.2 Hz, 1H), 5.75 (s, 1H).
Intermediate 97: N-(3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)indoline- 1 -carboxamide
Figure imgf000178_0002
Intermediat -(4-Bromo-3-methylphenyl)indoline-l -carboxamide
Figure imgf000178_0003
To a solution of l-bromo-4-isocyanato-2-methylbenzene (11 1 mg, 0.523 mmol) in CH2C12 (1 mL), was added indoline (68.6 mg, 0.576 mmol) in CH2C12 (1 mL). The mixture was stirred at rt for lh, then was concentrated. The residue was purified by flash chromatography (0-50% EtOAc/Hex) to afford Intermediate 97A (170 mg, 0.513 mmol, 98% yield) as a white solid. MS(ESI) m/z: 331.0 (M+H)+. Intermediate 97:
Figure imgf000179_0001
A mixture of Intermediate 97A (170 mg, 0.513 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (143 mg, 0.565 mmol), and potassium acetate (151 mg, 1.54 mmol) in dioxane (10 mL). PdCl2(dppf) CH2C12 adduct (11.27 mg, 0.015 mmol) was added, the reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 3 h. The reaction was quenched with water and extracted with EtO Ac. The organic phase was concentrated and the residue was purified via flash chromatography (0-40% EtO Ac/Hex) to afford Intermediate 97 (100 mg, 0.264 mmol, 51.5% yield). MS(ESI) m/z: 379.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 7.89 (d, J=7.9 Hz, IH), 7.74 (d, J=8.1 Hz, IH), 7.33 (d, J=2.0 Hz, IH), 7.26 - 7.16 (m, 3H), 7.01 - 6.93 (m, IH), 6.50 (s, IH), 4.08 (t, J=8.5 Hz, 2H), 3.23 (t, J=8.6 Hz, 2H), 2.54 (s, 3H), 1.35 (s, 12H).
Intermediate 98: Methyl 2-(3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamoyl)-lH-indazol-l-yl)acetate
Figure imgf000179_0002
Intermediate 98A: tert-Butyl 3-((4-bromophenyl)carbamoyl)-lH-indazole-l-carboxylate
Figure imgf000180_0001
To a solution of 4-bromoaniline (63.0 mg, 0.366 mmol), 1 -(I-butoxycarbonyl)- lH-indazole-3-carboxylic acid (96 mg, 0.366 mmol), and HATU (146 mg, 0.384 mmol) in DMF (3 mL), was added DIEA (0.32 mL, 1.83 mmol). The reaction mixture was stirred at rt for 16h, then was diluted with water. The mixture was extracted with EtOAc. The organic phase was washed with 10% LiCl and brine, then concentrated. The residue was purified by flash chromatography (0-20% EtO Ac/Hex) to afford Intermediate 98A (118 mg, 77% yield). MS(ESI) m/z: 416.1 (M+H)+; ¾ NMR (400MHz, chloroform-d) δ 8.98 (s, IH), 8.48 (dt, J=8.0, 0.9 Hz, IH), 8.12 (d, J=8.6 Hz, IH), 7.72 - 7.65 (m, 2H), 7.63 - 7.56 (m, IH), 7.54 - 7.48 (m, 2H), 7.45 (ddd, J=8.1, 7.1, 0.9 Hz, IH), 1.78 (s, 9H).
Intermediate 98B -(4-Bromophenyl)-lH-indazole-3-carboxamide
Figure imgf000180_0002
Intermediate 98A (118 mg, 0.283 mmol) was stirred with TFA (1 mL) and DCM (2 mL) for 30 min at rt, then was concentrated. The residue was purified by flash chromatography (0-50% EtO Ac/Hex) to afford Intermediate 98B (65 mg, 0.206 mmol, 72.5% yield) as a yellow solid. MS(ESI) m/z: 316.0 (M+H)+; XH NMR (400MHz, DMSO-d6) δ 13.80 (br. s., IH), 10.49 (s, IH), 8.22 (d, J=8.1 Hz, IH), 7.99 - 7.84 (m, 2H), 7.67 (d, J=8.4 Hz, IH), 7.57 - 7.49 (m, 2H), 7.46 (ddd, J=8.3, 7.0, 1.0 Hz, IH), 7.34 - 7.24 (m, IH).
Intermediate 98C: Methyl 2-(3-((4-bromophenyl)carbamoyl)-lH-indazol-l-yl)acetate
Figure imgf000181_0001
To a vial containing Intermediate 98B (65 mg, 0.21 mmol) in DMF (3 mL), were added methyl 2-bromoacetate (38 mg, 0.25 mmol) and K2CO3 (43 mg, 0.31 mmol). The vial was sealed and the mixture was stirred at rt for 3h. The reaction mixture was concentrated, then the residue was diluted with water and extracted with EtO Ac. The organic phase was dried over a2S04 and concentrated. The residue was purified by flash chromatography (0-50% EtO Ac/Hex) to afford Intermediate 98C (70 mg, 88% yield) as a yellow solid. MS(ESI) m/z: 388.0 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.80 (s, 1H), 8.44 (dt, J=8.1, 1.0 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.55 - 7.45 (m, 3H), 7.41 - 7.32 (m, 2H), 5.20 (s, 2H), 3.79 (s, 3H).
Intermediate 98:
Figure imgf000181_0002
To a mixture of Intermediate 98C (72 mg, 0.19 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (51.8 mg, 0.204 mmol), and potassium acetate (54.6 mg, 0.556 mmol) in dioxane (10 mL), was added PdCl2(dppf) CH2C12 adduct (4.1 mg, 5.6 μιηοΐ). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 1 10 °C for 3 h. The reaction was diluted with water, then was extracted with EtO Ac. The organic phase was concentrated, then the product was purified by flash chromatography (0-50% EtO Ac/Hex) to afford Intermediate 98 (80 mg, 99% yield) as a colorless oil. MS(ESI) m/z: 388.0 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 8.89 (s, 1H), 8.46 (dt, J=8.1, 1.0 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.81 - 7.73 (m, 2H), 7.53 - 7.43 (m, 1H), 7.35 (td, J=8.1, 1.0 Hz, 2H), 5.21 (s, 2H), 3.78 (s, 3H), 1.36 (s, 12H). Intermediate 99: Methyl 3-(3-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamoyl)-lH-indazol-l-yl)propanoate
Figure imgf000182_0001
According to the procedure for the preparation of Intermediate 98, substituting methyl 3-bromopropanoate for methyl 2-bromoacetate afforded Intermediate 99.
MS(ESI) m/z:450.3 (M+H)+.
Intermediate 100: l-(3-Hydroxy-3-methylbutyl)-N-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-lH-indazole-3-carboxamide
Figure imgf000182_0002
Intermediate 100A: Methyl 3-(3-((4-bromophenyl)carbamoyl)-lH-indazol-l- yl)propanoate
Figure imgf000182_0003
To a vial containing Intermediate 98B (150 mg, 0.474 mmol) in DMF (3 mL), were added methyl 3-bromopropanoate (95 mg, 0.569 mmol) and K2CO3 (98 mg, 0.712 mmol). The vial was sealed and the mixture was stirred at rt for 3h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with EtOAc. The organic phase was dried over Na2S04 and concentrated. The residue was purified by flash chromatography (0-50% EtO Ac/Hex) to afford Intermediate 100A (180 mg, 94% yield). MS(ESI) m/z: 402.2 (M+H)+; ¾ NMR (500MHz, chloroform-d) δ 8.80 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.56 - 7.44 (m, 4H), 7.32 (ddd, J=8.0, 6.9, 0.8 Hz, 1H), 4.71 (t, J=6.9 Hz, 2H), 3.73 - 3.66 (m, 3H), 3.05 (t, J=6.7 Hz, 2H).
Intermediate 100B : N-(4-Bromophenyl)- 1 -(3 -hydroxy-3 -methylbutyl)- 1 H-indazole-3 - carboxami
Figure imgf000183_0001
Intermediate 100A (85 mg, 0.211 mmol) was treated with 3M methylmagnesium chloride (0.704 mL, 2.11 mmol) at 0 °C to afford Intermediate 100B (68 mg, 80% yield) as a colorless oil. MS(ESI) m/z: 402.1 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.84 (s, 1H), 8.40 (dt, J=8.2, 1.0 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.52 - 7.40 (m, 4H), 7.31 (ddd, J=8.1, 6.7, 1.1 Hz, 1H), 4.64 - 4.52 (m, 2H), 2.20 - 2.09 (m, 2H), 1.34 (s, 6H). Intermediate 100:
Figure imgf000183_0002
A mixture of Intermediate 100B (70 mg, 0.17 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (49mg, 0.191 mmol), and potassium acetate (51 mg, 0.52 mmol) in dioxane (10 mL). Then PdCl2(dppf) CH2C12 adduct (3.8 mg, 5.22 μιηοΐ) was added, the reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 3 h. The reaction progress was quenched with water, extracted with EtO Ac. The organic phase was concentrated and was purified by flash chromatography (0-50% EtOAc/Hex) to afford Intermediate 100 (78 mg, 100% yield). MS(ESI) m/z: 450.3.
Intermediate 101 : 1 -(( 1 -(tert-Butoxycarbonyl)piperidin-4-yl)methyl)- 1 H-indazole-3 - carboxylic acid
Figure imgf000184_0001
According to the procedure for the preparation of Intermediate 21, substituting tert-butyl 4-(bromomethyl)piperidine- 1 -carboxylate, hydrobromide for benzyl 4- (bromomethyl)piperidine- 1 -carboxylate afforded Intermediate 101. MS(ESI) m/z: 360.3 (M+H)+; XH NMR (500MHz, methanol-cU) δ 8.14 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.31 - 7.25 (m, 1H), 4.36 (d, J=7.2 Hz, 2H), 4.06 - 3.97 (m, 2H), 2.66 (br. s., 2H), 2.21 (ddt, J=1 1.2, 7.5, 3.8 Hz, 1H), 1.53 - 1.45 (m, 2H), 1.44 - 1.35 (m, 9H), 1.26 - 1.17 (m, 2H). Intermediate 102: 4-(4-Amino-2-methoxyphenyl)phthalazin- 1 (2H)-one, TFA
Figure imgf000184_0002
Intermediate 102A: tert-But l 4-bromo-3-methox hen l carbamate
Figure imgf000184_0003
To a solution of 4-bromo-3-methoxyaniline, HC1 (0.6 g, 2.5 mmol) and B0C2O (0.824 g, 3.77 mmol) in MeOH (10 mL), was added sodium carbonate (0.80 g, 7.55 mmol). The mixture was stirred at rt for 3h. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford
Intermediate 102A (550 mg, 72% yield). MS(ESI) m/z: 302.2 (M+H)+; XH NMR
(400MHz, chloroform-d) δ 7.39 (d, J=8.4 Hz, 1H), 7.32 (s, 1H), 6.63 (dd, J=8.5, 2.3 Hz, 1H), 6.49 (br. s., 1H), 3.91 (s, 3H), 1.55 - 1.48 (m, 9H).
Intermediate 102B: tert-Butyl (3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamate
Figure imgf000185_0001
To a mixture of Intermediate 102A (340 mg, 1.13 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (314 mg, 1.24 mmol), and potassium acetate (331 mg, 3.38 mmol) in dioxane (8 mL), was added PdCl2(dppf) CH2C12 adduct (24.7 mg, 0.034 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 3 h. The reaction was diluted with water and extracted with EtO Ac. The organic phase was concentrated and the residue was purified by flash chromatography (0-50% EtO Ac/Hex) to afford Intermediate 102B (200 mg, 51% yield) as a colorless foam. MS(ESI) m/z: 350.3 (M+H)+; XH NMR (500MHz, chloroform-d) δ 7.59 (d, J=8.0 Hz, 1H), 7.18 (br. s., 1H), 6.81 (br. s., 1H), 6.75 (dd, J=8.1, 1.8 Hz, 1H), 3.81 (s, 3H), 1.54 - 1.48 (m, 9H), 1.36 - 1.31 (m, 12H).
Intermediate 102C: tert-Butyl (3-methoxy-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate
Figure imgf000186_0001
To a 5mL of microwave vial containing solution of Intermediate 102B (155 mg, 0.443 mmol) in dioxane (3 mL) were added potassium phosphate tribasic (235 mg, 1.107 mmol), dioxane (3 mL), water (0.3 mL) and PdCl2(dppf) CH2C12 adduct (36.2 mg, 0.044 mmol) at RT. The reaction was purged with nitrogen and then was heated with microwave at 130 °C for 15 min. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-80% EtOAc/Hex) to afford Intermediate 102C (88 mg, 54% yield). MS(ESI) m/z: 368.2 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 9.83 (s, 1H), 8.47 (dd, J=7.6, 1.2 Hz, 1H), 7.84 - 7.63 (m, 2H), 7.48 (s, 1H), 7.45 - 7.34 (m, 1H), 6.84 (dd, J=8.1, 2.0 Hz, 1H), 6.64 (s, 1H), 3.76 (s, 3H), 1.57 (s, 9H).
Intermediate 1
Figure imgf000186_0002
Intermediate 102C (85 mg, 0.231 mmol) was stirred with TFA (1 ml) and DCM (2 ml) at rt for 30 min, concentrated to give Intermediate 102 (78 mg, 88% yield). MS(ESI) m/z: 268.2 (M+H)+; ¾ NMR (500MHz, methanol-d4) δ 8.42 - 8.37 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.14 (dd, J=8.0, 1.9 Hz, 1H), 3.82 - 3.76 (m, 3H). Intermediate 103: 4-(4-Amino-2-ethoxyphenyl)phthalazin-l(2H)-one
Figure imgf000187_0001
According to the procedure for the preparation of Intermediate 102, substituting 4-bromo-3-ethoxyaniline for 4-bromo-3-methoxyaniline, HCl afforded after flash chromatography (0-90% EtOAc/Hex) Intermediate 103. MS(ESI) m/z: 282.2 (M+H)+; XH NMR (400MHz, DMSO-d6) δ 12.57 (s, 1H), 8.33 - 8.13 (m, 1H), 7.90 - 7.72 (m, 2H), 7.44 - 7.33 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 6.26 (dd, J=7.9, 2.0 Hz, 1H), 5.38 (s, 2H), 3.97 - 3.81 (m, 2H), 0.97 (t, J=7.0 Hz, 3H).
Intermediate 104: 4-(4-A l)phthalazin-l(2H)-one
Figure imgf000187_0002
According to the procedure for the preparation of Intermediate 102, substituting
4-bromo-2-methoxyaniline, HCl for 4-bromo-3-methoxyaniline, HCl afforded after flash chromatography (0-100% EtOAc/Hex) Intermediate 104. MS(ESI) m/z: 268.2 (M+H)+;
XH NMR (400MHz, THF) δ 1 1.64 (br. s., 1H), 8.43 - 8.34 (m, 1H), 7.87 - 7.81 (m, 1H), 7.77 - 7.69 (m, 2H), 7.01 (d, J=1.8 Hz, 1H), 6.91 (dd, J=7.9, 2.0 Hz, 1H), 6.71 (d, J=7.9
Hz, 1H), 3.84 (s, 3H).
Intermediate 105: 4-(4-Amino-3-hydroxyphenyl)phthalazin-l(2H)-one
Figure imgf000188_0001
Intermediate 105A: tert-Butyl (2-methoxy-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate
Figure imgf000188_0002
According to the procedure for the preparation of Intermediate 102C, substituting 4-bromo-2-methoxyaniline, HCl for 4-bromo-3-methoxyaniline, HCl afforded Intermediate 105A.
Figure imgf000188_0003
To a solution of Intermediate 105A (25 mg, 0.068 mmol) in DCM (2 mL), was add boron tribromide (0.34 mL, 0.34 mmol). The mixture was stirred at rt o/n, then was diluted with water and made basic with a2C03. The mixture was extracted with EtOAc, then the organic phase was concentrated. The residue was purified by flash
chromatography (0-100% EtOAc/Hex) to afford Intermediate 105 (8 mg, 46% yield). MS(ESI) m/z: 254.1 (M+H)+; ¾ NMR (400MHz, methanol-d4) δ 7.21 - 7.15 (m, 1H), 6.72 - 6.65 (m, 1H), 6.64 - 6.57 (m, 2H), 5.72 (d, J=1.8 Hz, 1H), 5.70 - 5.58 (m, 2H). Intermediate 106: Methyl 5- ihydrophthalazin-l-yl)benzoate
Figure imgf000189_0001
Intermediate 106A: Methyl 2-bromo-5-((tert-butoxycarbonyl)amino)benzoate
Figure imgf000189_0002
To a solution of methyl 5-amino-2-bromobenzoate (0.45 g, 1.96 mmol) and B0C2O (0.64 g, 2.93 mmol) in MeOH (10 mL), was added sodium carbonate (0.456 g, 4.30 mmol). The mixture was stirred at rt for 16h, then was concentrated. The residue was diluted with water and extracted with DCM. The organic phase was concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Hex) to afford
Intermediate 106A (540 mg, 84% yield). MS(ESI) m/z: 330.1 (M+H)+.
Intermediate 106B: Methyl 5-((tert-butoxycarbonyl)amino)-2-(4,4,5,5-tetramethyl- 1,3 ,2-dioxab
Figure imgf000189_0003
To a mixture of Intermediate 106A (360 mg, 1.09 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (305 mg, 1.20 mmol), and potassium acetate (321 mg, 3.27 mmol) in dioxane (3 mL), was added PdCl2(dppf) CH2CI2 adduct (24 mg 0.033 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 1 10 °C for 3 h. The reaction mixture was diluted with water, then extracted with EtO Ac. The organic phase was concentrated and the residue was purified by flash chromatography (0-40% EtO Ac/Hex) to afford Intermediate 106B (310 mg, 75% yield) as a yellow oil. MS(ESI) m/z: 376.3 (M+H)+; XH NMR (400 MHz, chloroform-d) d ppm 7.95 (1 H, d, J=1.98 Hz), 7.54 (1 H, dd, J=8.14,1.76 Hz), 7.40 (1 H, d, J=7.92 Hz), 7.03 (1 H, s), 3.87 (3 H, s), 1.50 (9 H, s), 1.39 (12 H, s).
Intermediate 106C: Methyl 5-((tert-butoxycarbonyl)amino)-2-(4-oxo-3,4- dihydrophthalazin- 1 -yl)benzoate
Figure imgf000190_0001
To a 5mL of microwave vial containing a solution of Intermediate 106B (92 mg, 0.24 mmol) in dioxane (3 mL) were added 4-chlorophthalazin-l(2H)-one (40 mg, 0.22 mmol), potassium phosphate tribasic (1 18 mg, 0.554 mmol), water (0.3 mL) and PdCl2(dppf) CH2C12 adduct (18.09 mg, 0.022 mmol) at RT. The reaction was purged with nitrogen, sealed and then heated in a microwave reactor at 130 °C for 15 min. The reaction mixture was diluted with water, then was extracted with EtO Ac. The organic phase was concentrated and the residue was purified by flash chromatography (0-80% EtO Ac/Hex) to afford Intermediate 106C (38 mg, 43% yield) as a white solid. MS(ESI) m/z: 396.3 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.44 - 8.38 (m, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.88 - 7.76 (m, 3H), 7.42 (d, J=8.4 Hz, 1H), 7.37 - 7.31 (m, 1H), 3.55 (s, 3H), 1.56 (s, 9H).
Intermediate 106:
Figure imgf000191_0001
Intermediate 106C (66 mg, 0.17 mmol) was stirred with TFA (1 mL) and DCM (1 mL) at rt for 30 min, then was concentrated. The residue was purified by flash chromatography (0-90% EtO Ac/Hex) to afford Intermediate 106 (47 mg, 95% yield). MS(ESI) m/z: 296.2 (M+H)+; ¾ NMR (400MHz, methanol-d4) δ 8.48 - 8.36 (m, 1H), 7.87 - 7.75 (m, 2H), 7.46 - 7.38 (m, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.96 (dd, J=8.1, 2.4 Hz, 1H), 3.49 (s, 3H). -(4-Amino-3-fluorophenyl)phthalazin-l(2H)-one, TFA
Figure imgf000191_0002
To a vial containing 4-chlorophthalazin-l(2H)-one (100 mg, 0.554 mmol), (4- ((ter?-butoxycarbonyl)amino)-3-fluorophenyl)boronic acid (155 mg, 0.609 mmol) and potassium phosphate tribasic (294 mg, 1.38 mmol), were added dioxane (1.8 mL) and water (0.2 mL). The mixture was degassed (evacuated and flushed with Ar (3x)), then was treated with Pd(Ph3P)4 (32 mg, 0.028 mmol). The mixture was degassed (3x), then the vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The mixture was partitioned between EtOAc and H20. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 100% ethyl acetate/hexanes) to afford Intermediate 107A as a white solid (124 mg, 63% yield). MS(ESI) m/z: 356.1 (M+H)+; ¾ NMR (400 MHz, methanol-d4) δ 8.40-8.48 (m, IH), 8.06 (t, J=8.36 Hz, IH), 7.86-7.96 (m, 2H), 7.81-7.86 (m, IH), 7.35-7.43 (m, 2H), 1.56 (s, 9H); 19F NMR (376 MHz, methanol-d4) δ -129.38 (s, IF).
Intermedia
Figure imgf000192_0001
To a suspension of Intermediate 107A (123 mg, 0.346 mmol) in DCM (2 mL), was added TFA (2 mL). The resultant yellow solution was stirred at rt for 1.25 h, then was concentrated to afford Intermediate 107 (128 mg, 100% yield) as a white solid. MS(ESI) m/z: 256.1 (M+H)+; ¾ NMR (400 MHz, methanol-d4) δ 8.39-8.46 (m, IH), 7.82-7.96 (m, 3H), 7.25 (dd, J=1.98, 11.88 Hz, IH), 7.19 (dd, J=1.98, 8.14 Hz, IH), 6.94- 7.04 (m, IH).
Intermedi -(4-Amino-2-(hydroxymethyl)phenyl)phthalazin-l(2H)-one
Figure imgf000192_0002
To a solution of Intermediate 106C (220 mg, 0.556 mmol) in THF (1 mL) was added 2.0 M (in THF) lithium borohydride (0.684 mL, 1.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16h, then was quenched with MeOH and concentrated. The residue was purified by flash chromatography (0-90% EtO Ac/Hex) to afford tert-butyl (3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate (88 mg, 59% yield). The material was stirred with TFA (1 mL) and DCM (1 mL) for 30 min, then was concentrated. The residue was purified by flash chromatography (0-20% MeOH/DCM) to afford Intermediate 108 (88 mg, 59% yield). MS(ESI) m/z: 268.2 (M+H)+; ¾ NMR (400MHz, methanol-d4) δ 8.48 - 8.36 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.54 - 7.41 (m, 1H), 7.23 - 7.15 (m, 2H), 6.93 (dd, J=7.9, 2.6 Hz, 1H), 4.42 (br. s., 2H).
Intermediate 109: l-((Tetrahydro l)-lH-indazole-3-carboxylic acid
Figure imgf000193_0001
Interme -((tetrahydrofuran-2-yl)methyl)-lH-indazole-3-carboxylate
Figure imgf000193_0002
To a vial containing ethyl lH-indazole-3-carboxylate (200 mg, 1.05 mmol) in acetonitrile (3 mL), were added 2-(bromomethyl)tetrahydrofuran (226 mg, 1.37 mmol) and CS2CO3 (514 mg, 1.58 mmol). The vial was sealed and the mixture was stirred at 70 °C overnight. The reaction mixture was diluted with water, then was extracted with EtO Ac. The organic phase was with 10% LiCl and brine, then was concentrated. The residue was purified by flash chromatography (0-60% EtO Ac/Hex) to afford
Intermediate 109A (199 mg, 69% yield). MS(ESI) m/z: 275.2 (M+H)+; 'H NMR
(400MHz, chloroform-d) δ 8.19 (dt, J=8.1, 1.0 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.41 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.29 (ddd, J=8.1, 7.0, 0.9 Hz, IH), 4.64 - 4.47 (m, 4H), 4.40 (qd, J=6.3, 4.5 Hz, IH), 3.81 - 3.63 (m, 2H), 2.05 - 1.94 (m, IH), 1.88 - 1.64 (m, 3H), 1.48 (t, J=7.2 Hz, 3H). Intermedia
Figure imgf000194_0001
To a solution of Intermediate 109A (205 mg, 0.747 mmol) in THF (3 mL), was added 1M lithium hydroxide (2.242 mL, 2.242 mmol), stirred at rt overnight. The reaction mixture was concentrated, then the residue was taken up in water and EtOAc, then acidified with 1 N HC1. The phases were separated, then the aqueous phase was extracted with EtOAc (3x). The combined organic phase was washed with brine, dried (Na2S04) and concentrated to afford Intermediate 109 (175 mg, 95% yield) as a colorless oil. MS(ESI) m/z: 247.1 (M+H)+; 'H NMR (400MHZ, methanol-d4) δ 8.15 (dt, J=8.1, 1.0 Hz, IH), 7.72 (dt, J=8.6, 0.9 Hz, IH), 7.47 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.31 (ddd, J=8.1, 7.0, 0.9 Hz, IH), 4.65 - 4.52 (m, 2H), 4.46 - 4.33 (m, IH), 3.87 - 3.62 (m, 2H), 2.16 - 1.94 (m, IH), 1.93 - 1.65 (m, 3H).
Intermediate 110: 4-(4-Aminophenyl)-7-methoxyphthalazin- 1 (2H)-one, TFA
Figure imgf000194_0002
Intermediate 110A: Ethyl 2-(4-((tert-butoxycarbonyl)amino)benzoyl)-5- methoxybenzoate
Figure imgf000195_0001
(4-((ter?-Butoxycarbonyl)amino)phenyl)boronic acid (915 mg, 3.86 mmol), ethyl 2-bromo-5-methoxybenzoate (500 mg, 1.930 mmol), PEPPSI-IPR catalyst (65.8 mg, 0.096 mmol), and Cs2C03 (1886 mg, 5.79 mmol) were placed in a vial. PhCl (10 mL) was added, and the vial was evacuated and backfilled with CO gas (3x). The mixture was heated with stirring at 80 °C under balloon of CO for 20 h. Most of PhCl was removed under reduced pressure, the residue was purified by flash chromatography (0-70% EtOAc/Hex) to afford Intermediate 110A (308 mg, 40% yield) as an amber oil, which solidified upon standing. MS(ESI) m/z: 400.2 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 9.78 (s, IH), 7.67 - 7.57 (m, 2H), 7.48 (d, J=8.4 Hz, IH), 7.40 (d, J=8.6 Hz, IH),
7.37 (d, J=2.4 Hz, IH), 7.26 (dd, J=8.6, 2.6 Hz, IH), 3.97 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 1.48 (s, 9H), 0.98 (t, J=7.2 Hz, 3H).
Intermediate 110B: tert-Butyl (4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamate
c
Figure imgf000195_0002
Intermediate 110A (308 mg, 0.799 mmol) was placed in a pressure vial, and dioxane (4 mL), and hydrazine hydrate (0.581 mL, 12.0 mmol) were added sequentially. The reaction mixture was stirred at rt for 15 min, and then at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3x), brine, and dried (Na2S04). The organic phase was concentrated and the residue was purified by flash chromatography (5-100% EtOAc/Hex) to afford Intermediate HOB (172 mg, 59% yield) as a white solid. MS(ESI) m/z: 368.1 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ ppm 12.69 (s, IH), 9.56 (s, IH), 7.71 (d, J=2.9 Hz, IH), 7.66 (d, J=8.8 Hz, IH), 7.61 (d, J=8.6 Hz, 2H), 7.49 - 7.42 (m, 3H), 3.95 (s, 3H), 1.50 (s, 9H).
Intermediate 110:
Figure imgf000196_0001
Intermediate HOB (172 mg, 0.468 mmol) was dissolved in TFA (2 mL), and the reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure, the residue triturated with Et20 to give Intermediate 110 (171 mg, 96% yield) as an off- white solid. MS(ESI) m/z: 268.1 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ ppm 12.65 (s, IH), 7.71 (d, J=2.6 Hz, IH), 7.68 (d, J=9.0 Hz, IH), 7.46 (dd, J=9.0, 2.9 Hz, IH), 7.38 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 3.95 (s, 3H).
Intermediate 111: N-(4-(3 -(Dicyclopropylmethyl)-4-oxo-3 ,4-dihydrophthalazin- 1 - yl)phenyl)-lH-pyrazole-4-carboxamide
Figure imgf000196_0002
Intermediate 111A: 4-(4-Bromophenyl)-2-(dicyclopropylmethyl)phthalazin- 1 (2H)-one
Figure imgf000197_0001
Ph3P (4.35 g, 16.60 mmol) was dissolved in dry THF (40 mL), and the stirred reaction mixture was cooled to 0 °C. Afterwards, DIAD (3.23 mL, 16.60 mmol) was added dropwise over 5 min, and the reaction mixture was stirred at 0 °C for 15 min (thick suspension formed). Then, a suspension of 4-(4-bromophenyl)phthalazin-l(2H)-one (2.000 g, 6.64 mmol) and dicyclopropylmethanol (0.979 mL, 8.30 mmol) in dry THF (20 mL) was added, and the reaction mixture was allowed to reach rt, and stirred at rt for 16 h. The reaction mixture was quenched with MeOH (5 mL), diluted with EtOAc (250 mL). Then CELITE® was added, the solvent was removed under reduced pressure and the residue was purified flash chromatography (EtOAc/hexane) to afford 1.396 g (53.2%) of Intermediate 111A as a white solid. MS(ESI) m/z: 395.1 (M+H)+; 'H NMR (400 MHz, DMSO-d6) δ ppm 8.56 - 8.47 (m, 1H), 7.85 - 7.72 (m, 3H), 7.71 - 7.63 (m, 2H), 7.59 - 7.48 (m, 2H), 3.81 (t, J=9.2 Hz, 1H), 1.63 - 1.56 (m, 2H), 0.75 - 0.63 (m, 2H), 0.57 - 0.46 (m, 2H), 0.43 - 0.30 (m, 4H).
Intermediate 11 IB : 4-(4-Aminophenyl)-2-(dicyclopropylmethyl)phthalazin- 1 (2H)-one
Figure imgf000197_0002
The following reaction was carried out behind the blast shield. Intermediate 111A (1.396 g, 3.53 mmol), L-Proline (0.529 g, 4.59 mmol), and cuprous oxide (0.505 g, 3.53 mmol) were placed into a round-bottom flask, and DMSO (20 mL) was added. The reaction mixture was degassed with stirring (3x vacuum/Ar), and sodium azide (0.459 g, 7.06 mmol) was added. The reaction mixture was degassed again (2x vacuum/Ar), and stirred under Ar at 100 °C for 3 h. The reaction mixture was cooled to rt, was quenched with NH4C1 (std. aq, 10 mL), diluted with EtOAc (500 mL) and water (200 mL). Organic phase was separated, washed with a2C03 (aq. std., 2x50 mL), water (1x100 mL), brine (1x50 mL), dried (Na2S04) and filtered. EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (EtOAc/hexane) to afford
Intermediate 111B (0.742 g, 63.4% yield) as an off-white solid. MS(ESI) m/z: 332.1 (M+H)+; XH NMR (400MHz, DMSO-d6) δ ppm 8.34 (dd, J=8.1, 1.3 Hz, 1H), 7.97 - 7.81 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 5.45 (s, 2H), 3.67 (t, J=9.0 Hz, 1H), 1.58 - 1.45 (m, 2H), 0.70 - 0.60 (m, 2H), 0.55 (dq, J=9.4, 4.9 Hz, 2H), 0.40 - 0.29 (m, 2H), 0.18 (dq, J=9.4, 4.9 Hz, 2H).
Intermediate 111:
Figure imgf000198_0001
lH-Pyrazole-4-carboxylic acid (0.301 g, 2.69 mmol) was suspended in DCM (20 mL), and a drop a DMF was added. Then, oxalyl chloride (2 M in DCM) (5.60 mL, 11.19 mmol) was added dropwise, and the reaction mixture was stirred for 2 h at rt (reaction mixture became homogeneous). Then, DCM was removed under reduced pressure, and the obtained acid chloride (white solid) was used in the subsequent step. In a separate flask, to a solution of Intermediate 111B (0.742 g, 2.239 mmol) in THF (20 mL), was added Trimethylsilyl cyanide (2.99 mL, 22.39 mmol). The resultant solution was stirred at rt for 10 min, and then was treated with a solution of lH-pyrazole-4-carboxylic acid chloride obtained as described above in THF (5 mL). The mixture was stirred at 50 °C for 1.5 h. Afterwards, the reaction mixture was concentrated, then trifluoroethanol (10 mL) was added. The mixture was stirred at 70 °C for 15 min, and then concentrated. The obtained reside was purified by flash chromatography (MeOH/DCM) to give 0.781 g (82%) of Intermediate 111. MS(ESI) m/z: 426.1 (M+H)+; 'H NMR (400MHZ, DMSO- d6) δ ppm 13.29 (br. s., 1H), 10.01 (s, 1H), 8.37 (dd, J=7.5, 1.3 Hz, 1H), 8.27 (br. s., 1H), 7.99 - 7.87 (m, 4H), 7.87 - 7.81 (m, 1H), 7.66 (d, J=8.6 Hz, 2H), 3.70 (t, J=9.2 Hz, 1H), 1.61 - 1.47 (m, 2H), 0.72 - 0.61 (m, 2H), 0.57 (dq, J=9.5, 4.8 Hz, 2H), 0.42 - 0.31 (m, 2H), 0.20 (dq, J=9.6, 4.9 Hz, 2H)
Intermediate 112: 5-Methyl-l-phenyl-lH-l,2,3-triazole-4-carboxylic acid
Figure imgf000199_0001
Intermediate 112A: Ethyl 5-methyl-l-phenyl-lH-l,2,3-triazole-4-carboxylate
Figure imgf000199_0002
To the solution of aniline (0.33 g, 3.54 mmol) in acetonitrile (6 mL) at 0 °C was added isoamyl nitrite (0.524 mL, 3.90 mmol), followed by azidotrimethylsilane (0.513 mL, 3.90 mmol) dropwise. After 5 min, the cold bath removed, and the reaction was stirred at rt for 10 min, then ethyl but-2-ynoate (0.795 g, 7.09 mmol) added, and the reaction stirred in a sealed tube at 80 °C for 20 h, then cooled to rt. The reaction mixture was concentrated, then the residue was purified via preparative HPLC to afford
Intermediate 112A (50 mg, 6% yield). MS(ESI) m/z: 232.0 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 7.63 - 7.55 (m, 3H), 7.49 - 7.41 (m, 2H), 4.47 (q, J=7.0 Hz, 2H), 2.60 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).
Intermediate 1
Figure imgf000199_0003
Intermediate 112A (36 mg, 0.16 mmol) was mixed with 1M lithium hydroxide (0.3 mL, 0.3 mmol) in THF (2 mL) and MeOH (2 mL), stirred rt for 2h. The reaction mixture was concentrated and the residue was purified via preparative HPLC to afford Intermediate 112 (26 mg, 82% yield). MS(ESI) m/z: 204.1 (M+H)+; 'H NMR (400MHZ, methanol-cU) δ 7.70 - 7.61 (m, 3H), 7.60 - 7.52 (m, 2H), 2.59 - 2.54 (m, 3H).
Intermediate 113: l-(4-Methoxyphenyl)-5-methyl-lH-l,2,3-triazole-4-carboxylic acid
Figure imgf000200_0001
Intermediate 113A: Ethyl l-(4-methoxyphenyl)-5-methyl-lH-l,2,3-triazole-4- carboxylate
Intermediate 113B: Ethyl l-(4-methoxyphenyl)-4-methyl-lH-l,2,3-triazole-5- carboxylate
Figure imgf000200_0002
Intermediate 113A Intermediate 113B To the solution of 4-methoxyaniline (0.31 g, 2.5 mmol) in acetonitrile (6 mL) at 0
°C was added isoamyl nitrite (0.372 mL, 2.77 mmol), followed by azidotrimethylsilane (0.364 mL, 2.77 mmol) dropwise. After 5 min, the cold bath removed, and the reaction was stirred at rt for 10 min, then ethyl but-2-ynoate (0.564 g, 5.03 mmol) was added, and the reaction stirred in a sealed tube at 80 °C. The reaction was stirred at 80 °C for 20 h, then cooled to rt. The reaction mixture was concentrated, then the residue was purified via preparative HPLC to afford Intermediate 113A (60 mg, 9% yield) and Intermediate 113B (22 mg, 3% yield). Intermediate 113A: MS(ESI) m/z: 262.2 (M+H)+; 'H NMR (400MHZ, chloroform-d) δ 7.36 - 7.30 (m, 2H), 7.06 - 7.00 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 3.86 ( 3H), 2.53 (s, 3H), 1.42 (t, J=7.2 Hz, 3H).
Intermediate 113B: MS(ESI) m/z: 262.2 (M+H)+; XH NMR (400MHz, chloroform-d) δ 7.37 - 7.31 (m, 2H), 7.03 - 6.97 (m, 2H), 4.27 (q, J=7.0 Hz, 2H), 3.87 ( 3H), 2.62 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).
Intermediate
Figure imgf000201_0001
Intermediate 113A (60 mg, 0.23 mmol) was mixed with 1M lithium hydroxide
(0.5 mL, 0.5 mmol) in THF (1 mL) and MeOH (1 mL). The reaction mixture was stirred rt for 3h. The reaction mixture was concentrated and the residue was purified via preparative HPLC to afford Intermediate 113 (48 mg, 90% yield) as a white solid. MS(ESI) m/z: 234.0 (M+H)+; ¾ NMR (400MHz, methanol-d4) δ 7.48 - 7.41 (m, 2H), 7.17 - 7.11 (m, 2H), 3.88 (s, 3H), 2.52 (s, 3H).
Intermed oxylic acid
Figure imgf000201_0002
Intermediate 113B (22 mg, 0.084 mmol) was mixed with 1M lithium hydroxide (0.2 mL, 0.2 mmol) in THF (1 mL) and MeOH (1 mL) and was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was acidified with TFA. The mixture was concentrated and the residue was purified by flash chromatography (0-20%
MeOH/DCM) to afford Intermediate 114. MS(ESI) m/z: 234.0 (M+H)+; XH NMR (400MHz, methanol-cU) δ 7.45 - 7.24 (m, 2H), 7.08 - 6.90 (m, 2H), 3.87 (s, 3H), 2.58 (s, 3H).
Example 1: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-l(2H)-one
Figure imgf000202_0001
To 4-chlorophthalazin- 1 (2H)-one (9.9 mg, 0.055 mmol), Intermediate 8 (14 mg, 0.050 mmol) and potassium phosphate (26.4 mg, 0.125 mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (2.9 mg, 2.5 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated, then was purified by preparative HPLC to afford 4.4 mg (18%) of Example 1. MS(ESI) m/z: 382.20 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.82 (s, 1H), 8.42 - 8.29 (m, 1H), 7.96 - 7.84 (m, 2H), 7.77 - 7.67 (m, 1H), 7.61 - 7.52 (m, 2H), 7.52 - 7.43 (m, 2H), 7.41 - 7.36 (m, 2H), 7.36 - 7.27 (m, 2H), 4.98 (s, 2H), 4.70 (s, 2H), 3.89 (s, 2H); Analytical HPLC RT = 1.51 min (Method E), 1.52 min (Method F).
Example 2: 4-(4-(2-(5-Fluoroisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin- 1 (2H)-one
Figure imgf000202_0002
According a method similar to the preparation of Example 1, substitution of isoindoline with 5-fluoroisoindoline afforded Example 2. MS(ESI) m/z: 400.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.82 (s, 1H), 8.38 - 8.31 (m, 1H), 7.93 - 7.86 (m, 2H), 7.74 - 7.69 (m, 1H), 7.66 - 7.36 (m, 5H), 7.23 (d, J=9.1 Hz, 1H), 7.18 - 7.10 (m, 1H), 4.95 (d, J=16.8 Hz, 2H), 4.68 (d, J=16.8 Hz, 2H), 3.87 (s, 2H); Analytical HPLC RT = 1.53 min (Method E), 1.52 min (Method F).
Example -(4-(2-(5-Methoxyisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin- 1 (2H)-one
Figure imgf000203_0001
To a solution of Intermediate 1 (25 mg, 0.089 mmol) in DMF (3 mL), was added 5-methoxyisoindoline (20 mg, 0.134 mmol), PyBOP (69.6 mg, 0.134 mmol), and DIEA (0.078 mL, 0.446 mmol). The mixture was stirred at rt for 2h, then was purified by preparative HPLC to afford 28.1 mg (59%) of Example 3. MS(ESI) m/z: 412.2 (M+H)+; XH NMPv (500MHz, DMSO-d6) δ 12.82 (s, 1H), 8.36 - 8.31 (m, 1H), 7.93 - 7.86 (m, 2H), 7.73 - 7.68 (m, 1H), 7.55 (d, J=7.7 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.3, 4.4 Hz, 1H), 6.95 (d, J=l 1.6 Hz, 1H), 6.88 (dd, J=8.4, 1.8 Hz, 1H), 4.95 - 4.86 (m, 2H), 4.69 - 4.59 (m, 2H), 3.87 (s, 2H), 3.75 (s, 3H); Analytical HPLC RT = 1.61 min (Method E), 1.61 min (Method F).
The following Examples in Table 1 were made by using the same procedure as shown in Example 3. Intermediate 1 was coupled with the appropriate amine. Various coupling reagents could be used other than the one described in Example 3 such as BOP, PyBop, EDC/HOBt or HATU.
Figure imgf000204_0001
Table 1
Figure imgf000204_0002
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Example 36: 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phi
-2-yl)ethanone
Figure imgf000218_0001
To a vial containing Intermediate 4 (34.8 mg, 0.091 mmol), 4-chlorophthalazin- l(2H)-one (15 mg, 0.083 mmol) and potassium phosphate (44 mg, 0.21 mmol), were added dioxane (0.9 mL) and water (0.1 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). To this mixture was added Pd(Ph3P)4 (4.8 mg, 4.2 μιηοΐ). The mixture was degassed (3x), then the vial was sealed. The vial was heated in a microwave reactor at 150 °C for 25 min. The mixture was concentrated, then was diluted with 4 mL 1 : 1 DMSO/MeOH. TFA (0.1 mL) was added, then the suspension was filtered and the solid collected. The solid was washed with H20 (~5 mL), then MeOH (~5 mL), sucked dry and dried in vacuo to afford 34.8 mg (42%) of Example 36 as a white solid.
MS(ESI) m/z: 400.0 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.89 (s, 1H), 8.38 - 8.32 (m, 1H), 7.92 (quind, J=7.1, 1.7 Hz, 2H), 7.76 - 7.71 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.43 (dd, J=10.5, 1.4 Hz, 1H), 7.41 - 7.37 (m, 3H), 7.35 - 7.30 (m, 2H), 5.02 (s, 2H), 4.71 (s, 2H), 3.92 (s, 2H); HPLC RT = 7.96 min (Method A), 8.02 min (Method B). -(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-l(2H)-one
Figure imgf000218_0002
To a vial containing Intermediate 5 (34.8 mg, 0.091 mmol), 4-chlorophthalazin- l(2H)-one (15 mg, 0.083 mmol) and potassium phosphate (44.1 mg, 0.208 mmol), were added dioxane (0.9 mL) and water (0.1 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). To this mixture was added Pd(Ph3P)4 (4.8 mg, 4.15 μιηοΐ). The mixture was degassed (3x), then the vial was sealed. The vial was heated in a microwave reactor at 150 °C for 25 min. The reaction mixture separated into two phases upon cooling. The organic phase was collected and was purified by preparative HPLC to afford 1 1.7 mg (35%) of Example 37. MS(ESI) m/z: 400.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.94 (br. s., IH), 8.37 - 8.29 (m, IH), 7.92 - 7.86 (m, 2H), 7.65 - 7.49 (m, 4H), 7.45 - 7.28 (m, 4H), 4.99 (s, 2H), 4.71 (s, 2H), 3.93 (s, 2H); HPLC RT = 1.56 min (Method E), 1.52 min (Method F).
Example 38: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-l(2H)-one
Figure imgf000219_0001
According to the procedure for the preparation of Example 36, coupling of
Intermediate 6 (30 mg, 0.13 mmol) and Intermediate 9 (51 mg, 0.14 mmol) afforded 17 mg (33%) of Example 38. MS(ESI) m/z: 381.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 1 1.43 (d, J=5.8 Hz, IH), 8.29 (dd, J=8.1, 1.2 Hz, IH), 7.69 (td, J=7.7, 1.4 Hz, IH), 7.61 - 7.51 (m, 2H), 7.44 - 7.35 (m, 6H), 7.33 - 7.28 (m, 2H), 7.08 (s, IH), 4.97 (s, 2H), 4.69 (s, 2H), 3.84 (s, 2H); HPLC RT = 8.20 min (Method A), 7.53 min (Method B).
Figure imgf000219_0002
According to the procedure for the preparation of Example 3, coupling of
Intermediate 11 (13 mg, 0.044 mmol) and indoline (7.9 mg, 0.066 mmol) using HATU afforded 8.2 mg (46%) of Example 42. MS(ESI) m/z: 396.15 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 12.85 (s, 1H), 8.38 - 8.30 (m, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.74 - 7.68 (m, 1H), 7.62 - 7.55 (m, J=8.4 Hz, 2H), 7.55 - 7.49 (m, J=8.4 Hz, 2H), 7.20 (d, J=7.4 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.02 - 6.94 (m, 1H), 4.37 (td, J=10.4, 6.4 Hz, 1H), 4.23 (q, J=6.4 Hz, 1H), 3.91 - 3.75 (m, 1H), 3.16 - 3.00 (m, 2H), 1.46 (d, J=6.4 Hz, 3H); HPLC RT = 1.77 min (Method E), 1.75 min (Method F). -(4-(l -(Isoindolin-2-yl)- 1 -oxopropan-2-yl)phenyl)phthalazin- 1 (2H)-one
Figure imgf000220_0001
According to the procedure for the preparation of Example 3, coupling of
Intermediate 11 (13 mg, 0.044 mmol) and isoindoline (7.9 mg, 0.066 mmol) using HATU afforded 9.0 mg (52%) of Example 43. MS(ESI) m/z: 396.15 (M+H)+; 'H NMR (500MHz, 1 : 1 CD30D/CDC13) δ 8.49 - 8.43 (m, 1H), 7.90 - 7.83 (m, 2H), 7.83 - 7.78 (m, 1H), 7.61 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.35 - 7.23 (m, 4H), 5.04 (d, J=13.9 Hz, 1H), 4.92 - 4.85 (m, 1H), 4.83 - 4.77 (m, 1H), 4.66 (d, J=13.9 Hz, 1H), 4.09 (q, J=6.9 Hz, 1H), 1.58 (d, J=6.9 Hz, 3H). Example 44: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-2,3 -dihydro- lH-indene-2- carboxamide
Figure imgf000221_0001
Example 44 A: N-(4-Bromophenyl)-2,3-dihydro-lH-indene-2-carboxamide
Figure imgf000221_0002
To a solution of 2,3-dihydro-lH-indene-2-carboxylic acid (141 mg, 0.872 mmol) in DMF (3 mL), were added 4-bromoaniline (150 mg, 0.872 mmol), PyBOP (499 mg, 0.959 mmol), and DIEA (0.457 mL, 2.62 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc, washed with 10% LiCl, IN HC1 and brine. The crude product was purified via flash
chromatography to afford 90 mg (33%) of Example 44A. MS(ESI) m/z: 316.0 (M+H)+.
Example 44B: N-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro- l -indene-2-carboxamide
Figure imgf000221_0003
A mixture of Example 44A (62 mg, 0.20 mmol), bis(pinacolato)diboron (74.7 mg, 0.294 mmol), and potassium acetate (57.7 mg, 0.588 mmol) in dioxane (3 mL) was degassed (3x vacuum/Ar). PdC dppf) (¾(¾ adduct (4.3 mg, 5.9 μιηοΐ) was added. The reaction mixture was degassed again (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction mixture was filtered and concentrated to afford 40 mg (56%) of Example 44B, which was used as is in the following step. MS(ESI) m/z: 364.2 (M+H)+. Example 44:
Figure imgf000222_0001
To 4-chlorophthalazin-l(2H)-one (28.3 mg, 0.157 mmol), Example 44B (40 mg, 0.1 1 mmol) and potassium phosphate (76 mg, 0.36 mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (8.2 mg, 7.1 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated, then was purified by preparative HPLC to yield 17.1 mg (24%) of Example 44. MS(ESI) m/z: 382.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.38 - 8.31 (m, 1H), 7.93 - 7.85 (m, 2H), 7.84 - 7.79 (m, J=8.5 Hz, 2H), 7.76 - 7.69 (m, 1H), 7.59 - 7.50 (m, J=8.5 Hz, 2H), 7.24 (dd, J=5.1, 3.4 Hz, 2H), 7.15 (dd, J=5.4, 3.2 Hz, 2H), 3.46 (t, J=8.5 Hz, 1H), 3.21 (dd, J=8.4, 3.2 Hz, 4H); HPLC RT = 1.67 min (Method E), 1.66 min (Method F).
Example 45: N-(4-(4-Oxo-3,4-dihydrophthalazin- 1 -yl)phenyl)-2-(pyridin-4-yl)thiazole- 4-carboxamide
Figure imgf000223_0001
To a mixture of Intermediate 3 (25 mg, 0.105 mmol), 2-(pyridin-4-yl)thiazole-4- carboxylic acid (44 mg, 0.21 mmol), and HATU (60 mg, 0.16 mmol) in THF (1 mL), were added DIEA (0.046 mL, 0.26 mmol) and DMF (1 mL). The mixture was stirred at rt for 2h, then was concentrated. The crude product was purified via preparative HPLC to afford 25 mg (36%) of Example 45. MS(ESI) m/z: 426.0 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.84 (s, 1H), 10.53 (s, 1H), 8.86 (d, J=4.1 Hz, 2H), 8.73 (s, 1H), 8.44 - 8.32 (m, 1H), 8.25 (d, J=6.1 Hz, 2H), 8.12 - 8.02 (m, 2H), 7.97 - 7.86 (m, 2H), 7.82 - 7.76 (m, 1H), 7.68 - 7.60 (m, 2H); HPLC RT = 5.13 min (Method A), 5.69 min (Method B).
The following Examples in Table 2 were made by using the same procedure as shown in Example 45. Intermediate 3 was coupled with the appropriate carboxylic acid. Various coupling reagents could be used other than the one described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.
Figure imgf000224_0001
Figure imgf000224_0002
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Example 68: 4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl isoindoline-2-carboxylate
Figure imgf000232_0001
-Bromophenyl isoindoline-2-carboxylate
Figure imgf000232_0002
To a solution of isoindoline (167 mg, 1.401 mmol) and DIEA (0.445 mL, 2.55 mmol) in (¾(¾ (3 mL), was added 4-bromophenyl carbonochloridate (300 mg, 1.274 mmol). The mixture was stirred at rt for lh, then was quenched with water. The mixture was diluted with EtOAc (100 mL), then was washed with IN HC1, sat a2C03 and brine, dried over Na2S04, and concentrated. The crude product was purified via flash chromatography to afford 310 mg (76%) of Example 68A. MS(ESI) m/z: 318.0 (M+H)+; XH NMR (500MHz, CDC13) δ 7.53 - 7.48 (m, 2H), 7.36 - 7.29 (m, 4H), 7.13 - 7.07 (m, 2H), 4.94 (s, 2H), 4.84 (s, 2H). Example 68B: (4-((Isoindoline-2-carbonyl)oxy)phenyl)boronic acid
Figure imgf000232_0003
dioxane, 110 °C
A mixture of Example 68A (100 mg, 0.314 mmol), bis(pinacolato)diboron (104 mg, 0.409 mmol), and potassium acetate (93 mg, 0.943 mmol) in dioxane (3 mL) was degassed (3x vacuum/Ar). PdC dppf) CH2CI2 adduct (6.90 mg, 9.43 μιηοΐ) was added, then the reaction mixture was degassed again (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction was concentrated and purified via preparative HPLC to afford 75 mg (84%) of Example 68B. MS(ESI) m/z: 284.1 (M+H)+; ¾ NMR (400MHz, CD3OD) δ 7.83 - 7.76 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.40 - 7.28 (m, 4H), 7.24 - 7.10 (m, 2H), 4.95 (s, 2H), 4.78 (s, 2H).
Example 68:
Figure imgf000233_0001
To 4-chlorophthalazin-l(2H)-one (18.24 mg, 0.101 mmol), Example 68B (26 mg, 0.092 mmol) and potassium phosphate (48.7 mg, 0.230 mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (5.31 mg, 4.59 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The crude product was purified by preparative HPLC to afford 9 mg (20%) of Example 68. MS(ESI) m/z: 384.2 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.86 (s, 1H), 8.45 - 8.29 (m, 1H), 7.92 (qd, J=7.3, 5.8 Hz, 2H), 7.75 - 7.69 (m, 1H), 7.67 - 7.59 (m, 2H), 7.46 - 7.37 (m, 4H), 7.36 - 7.28 (m, 2H), 4.96 (s, 2H), 4.76 (s, 2H); HPLC RT = 1.77 min (Method E), 1.78 min (Method F). Example 69: 4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl 3-phenylpyrrolidine-l- carboxylate
Figure imgf000233_0002
-Bromophenyl 3-phenylpyrrolidine-l-carboxylate
Figure imgf000234_0001
To a mixture of 3-phenylpyrrolidine (141 mg, 0.956 mmol) and DIEA (0.223 mL, 1.274 mmol) in CH2CI2 (3 mL) at 0 °C, was added 4-bromophenyl carbonochloridate (150 mg, 0.637 mmol). The mixture was stirred at rt for lh.The reaction mixture was quenched with water and EtOAc (100 mL) was added. The organic phase was washed with IN HC1, sat a2C03 and brine, dried over Na2S04, concentrated and purified flash chromatography to afford 210 mg (95%) of Example 69A. MS(ESI) m/z: 345.9 (M+H)+; XH NMR (500MHz, CDC13) δ 7.56 - 7.44 (m, 2H), 7.40 - 7.34 (m, 2H), 7.31 - 7.26 (m, 3H), 7.09 - 6.99 (m, 2H), 4.12 - 3.94 (m, 1H), 3.89 - 3.73 (m, 1H), 3.64 (td, J=10.2, 6.7 Hz, 1H), 3.60 - 3.40 (m, 3H), 2.36 (ddtd, J=18.5, 12.4, 6.3, 2.6 Hz, 1H), 2.18 - 2.01 (m, 1H). Example 69B: 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl 3- phenylpyrrolidine- 1 -carboxylate
Figure imgf000234_0002
To a mixture of Example 69A (210 mg, 0.607 mmol), bis(pinacolato)diboron (185 mg, 0.728 mmol), and potassium acetate (179 mg, 1.820 mmol) in dioxane (5 mL), was added PdC dppf) CH2CI2 adduct (13.31 mg, 0.018 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was concentrated, then purified via flash chromatography (EtOAc/hexanes) to afford 220 mg (92%) of Example 69B. MS(ESI) m/z: 394.2 (M+H)+; XH NMR (500MHz, CDC13) δ 7.86 (dd, J=7.8, 3.7 Hz, 2H), 7.42 - 7.35 (m, 2H), 7.33 - 7.26 (m, 3H), 7.22 (t, j=7.0 Hz, 2H), 4.13 - 3.99 (m, 1H), 3.92 - 3.77 (m, 1H), 3.72 - 3.41 (m, 3H), 2.38 (t, J=13.1 Hz, 1H), 2.19 - 2.07 (m, 1H), 1.37 (s, 12H).
Example 69:
Figure imgf000235_0001
To 4-chlorophthalazin- 1 (2H)-one (28 mg, 0.16 mmol), Example 69B (79 mg, 0.20 mmol) and potassium phosphate (82 mg, 0.39 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (9.0 mg, 7.8 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 35 min. The reaction mixture was concentrated, then was purified by preparative HPLC to afford 8.2 mg (10%) of the Example 69. MS(ESI) m/z: 412.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.85 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 7.99 - 7.86 (m, 2H), 7.70 (d, J=7.4 Hz, 1H), 7.62 (dd, J=8.5, 3.9 Hz, 2H), 7.44 - 7.30 (m, 6H), 7.29 - 7.19 (m, 1H), 4.13 - 3.97 (m, 1H), 3.97 - 3.76 (m, 1H), 3.72 - 3.59 (m, 1H), 3.55 - 3.42 (m, 2H), 2.42 - 2.26 (m, 1H), 2.17 - 1.99 (m, 1H); HPLC RT = 1.73 min (Method E), 1.74 min (Method F).
Example 70: 4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl 5-methoxyisoindoline-2- carboxylate
Figure imgf000235_0002
E -Bromophenyl 5-methoxyisoindoline-2-carboxylate
Figure imgf000236_0001
To a solution of 5-methoxyisoindoline (80 mg, 0.54 mmol) and DIEA (0.18 mL, 1.02 mmol) in CH2CI2 (3 mL) at 0 °C, was added 4-bromophenyl carbonochloridate (120 mg, 0.51 mmol). The reaction mixture was stirred rt for lh, then was quenched with water. The mixture was diluted with EtOAc (100 mL). The organic phase was washed with IN HC1, sat. a2C03 and brine, dried over Na2S04, and concentrated. The crude product was purified via flash chromatography to afford 112 mg (63%) of Example 70A. MS(ESI) m/z: 348.0 (M+H)+; ¾ NMR (500MHz, CDC13) δ 7.55 - 7.45 (m, 2H), 7.19 (dd, J=12.2, 8.4 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.88 (dd, J=8.4, 2.3 Hz, 1H), 6.82 (dd, J=10.5, 1.9 Hz, 1H), 4.87 (d, J=16.2 Hz, 2H), 4.78 (d, J=17.1 Hz, 2H), 3.83 (s, 3H).
Example 70B: 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl 5- methoxyisoindoline-2-carboxylate
Figure imgf000236_0002
To a mixture of Example 70A (112 mg, 0.322 mmol), bis(pinacolato)diboron (98 mg, 0.39 mmol), and potassium acetate (95 mg, 0.97 mmol) in dioxane (10 mL), was added PdC dppf) CH2CI2 adduct (7.1 mg, 9.7 μιηοΐ). The reaction mixture was degassed (3x vacuum/ Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction was diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was purified via flash chromatography to afford 100 mg (79%) of Example 70B. MS(ESI) m/z: 396.2 (M+H)+; ¾ NMR (500MHz, CDC13) δ 7.85 (d, J=8.3 Hz, 2H), 7.25 - 7.15 (m, 3H), 6.92 - 6.80 (m, 2H), 4.89 (d, J=16.5 Hz, 2H), 4.79 (d, J=18.2 Hz, 2H), 3.83 (s, 3H), 1.44 - 1.32 (m, 12H).
Example 70:
Figure imgf000237_0001
To 4-chlorophthalazin-l(2H)-one (13 mg, 0.072 mmol), Example 70B (29.9 mg, 0.076 mmol) and potassium phosphate (38.2 mg, 0.180 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (4.2 mg, 3.6 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated, then was purified via preparative HPLC to afford 9 mg (23%) of Example 70. MS(ESI) m/z: 414.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.86 (s, 1H), 8.35 (dd, J=7.6, 1.2 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.76 - 7.70 (m, 1H), 7.68 - 7.61 (m, J=8.5 Hz, 2H), 7.43 - 7.36 (m, J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 6.99 (br. s., 1H), 6.91 (d, J=8.3 Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 3.81 - 3.72 (m, 3H); HPLC RT = 9.48 min (Method A), 8.98 min (Method B).
Example 71: 4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl 5-fluoroisoindoline-2- carboxylate
Figure imgf000237_0002
Example 71A: 4-Bromophenyl 5-fluoroisoindoline-2-carboxylate
Figure imgf000238_0001
To a mixture of 5-fluoroisoindoline (141 mg, 1.03 mmol) and DIEA (0.326 mL, 1.87 mmol) in CH2CI2 (3 mL) at 0 °C, was added 4-bromophenyl carbonochloridate (220 mg, 0.934 mmol). The mixture was stirred at rt for lh, then was quenched with water. The mixture was diluted with EtOAc (100 mL), then was washed with IN HC1, sat a2C03 and brine, dried over Na2S04, and concentrated. The crude product was purified via flash chromatography (EtOAc/hexanes) to afford 190 mg (61%) of Example 71A. MS(ESI) m/z: 414.1 (M+H)+; ¾ NMR (500MHz, CDC13) δ 7.56 - 7.46 (m, 2H), 7.34 - 7.21 (m, 1H), 7.16 - 7.07 (m, 2H), 7.05 - 6.97 (m, 2H), 4.92 (d, J=14.0 Hz, 2H), 4.82 (d, J=14.0 Hz, 2H).
Example 71B: 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl 5- fluoroisoindoline-2-carboxylate
Figure imgf000238_0002
To a mixture of Example 71 A (182 mg, 0.541 mmol), bis(pinacolato)diboron
(165 mg, 0.65 mmol), and potassium acetate (159 mg, 1.62 mmol) in dioxane (4 mL), was added PdCl2(dppf) CH2CI2 adduct (11.9 mg, 0.016 mmol). The reaction mixture was degassed (3x vacuum/Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was concentrated and the residue was purified via flash chromatography to afford 150 mg (72%) of
Example 71B. MS(ESI) m/z: 384.2 (M+H)+; 'H NMR (500MHZ, CDCI3) δ 7.88 - 7.83 (m, 2H), 7.28 - 7.19 (m, 3H), 7.09 - 6.95 (m, 2H), 4.93 (d, J=14.3 Hz, 2H), 4.82 (d, J=14.0 Hz, 2H), 1.43 - 1.34 (m, 12H). Example 71:
Figure imgf000239_0001
To 4-chlorophthalazin- 1 (2H)-one (20 mg, 0.1 1 mmol), Example 71B (44.6 mg, 0.1 16 mmol) and potassium phosphate (58.8 mg, 0.277 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (6.4 mg, 5.5 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated and the residue purified via preparative HPLC to afford 5 mg (8%) of Example 71. MS(ESI) m/z: 402.1 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.86 (s, 1H), 8.39 - 8.32 (m, 1H), 7.95 - 7.89 (m, 2H), 7.75 - 7.69 (m, 1H), 7.66 - 7.60 (m, 2H), 7.44 - 7.35 (m, 4H), 7.29 - 7.15 (m, 4H), 4.94 (d, J=17.3 Hz, 2H), 4.74 (d, J=17.1 Hz, 2H); HPLC RT = 9.62 min (Method A), 9.15 min (Method B).
Example 72: 4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl 5-((4-methylpiperazin-l- yl)methyl)isoindoline-2-carboxylate, 2 TFA
Figure imgf000239_0002
Example 72A: 4-Bromophenyl 5-((4-methylpiperazin-l-yl)methyl)isoindoline-2- carboxylate, 2 TFA
Figure imgf000239_0003
To a solution of Intermediate 2 (196 mg, 0.849 mmol) and DIEA (0.297 mL, 1.70 mmol) in CH2CI2 (3 mL) at 0 °C, was added 4-bromophenyl carbonochloridate (200 mg, 0.849 mmol). The mixture was stirred at rt for Ih.The reaction mixture was quenched with water and diluted with EtOAc (100 mL). The organic phase was washed with IN HC1, sat a2C03 and brine, dried over Na2S04 and concentrated. The crude product was purified by flash chromatography, followed by preparative HPLC to afford 280 mg (50%) of Example 72A. MS(ESI) m/z: 430.1 (M+H)+; XH NMR (500MHz, CD3OD) δ 7.60 - 7.51 (m, 2H), 7.49 - 7.38 (m, 3H), 7.21 - 7.10 (m, 2H), 4.96 (s, 2H), 4.79 (s, 2H), 4.15 (s, 2H), 3.49 (br. s., 4H), 3.30 - 3.19 (m, 4H), 2.94 (s, 3H).
Example 72B: 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl 5-((4- methylpiperazin- 1 -yl)methyl)isoindoline-2-carboxylate
Figure imgf000240_0001
To a mixture of Example 72A (70 mg, 0.106 mmol), bis(pinacolato)diboron (32.4 mg, 0.128 mmol), and potassium acetate (31.3 mg, 0.319 mmol) in dioxane (10 mL), was added PdCi2(dppf) CH2CI2 adduct (2.3 mg, 3.2 μιηοΐ). The reaction mixture was degassed (3x vacuum/ Ar), sealed in a vial and heated at 110 °C for 2 h. The reaction was quenched with water, then extracted with EtOAc. The organic phase was concentrated to afford 80 mg of Example 72B, which was used as is in the following step without further purification. MS(ESI) m/z: 478.4 (M+H)+.
Example 72:
Figure imgf000240_0002
To a vial containing 4-chlorophthalazin-l(2H)-one (22 mg, 0.12 mmol), Example 72B (80 mg, 0.106 mmol) and potassium phosphate (64.6 mg, 0.305 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (7.0 mg, 6.1 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated and purified via preparative HPLC to afford 22 mg (25%) of Example 72. MS(ESI) m/z: 496.2 (M+H)+; XH NMR (500MHz, DMSO- d6) δ 12.86 (s, 1H), 8.43 - 8.31 (m, 1H), 8.02 - 7.86 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.47 - 7.34 (m, 4H), 7.30 (d, J=7.4 Hz, 1H), 4.95 (s, 2H), 4.76 (br. s., 2H), 3.65 (br. s., 2H), 2.99 (br. s., 4H), 2.77 (br. s., 3H), 2.36 (br. s., 2H); HPLC RT = 4.32 min (Method A), 5.17 min (Method B).
Example 73 : 4-(4-((5-Phenyloxazol-2-yl)amino)phenyl)phthalazin- 1 (2H)-one
Figure imgf000241_0001
-(4-Bromophenyl)-5-phenyloxazol-2-amine
Figure imgf000241_0002
To a solution of 2-azido-l-phenylethanone (Angew. Chem. Int. Ed., 46:4489-4491
(2007)) (126 mg, 0.782 mmol) and l-bromo-4-isothiocyanatobenzene (167 mg, 0.782 mmol) in dioxane (4 mL) at 80 °C, was added triphenylphosphine (205 mg, 0.782 mmol). The mixture was stirred at 85 °C for 30 min, then was cooled to rt. The reaction mixture was concentrated. The solid was recrystallized from hot CH3C1 (~5 mL). The precipitate was suspended in EtOAc (~3 mL), filtered and collected to afford 134 mg (54%) of Example 73A as a white solid. MS(ESI) m/z: 315.0 (M+H)+; XH NMR (400MHz, CD3OD) δ 7.62 - 7.57 (m, 2H), 7.51 - 7.46 (m, 2H), 7.46 - 7.41 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.26 (dt, J=7.4, 1.3 Hz, 1H), 7.24 (s, 1H).
Example 73B: 5-Phenyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)oxazol-2-amine
Figure imgf000242_0001
To a vial containing Example 73A (136 mg, 0.432 mmol), bis(pinacolato)diboron (164 mg, 0.647 mmol) and potassium acetate (127 mg, 1.30 mmol), was added dioxane (2 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). PdCl2(dppf)
CH2CI2 adduct (17.6 mg, 0.022 mmol) was added, then the mixture was degassed (2x), then was sealed. The mixture was stirred at 1 10 °C for 2 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with H20 and brine, dried (Na2S04) and concentrated. The crude product was purified by flash chromatography (gradient from 0 to 50% ethyl acetate/hexanes) to afford 122 mg (78%) of Example 73B as a white solid. MS(ESI) m/z: 363.1 (M+H)+; XH NMR (400MHz, CDC13) δ 7.81 (d, J=8.8 Hz, 2H), 7.55 (dd, J=8.3, 1.2 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.42 - 7.36 (m, 2H), 7.29 - 7.23 (m, 1H), 7.18 (s, 1H), 1.35 (s, 12H).
Example 73:
Figure imgf000242_0002
To 4-chlorophthalazin- 1 (2H)-one (36.7 mg, 0.203 mmol), Example 73B (67 mg, mmol) and potassium phosphate (98 mg, 0.46 mmol) in dioxane (3 mL) and water (0.5 mL), was added Pd(PPh3)4 (10.7 mg, 9.25 μιηοΐ). The mixture was degassed (3x), then the reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The crude product was purified by preparative HPLC to afford 9.7 mg (11%) of Example 73. MS(ESI) m/z: 381.1 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.78 (s, 1H), 10.60 (s, 1H), 8.40 - 8.30 (m, 1H), 7.96 - 7.87 (m, 2H), 7.84 - 7.73 (m, 3H), 7.62 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.33 - 7.24 (m, 1H); HPLC RT = 8.99 min (Method A), 8.46 min (Method B).
Example 74: 4-(4-((4-Phenylthiazol-2-yl)amino)phenyl)phthalazin-l(2H)-one
Figure imgf000243_0001
-(4-Bromophenyl)-4-phenylthiazol-2-amine
Figure imgf000243_0002
2-Bromo-l-phenylethanone (105 mg, 0.528 mmol) and l-(4- bromophenyl)thiourea (122 mg, 0.528 mmol) were mixed in glycerol (5 mL) and stirred at 90 °C for 2 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was concentrated and purified via flash chromatography (EtOAc/hexanes) to afford 165 mg (94%) of Example 74A. MS(ESI) m/z: 331.0 (M+H)+; 'H NMR (500MHz, CDC13) δ 7.87 - 7.82 (m, 2H), 7.44 - 7.38 (m, 4H), 7.36 - 7.31 (m, 1H), 7.29 - 7.22 (m, 2H), 6.84 (s, 1H).
Example 74B: 4-Phenyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)thiazol-2-amine
Figure imgf000244_0001
To a mixture of Example 74A (160 mg, 0.483 mmol), bis(pinacolato)diboron (147 mg, 0.580 mmol), and potassium acetate (142 mg, 1.45 mmol) in dioxane (10 mL), was added PdC dppf) (¾(¾ adduct (10.6 mg, 0.014 mmol). The reaction mixture was degassed (3x vacuum/ Ar), sealed in a vial and heated at 1 10 °C for 2 h. The reaction was diluted with water and extracted with EtOAc. The organic phase was concentrated and the product purified via flash chromatography to afford 130 mg (71%) of Example 74B. MS(ESI) m/z: 379.0 (M+H)+.
Figure imgf000244_0002
To 4-chlorophthalazin-l(2H)-one (18 mg, 0.10 mmol), Example 74B (45.2 mg, 0.120 mmol) and potassium phosphate (53 mg, 0.25 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (5.8 mg, 5.0 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 35 min. The reaction mixture was concentrated, then was purified by preparative HPLC to afford 2.0 mg (3.9%) of Example 74. MS(ESI) m/z: 397.0 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.78 (s, 1H), 10.53 (s, 1H), 8.39 - 8.31 (m, 1H), 8.01 - 7.86 (m, 6H), 7.81 (d, J=7.4 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.48 - 7.38 (m, 3H), 7.37 - 7.30 (m, 1H); HPLC RT = 1.85 min (Method E), 1.90 min (Method F).
Example 75: 4-(4-(Benzo[d]oxazol-2-ylamino)phenyl)phthalazin-l(2H)-one
Figure imgf000245_0001
Intermediate 3 (35 mg, 0.100 mmol), 2-chlorobenzo[d]oxazole (0.015 mL, 0.130 mmol), and DIEA (0.087 mL, 0.498 mmol) were dissolved in NMP (1 mL) and the reaction mixture was heated in a capped vial at 150 °C for 18 h. The reaction mixture was purified by preparative HPLC to afford 5.0 mg (14%) of Example 75. MS(ESI) m/z: 355.05 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 10.90 (br. s., 1H), 8.39 - 8.30 (m, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.93 - 7.87 (m, 2H), 7.80 - 7.76 (m, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (dd, J=16.6, 7.7 Hz, 2H), 7.28 - 7.22 (m, 1H), 7.19 - 7.14 (m, 1H); HPLC RT = 1.58 min (Method E), 1.64 min (Method F).
Example 76: N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)indoline- 1 -carboxamide
Figure imgf000246_0001
To 4-chlorophthalazin- 1 (2H)-one (29 mg, 0.16 mmol), Intermediate 10 and potassium phosphate (85 mg, 0.40 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (9.28 mg, 8.03 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was concentrated and purified via preparative HPLC to afford 6.1 mg (9.4%) of Example 76. MS(ESI) m/z: 383.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.81 (s, 1H), 8.74 (s, 1H), 8.34 (dd, J=7.7, 1.2 Hz, 1H), 8.00 - 7.85 (m, 3H), 7.76 (d, J=8.9 Hz, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 4.18 (t, J=8.7 Hz, 2H), 3.20 (t, J=8.7 Hz, 2H); HPLC RT = 1.65 min (Method E), 1.66 min (Method F). Example 77: N-(4-(l -Oxo- l,2-dihydroisoquinolin-4-yl)phenyl)indoline-l -carboxamide
Figure imgf000247_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 6 (28 mg, 0.125 mmol) and Intermediate 10 (54.6 mg, 0.150 mmol) afforded 7.5 mg (16%) of Example 77. MS(ESI) m/z: 382.1 (M+H)+; 'H NMR
(500MHz, DMSO-d6) δ 11.41 (br. s., IH), 8.63 (s, IH), 8.30 (d, J=8.0 Hz, IH), 7.89 (d, J=8.3 Hz, IH), 7.75 - 7.66 (m, 3H), 7.59 - 7.51 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.21 (d, J=7.4 Hz, IH), 7.13 (t, J=7.7 Hz, IH), 7.07 (s, IH), 6.91 (t, J=7.3 Hz, IH), 4.17 (t, J=8.5 Hz, 2H), 3.20 (t, J=8.3 Hz, 2H); HPLC RT = 1.77 min (Method E), 1.73 min (Method F).
Example 78: 4- {4-[(Quinazolin-2-yl)amino]phenyl}-l,2-dihydrophthalazin-l-one, TFA
Figure imgf000248_0001
According to the procedure for the preparation of Example 75, Intermediate 3 (35 mg, 0.100 mmol) was reacted with 2-chloroquinazoline at 150 °C for 40 h to afford 4.1 mg (8.6%) of Example 78. MS(ESI) m/z: 366.2 (M+H)+; XH-NMR: (500 MHz,
DMSO-d6) 5 ppm 12.78 (s, 1H), 10.14 (s, 1H), 9.37 (s, 1H), 8.38 - 8.31 (m, 1H), 8.19 (d, J=8.5 Hz, 2H), 7.96 (d, J=7.7 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.84 - 7.78 (m, 2H), 7.72 (d, J=8.3 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.42 (t, J=7.3 Hz, 1H); HPLC RT = 1.45 min (Method E), 1.70 min (Method F). -(4-(Quinazolin-2-ylamino)phenyl)phthalazin-l(2H)-one, TFA
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin- 1 (2H)-one (25 mg, 0.14 mmol) and Intermediate 12 (60.0 mg, 0.152 mmol) afforded 2.5 mg (4.3%) of Example 79. MS(ESI) m/z: 413.2 (M+H)+; XH NMR (500MHz, DMSO-d6) d 12.79 (br. s., IH), 8.72 (s, IH), 8.38 - 8.30 (m, IH), 8.01 - 7.86 (m, 2H), 7.76 (d, J=8.5 Hz, 3H), 7.60 - 7.49 (m, 3H), 7.09 (d, J=8.3 Hz, IH), 6.49 (dd, J=8.3, 2.5 Hz, IH), 4.19 (t, J=8.7 Hz, 2H), 3.72 (s, 3H), 3.12 (t, J=8.5 Hz, 2H); HPLC RT = 1.67 min (Method E), 1.67 min (Method F).
Example 80 : 6-Methoxy-N-(4-( 1 -oxo- 1 ,2-dihydroisoquinolin-4-yl)phenyl)indoline- 1 - carboxamide
Figure imgf000249_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 6 (29 mg, 0.129 mmol) and Intermediate 12 (61.2 mg, 0.155 mmol) afforded 5.9 mg (1 1%) of Example 80. MS(ESI) m/z: 412.2 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 11.42 (br. s., IH), 8.63 (s, IH), 8.30 (d, J=8.0 Hz, IH), 7.75 - 7.66 (m, 3H), 7.60 - 7.51 (m, 3H), 7.35 (d, J=8.5 Hz, 2H), 7.11 - 7.03 (m, 2H), 6.48 (dd, J=8.1, 2.3 Hz, IH), 4.18 (t, J=8.5 Hz, 2H), 3.72 (s, 3H), 3.1 1 (t, J=8.5 Hz, 2H); HPLC RT = 1.47 min (Method E), 1.48 min (Method F).
Example 81 : (R)-N-(2,3 -Dihydro- 1 H-inden- 1 -yl)-2-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 - yl)phenyl)acetamide
Figure imgf000250_0001
According to the procedure for the preparation of Example 3, coupling of
Intermediate 1 (25 mg, 0.089 mmol) with (R)-2,3-dihydro-lH-inden-l -amine (14.3 mg, 0.107 mmol) afforded 13.7 mg (38%) of Example 81. MS(ESI) m/z: 396.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.38 - 8.32 (m, 1H), 7.94 - 7.85 (m, 2H), 7.74 - 7.68 (m, 1H), 7.58 - 7.52 (m, 2H), 7.50 - 7.45 (m, 2H), 7.29 - 7.24 (m, 1H), 7.24 - 7.14 (m, 3H), 5.29 (q, J=7.8 Hz, 1H), 3.64 - 3.54 (m, 2H), 2.99 - 2.90 (m, 1H), 2.86 - 2.76 (m, 1H), 2.46 - 2.37 (m, 1H), 1.81 (dq, J=12.7, 8.4 Hz, 1H); HPLC RT = 1.58 min (Method E), 1.60 min (Method F).
Example 82 : (5)-N-(2,3 -Dihydro- 1 H-inden- 1 -yl)-2-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 - yl)phenyl)acetamide
Figure imgf000251_0001
According to the procedure for the preparation of Example 3, coupling of
Intermediate 1 (25 mg, 0.089 mmol) with (5)-2,3-dihydro-lH-inden-l-amine (14.3 mg, 0.107 mmol) afforded 19.7 mg (56%) of Example 82. MS(ESI) m/z: 396.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.38 - 8.31 (m, 1H), 7.94 - 7.86 (m, 2H), 7.75 - 7.68 (m, 1H), 7.58 - 7.52 (m, 2H), 7.50 - 7.45 (m, 2H), 7.28 - 7.24 (m, 1H), 7.24 - 7.14 (m, 3H), 5.29 (q, J=7.9 Hz, 1H), 3.65 - 3.54 (m, 2H), 2.99 - 2.91 (m, 1H), 2.81 (dt, J=16.0, 8.3 Hz, 1H), 2.46 - 2.37 (m, 1H), 1.81 (dq, J=12.5, 8.4 Hz, 1H); HPLC RT = 1.63 min (Method E), 1.63 min (Method F).
Example 83: 4-(4-(2-(6-(Benzyloxy)indolin-l-yl)-2-oxoethyl)phenyl)phthalazin-l(2H)- one
Figure imgf000252_0001
According to the procedure for the preparation of Example 3, coupling of
Intermediate 1 (56 mg, 0.20 mmol) with 6-(benzyloxy)indoline (71.2 mg, 0.21 mmol) afforded 38 mg (38%) of Example 83. MS(ESI) m/z: 488.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.40 - 8.30 (m, 1H), 7.99 - 7.81 (m, 3H), 7.76 - 7.69 (m, 1H), 7.60 - 7.53 (m, 2H), 7.50 - 7.44 (m, J=8.0 Hz, 2H), 7.44 - 7.40 (m, 2H), 7.39 - 7.34 (m, 2H), 7.34 - 7.26 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.66 (dd, J=8.1, 2.3 Hz, 1H), 5.05 (s, 2H), 4.24 (t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.10 (t, J=8.3 Hz, 2H); HPLC RT = 10.56 min (Method A), 9.34 min (Method B).
Figure imgf000252_0002
Intermediate 13 (50 mg, 0.12 mmol), benzo[d]thiazol-2-amine (17.8 mg, 0.1 19 mmol), di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,r-biphenyl]-2-yl)phosphine (7.6 mg, 0.016 mmol), Pd2(dba)3 (3.3 mg, 3.6 μιηοΐ) and K2C03 (23 mg, 0.17 mmol) were added in a pressure vial. The reaction mixture was degassed (3x vacuum/Ar), and then tBuOH (1 mL) and AcOH (1 drop) were added. The reaction mixture was degassed again, capped, and stirred at 110 °C for 3 h. The reaction mixture was diluted with MeOH/DMSO, filtered and purified by preparative HPLC to afford 4-(4-
(benzo[d]thiazol-2-ylamino)phenyl)-2-(4-methoxybenzyl)phthalazin-l(2H)-one (45.9 mg, 79% yield) as a white solid. MS(ESI) m/z: 491.1 (M+H)+; XH NMR (400 MHz, DMSO- d6) δ ppm 10.77 (br. s., IH), 8.38 (br. s., IH), 7.99 (d, J=7.9 Hz, 2H), 7.92 (d, J=3.3 Hz, 2H), 7.85 (d, J=7.7 Hz, 2H), 7.69 - 7.56 (m, 3H), 7.35 (d, J=6.2 Hz, 3H), 7.19 (t, J=7.0 Hz, IH), 6.90 (d, J=7.9 Hz, 2H), 5.32 (br. s., 2H), 3.71 (s, 3H). The residue was dissolved in TFA (3 mL) and was sealed vial and was heated in a microwave reactor at 150 °C for 30 min. The reaction mixture was evaporated and was purified by preparative HPLC to afford 2.3 mg (6%) of Example 84. MS(ESI) m/z: 371.1 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (s, IH), 10.72 (s, IH), 8.35 (d, J=7.4 Hz, IH), 7.98 (d, J=8.5 Hz, 2H), 7.94 - 7.89 (m, 2H), 7.85 (d, J=8.0 Hz, IH), 7.79 (d, J=7.7 Hz, IH), 7.65 (d, J=8.0 Hz, IH), 7.61 (d, J=8.5 Hz, 2H), 7.36 (t, j=7.7 Hz, IH), 7.19 (t, j=7.6 Hz, IH); HPLC RT = 1.68 min (Method E), 1.84 min (Method F).
Example 85: 4-(4-(Phthal l)phthalazin- 1 (2H)-one
Figure imgf000253_0001
According to the procedure for the preparation of Example 84, Intermediate 13 (50 mg, 0.12 mmol) and 1 -chlorophthalazine (25.3 mg, 0.154 mmol) afforded after coupling and deprotection 6.6 mg (40%) of Example 85. MS(ESI) m/z: 366.1 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, IH), 9.39 (s, IH), 9.20 (s, IH), 8.65 (d, J=8.0 Hz, IH), 8.36 (d, J=7.7 Hz, IH), 8.16 (d, J=8.3 Hz, 2H), 8.09 - 8.05 (m, IH), 8.03 (d, J=7.7 Hz, IH), 8.02 - 7.97 (m, IH), 7.96 - 7.88 (m, 2H), 7.84 (d, J=7.7 Hz, IH), 7.61 (d, J=8.5 Hz, 2H); HPLC RT = 1.07 min (Method E), 1.40 min (Method F).
Example 86: 4- {4-[(5-Methyl-l,3-benzoxazol-2-yl)amino]phenyl}-l,2- - 1 -one
Figure imgf000254_0001
According to the procedure for the preparation of Example 76, coupling of 2- chloro-5-methylbenzo[d]oxazole (25.05 mg, 0.149 mmol) and Intermediate 12 (35 mg, 0.10 mmol) afforded 6.8 mg (18%) of Example 86. MS(ESI) m/z: 469.2 (M+H)+; XH NMR (500MHz, DMSO-d6) d 12.80 (br. s., IH), 8.34 (d, J=7.7 Hz, IH), 7.97 - 7.84 (m, 4H), 7.78 (d, J=7.7 Hz, IH), 7.61 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, IH), 7.29 (s, IH), 6.96 (d, J=8.3 Hz, IH), 2.38 (s, 3H); HPLC RT = 1.75 min (Method E), 1.81 min (Method F). Ex -(4-((5-Phenyl-l,3,4-thiadiazol-2-yl)amino)phenyl)phthalazin-l(2H)-one
Figure imgf000254_0002
Intermediate 14 (50 mg, 0.14 mmol) and 2-chloro-5 -phenyl- 1, 3, 4-thiadiazole (33 mg, 0.17 mmol) were dissolved in dry THF (2 mL). Then, LiHMDS (1 M in THF) (0.364 mL, 0.364 mmol) was added dropwise to the stirred reaction mixture. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled to rt, quenched with MeOH (1 niL), and concentrated under reduced pressure. The residue was redissolved in TFA (3 mL), and stirred at 150 °C for 15 min under microwave irradiation. TFA was evaporated, then the residue was purified by prep HPLC to afford 14.1 mg (25%) of Example 87. MS(ESI) m/z: 498.1 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (s, 1H), 10.79 (br. s., 1H), 8.35 (d, J=7.4 Hz, 1H), 7.98 - 7.87 (m, 4H), 7.85 (d, J=8.0 Hz, 2H), 7.78 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.56 - 7.48 (m, 3H); HPLC RT = 1.67 min (Method E), 1.68 min (Method F). -(4-((5-Phenylthiazol-2-yl)amino)phenyl)phthalazin-l(2H)-one
Figure imgf000255_0001
According to the procedure for the preparation of Example 87, coupling of
Intermediate 14 (40 mg, 0.112 mmol) and 2-chloro-5-phenylthiazole (26.3 mg, 0.134 mmol) afforded after TFA deprotection and HPLC purification 1.3 mg (3%) on Example 88. MS(ESI) m/z: 397.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1H), 10.59 (br. s., 1H), 8.34 (d, J=7.2 Hz, 1H), 7.96 - 7.87 (m, 2H), 7.85 - 7.76 (m, 3H), 7.74 (s, 1H), 7.56 (d, J=7.7 Hz, 4H), 7.40 (t, J=7.2 Hz, 2H), 7.31 - 7.24 (m, 1H); HPLC RT = 1.74 min (Method E), 1.95 min (Method F).
The following Examples in Table 3 were made by using the same procedure as shown in Example 45. Intermediate 3 was coupled with the appropriate carboxylic acid. Various coupling reagents could be used other than the one described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.
Figure imgf000256_0001
Table 3
Figure imgf000256_0002
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
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
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Example 244: 3-(Dimethylamino)-N-[4-(l-oxo-l,2-dihydroisoquinolin-4- yl)phenyl]benzamide, TFA
Figure imgf000315_0001
Intermediate 66 (15 mg, 0.043 mmol), 3-(dimethylamino)benzoic acid (14 mg,
0.086 mmol), and HATU (24 mg, 0.064 mmol) were dissolved in DMF (1 mL). DIEA (0.037 mL, 0.21 mmol) was added, then the mixture was stirred at rt for 24 h. The mixture was concentrated, then was purified by prep HPLC to afford Example 244 (9 mg, 41% yield). MS(ESI) m/z: 384.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 11.43 (d, J=5.8 Hz, 1H), 10.24 (s, 1H), 8.30 (dd, J=8.0, 0.8 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.77 - 7.68 (m, 1H), 7.60 - 7.52 (m, 2H), 7.49 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 7.29 - 7.20 (m, 2H), 7.09 (d, J=5.8 Hz, 1H), 6.99 - 6.91 (m, 1H), 2.98 (s, 6H); HPLC RT = 5.63 min (Method A), 5.22 min (Method B). Example 245: 4-(Dimethylamino)-N-(4-(l-oxo-l,2-dihydroisoquinolin-4- yl)phenyl)benzamide, formate salt
Figure imgf000316_0001
According to the procedure for the preparation of Example 244, coupling of
Intermediate 66 (15 mg, 0.043 mmol) and 4-(dimethylamino)benzoic acid (14.15 mg, 0.086 mmol) afforded Example 245 (2.1 mg, 11% yield). MS(ESI) m/z: 384.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.42 (d, J=4.4 Hz, 1H), 9.98 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.5 Hz, 4H), 7.71 (t, J=7.6 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.38 (d, J=7.7 Hz, 2H), 7.08 (d, J=5.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 3.01 (s, 6H); HPLC RT = 1.51 min (Method E), 1.71 min (Method F).
Example 246: N-(4-(l-Oxo-l,2-dihydroisoquinolin-4-yl)phenyl)-4,5,6,7- tetrahydrobenzo[d]thiazole-2-carboxamide
Figure imgf000316_0002
According to the procedure for the preparation of Example 244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and 4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxylic acid (12 mg, 0.064 mmol) afforded Example 246 (7.9 mg, 46% yield).
MS(ESI) m/z: 402.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 11.51 (br. s., 1H), 10 (br. s., 1H), 8.29 (d, J=7.2 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.71 (br. s., 1H), 7.58 - 7.51 2H), 7.47 - 7.37 (m, J=7.7 Hz, 2H), 7.10 (br. s., 1H), 2.95 - 2.81 (m, 4H), 1.85 (br. s 4H); HPLC RT = 2.02 min (Method E), 2.02 min (Method F).
Example 247: N-(4-(l-Oxo-l,2-dihydroisoquinolin-4-yl)phenyl)benzo[c]isoxazole-3- carboxamide
Figure imgf000317_0001
According to the procedure for the preparation of Example 244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and benzo[c]isoxazole-3-carboxylic acid (10.5 mg, 0.064 mmol) afforded Example 247 (4 mg, 19% yield). MS(ESI) m/z: 382.0 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 11.46 (br. s., IH), 11.25 (br. s., IH), 8.31 (d, J=8.0 Hz, IH), 8.05 (d, J=8.8 Hz, IH), 8.00 (d, J=6.9 Hz, 2H), 7.83 (d, J=9.1 Hz, IH), 7.72 (br. s., IH), 7.56 (d, J=7.2 Hz, 3H), 7.47 (d, J=6.9 Hz, 2H), 7.39 - 7.31 (m, IH), 7.13 (d, J=5.5 Hz, IH); HPLC RT = 8.83 min (Method A), 7.54 min (Method B). Example 248: l-Methyl-N-(4-(l-oxo-l,2-dihydroisoquinolin-4-yl)phenyl)-lH-indole-2- carboxamide
Figure imgf000317_0002
According to the procedure for the preparation of Example 244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and 1 -methyl- lH-indole-2-carboxylic acid (11.3 mg, 0.064 mmol) afforded Example 248 (1.4 mg, 8% yield). MS(ESI) m/z: 394.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 11.44 (br. s., IH), 10.44 (br. s., IH), 8.31 (d, J=7.7 Hz, IH), 7.92 - 7.88 (m, J=7.7 Hz, 2H), 7.71 (br. s., 2H), 7.64 - 7.51 (m, 3H), 7.48 - 7.40 (m, J=7.7 Hz, 2H), 7.37 - 7.29 (m, 2H), 7.15 (t, J=7.0 Hz, IH), 7.10 (br. s., IH), 4.04 (br. s., 3H); HPLC RT = 1.96 min (Method E), 1.94 min (Method F). Example 249 : N-(4-( 1 -Oxo- 1 ,2-dihydroisoquinolin-4-yl)phenyl)-4-(piperidin- 1 - yl)benzamide
Figure imgf000318_0001
According to the procedure for the preparation of Example 244, coupling of Intermediate 66 (15 mg, 0.043 mmol) and 4-(piperidin-l-yl)benzoic acid (12 mg, 0.059 mmol) afforded Example 249 (4.8 mg, 26% yield). MS(ESI) m/z: 424.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.43 (br. s., IH), 10.03 (br. s., IH), 8.30 (d, J=7.7 Hz, IH), 7.93 - 7.85 (m, 4H), 7.75 - 7.67 (m, IH), 7.58 - 7.49 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.08 (s, IH), 7.00 (d, J=8.3 Hz, 2H), 1.60 (br. s., 6H); HPLC RT = 1.39 min (Method E), 1.97 min (Method F).
Example 250: 4-Morpholino-N-(4-(l-oxo-l,2-dihydroisoquinolin-4- yl)phenyl)benzamide
Figure imgf000318_0002
According to the procedure for the preparation of Example 244, coupling of
Intermediate 66 (13 mg, 0.037 mmol) and 4-morpholinobenzoic acid (11.54 mg, 0.056 mmol) afforded Example 250 (3.7 mg, 22% yield). MS(ESI) m/z: 422.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.41 (br. s., IH), 10.08 (br. s., IH), 8.30 (d, J=8.0 Hz, IH), 8.02 - 7.86 (m, 4H), 7.71 (t, J=7.4 Hz, IH), 7.60 - 7.52 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.11 - 7.02 (m, 3H), 3.76 (br. s., 4H), 3.27 (br. s., 4H); HPLC RT = 1.51 min (Method E), 1.51 min (Method F). Example 251 : N-(4-( 1 -Oxo- 1 ,2-dihydroisoquinolin-4-yl)phenyl)-4-(pyrrolidin- 1 - yl)benzamide
Figure imgf000319_0001
According to the procedure for the preparation of Example 244, coupling of Intermediate 66 (13 mg, 0.037 mmol) and 4-(pyrrolidin- 1 -yl)benzoic acid (10.65 mg, 0.056 mmol) afforded Example 251 (0.4 mg, 3% yield). MS(ESI) m/z: 410.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 9.95 (br. s., 1H), 8.30 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 4H), 7.76 - 7.67 (m, 1H), 7.59 - 7.51 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.61 (d, J=8.3 Hz, 2H), 3.90 (s, 1H), 1.99 (br. s., 4H); HPLC RT = 1.92 min (Method E), 1.91 min (Method F).
Example 252: 4-(4-(2-(5-Methoxy-7-methylindolin-l-yl)-2-oxoethyl)phenyl)phthalazin- -one
Figure imgf000319_0002
Intermediate 1 (15 mg, 0.038 mmol), 5-methoxy-7-methylindoline (9.3 mg,
0.057 mmol), and HATU (21.8 mg, 0.057 mmol) were dissolved in DMF (1 mL). The this mixture was added DIEA (0.017 mL, 0.095 mmol). The mixture was stirred at rt overnight, then was concentrated. The residue was purified by prep HPLC to afford
Example 252 (11 mg, 65% yield). MS(ESI) m/z: 426.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.34 (d, J=6.9 Hz, 1H), 7.98 - 7.85 (m, 2H), 7.71 (d, J=6.6 Hz, 1H), 7.63 - 7.54 (m, J=7.4 Hz, 2H), 7.50 - 7.42 (m, J=7.4 Hz, 2H), 6.72 (br. s., 1H), 6.57 (br. s., 1H), 4.12 (t, J=7.0 Hz, 2H), 4.00 (br. s., 2H), 3.71 (s, 3H), 2.97 (t, J=6.9 Hz, 2H), 2.13 (s, 3H); HPLC RT = 1.77 min (Method E), 1.76 min (Method F).
Example 253: 4-(4-(2-(7-Bromo-5-(trifluoromethoxy)indolin-l-yl)-2- - 1 (2H)-one
Figure imgf000320_0001
According to the procedure for the preparation of Example 252, coupling of Intermediate 1 (15 mg, 0.038 mmol) and 7-bromo-5-(trifluoromethoxy)indoline, HCl (18.2 mg, 0.057 mmol) afforded Example 253 (11 mg, 54% yield). MS(ESI) m/z: 544.1 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 8.34 (d, J=6.9 Hz, 1H), 8.00 - 7.82 (m, 2H), 7.71 (d, J=6.9 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.51 - 7.43 (m, 3H), 7.40 (br. s., 1H), 4.22 (t, J=7.3 Hz, 2H), 4.06 (s, 2H), 3.15 (t, J=7.2 Hz, 2H); HPLC RT = 2.08 min (Method E), 2.06 min (Method F). Example 254: 4-(4-(2-(6-Ethoxyindolin-l-yl)-2-oxoethyl)phenyl)isoquinolin-l(2H)-one
t
Figure imgf000320_0002
According to the procedure for the preparation of Example 252, coupling of Intermediate 67 (12 mg, 0.043 mmol) and 6-ethoxyindoline (0.430 mL, 0.086 mmol) afforded Example 254 (10.5 mg, 55% yield). MS(ESI) m/z: 425.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.44 (br. s., 1H), 8.30 (d, J=7.7 Hz, 1H), 7.75 (br. s., 1H), 7.73 7.66 (m, 1H), 7.54 (d, J=7.7 Hz, 2H), 7.40 (s, 4H), 7.13 - 7.05 (m, 2H), 6.55 (d, J=8.0 Hz, 1H), 4.23 (t, J=7.8 Hz, 2H), 3.95 (q, J=6.6 Hz, 2H), 3.91 (br. s., 2H), 3.08 (t, J=8.0 Hz, 2H), 1.29 (t, J=6.7 Hz, 3H); HPLC RT = 1.95 min (Method E), 1.95 min (Method F). Example 255: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)-6,7-dimethoxyisoquinolin- l(2H)-one
Figure imgf000321_0001
To Intermediate 68 (20 mg, 0.070 mmol), Intermediate 9 (25.6 mg, 0.070 mmol) and K3PO4 (37.4 mg, 0.176 mmol), were added dioxane (3 mL) and water (0.333 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (4.1 mg, 3.5 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The reaction mixture was concentrated then was purified by prep HPLC to afford Example 255 (7.5 mg, 24% yield). MS(ESI) m/z: 441.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 11.30 (br. s., 1H), 7.68 (s, 1H), 7.50 - 7.33 (m, 6H), 7.31 (br. s., 2H), 6.98 (br. s., 2H), 4.96 (br. s., 2H), 4.69 (br. s., 2H), 3.95 - 3.86 (m, 3H), 3.84 (br. s., 2H), 3.72 (s, 3H); HPLC RT = 1.62 min (Method E), 1.62 min (Method F).
Example 256: 4-(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin- 1 (2H)- one
Figure imgf000321_0002
According to the procedure for the preparation of Example 255, coupling of Intermediate 5 (37 mg, 0.098 mmol) and 4-bromoisoquinolin-l(2H)-one (20 mg, 0.089 mmol) afforded Example 256 (6.6 mg, 18% yield). MS(ESI) m/z: 339.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.50 (br. s., IH), 8.28 (d, J=8.0 Hz, IH), 7.69 (t, J=7.4 Hz, IH), 7.53 (t, J=7.3 Hz, IH), 7.37 (d, J=4.4 Hz, 3H), 7.34 - 7.20 (m, 5H), 7.16 (br. s., IH), 4.98 (br. s., 2H), 4.70 (br. s., 2H), 3.88 (br. s., 2H); HPLC RT = 1.72 min (Method E), 1.70 min (Method F).
Example 257: N-(4-(6,7-Dimethoxy-l-oxo-l,2-dihydroisoquinolin-4-yl)phi
- 1 -carboxamide
Figure imgf000322_0001
According to the procedure for the preparation of Example 255, coupling of
Intermediate 12 (33 mg, 0.084 mmol) and Intermediate 68 (20 mg, 0.070 mmol) afforded Example 257 (8.9 mg, 27% yield). MS(ESI) m/z: 472.1 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 11.28 (br. s., IH), 8.61 (br. s., IH), 7.95 (br. s., IH), 7.74 - 7.66 (m, 3H), 7.55 (br. s., IH), 7.40 (d, J=8.0 Hz, 2H), 7.08 (d, J=7.7 Hz, IH), 7.03 - 6.93 (m, 2H), 6.48 (d, J=8.0 Hz, IH), 4.17 (t, J=8.1 Hz, 2H), 3.89 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.1 1 (t, J=8.3 Hz, 2H); HPLC RT = 1.71 min (Method E), 1.70 min (Method F).
Example 258: 4-(4-(2-(6-Isopropoxyindolin-l-yl)-2-oxoethyl)phenyl)phthalazin-l(2H)- one
Figure imgf000322_0002
To a solution of Intermediate 1 (12 mg, 0.043 mmol), Intermediate 69 (12.5 mg, 0.043 mmol), and HATU (24.4 mg, 0.064 mmol) in DMF (1 mL), was add DIEA (0.037 mL, 0.21 mmol). The mixture was stirred rt for 16h, then the mixture was purified via prep HPLC to afford Example 258 (13 mg; 69% yield) as white solid. MS(ESI) m/z: 440.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.86 (br. s., 1H), 8.40 - 8.32 (m, 1H), 7.90 (br. s., 2H), 7.74 (br. s., 2H), 7.60 - 7.53 (m, 2H), 7.48 - 7.42 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.55 (d, J=7.7 Hz, 1H), 4.48 (d, J=5.2 Hz, 1H), 4.28 - 4.17 (m, 2H), 3.96 (br. s., 2H), 3.09 (br. s., 2H), 1.23 (br. s., 6H); HPLC RT = 1.93 min (Method E), 191 min (Method F). -(4-(2-(Indolin-l-yl)-2-oxoethyl)-2-methylphenyl)phthalazin-l(2H)-one
Figure imgf000323_0001
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin- 1 (2H)-one (15 mg, 0.083 mmol) and Intermediate 71 (34.5 mg, 0.091 mmol), afforded 1.8 mg (5.5%) of Example 259. MS(ESI) m/z: 396.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (br. s., 1H), 8.33 (d, J=3.3 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.87 (d, J=3.3 Hz, 2H), 7.34 - 7.21 (m, 5H), 7.15 (br. s., 1H), 7.00 (br. s., 1H), 4.23 (t, J=7.8 Hz, 2H), 3.92 (br. s., 2H), 3.19 (br. s., 2H), 2.07 (br. s., 3H); HPLC RT = 1.96 min (Method E), 1.99 min (Method F).
Example 260: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)phthalazin- 1 (2H)- one
Figure imgf000324_0001
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin- 1 (2H)-one (15 mg, 0.083 mmol) and Intermediate 70 (34.5 mg, 0.091 mmol), afforded 10.4 mg (32%) of Example 260. MS(ESI) m/z: 396.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, 1H), 8.35 - 8.29 (m, 1H), 7.90 - 7.81 (m, 2H), 7.41 - 7.34 (m, 2H), 7.34 - 7.29 (m, 3H), 7.27 (s, 2H), 7.24 - 7.20 (m, 1H), 4.98 (s, 2H), 4.70 (s, 2H), 3.84 (s, 2H), 2.07 (s, 3H); HPLC RT = 1.70 min (Method E), 1.73 min (Method F). -(2-Fluoro-4-(2-(indolin- 1 -yl)-2-oxoethyl)phenyl)phthalazin- 1 (2H)-one
Figure imgf000324_0002
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin- 1 (2H)-one (15 mg, 0.083 mmol) and Intermediate 72 (34.8 mg, 0.091 mmol), afforded 10.6 mg (31%) of Example 261. MS(ESI) m/z: 400.2 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 12.98 (br. s., 1H), 8.36 - 8.30 (m, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.53 (t, J=7.7 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.36 (d, J=l 1.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.05 - 6.97 (m, 1H), 4.24 (t, J=8.5 Hz, 2H), 4.01 (s, 2H), 3.20 (t, J=8.4 Hz, 2H); HPLC RT = 1.81 min (Method E), 1.83 min (Method F). Example 262: 4-{4-[2-(2,3-Dihydro-lH-isoindol-2-yl)-2-oxoethyl]phenyl}-6-methoxy-
1,2-dihydroisoquinolin-l-one
Figure imgf000325_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (25 mg, 0.098 mmol) and Intermediate 9 (35.7 mg, 0.098 mmol), afforded 14.4 mg (35%) of Example 262. MS(ESI) m/z: 41 1.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.30 (br. s., IH), 8.22 (d, J=8.8 Hz, IH), 7.41 (s, 4H), 7.38 - 7.34 (m, 2H), 7.32 - 7.28 (m, 2H), 7.14 (dd, J=8.8, 2.5 Hz, IH), 7.06 (s, IH), 6.92 (d, J=2.5 Hz, IH), 4.96 (s, 2H), 4.69 (s, 2H), 3.84 (s, 2H), 3.75 (s, 3H); HPLC RT = 1.61 min (Method E), 1.62 min (Method F). Example 263: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)isoquinolin-l(2H)- one
Figure imgf000325_0002
According to the procedure for the preparation of Example 255, coupling of Intermediate 70 (32.8 mg, 0.087 mmol) and 4-bromoisoquinolin- 1 (2H)-one (15 mg, 0.067 mmol) afforded Example 263 (2.1 mg, 8% yield). MS(ESI) m/z: 395.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.40 (d, J=5.8 Hz, IH), 8.27 (dd, J=8.0, 1.1 Hz, IH), 7.64 (ddd, J=8.3, 7.0, 1.5 Hz, IH), 7.53 - 7.48 (m, IH), 7.40 - 7.34 (m, 2H), 7.34 - 7.29 (m, 2H), 7.28 (s, IH), 7.24 - 7.19 (m, IH), 7.18 - 7.14 (m, IH), 7.03 - 6.97 (m, 2H), 4.97 (s, 2H), 4.69 (s, 2H), 3.80 (s, 2H), 2.03 (s, 3H); HPLC RT = 1.68 min (Method E), 1.67 min (Method F). -(4-(2-(Indolin- 1 -yl)-2-oxoethyl)-2-methylphenyl)isoquinolin- 1 (2H)-one
Figure imgf000326_0001
According to the procedure for the preparation of Example 255, coupling of Intermediate 71 (32.8 mg, 0.087 mmol) and 4-bromoisoquinolin- 1 (2H)-one (15 mg, 0.067 mmol) afforded Example 264 (1.7 mg, 6% yield). MS(ESI) m/z: 395.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.41 (d, J=4.4 Hz, IH), 8.28 (dd, J=8.0, 1.1 Hz, IH), 8.09 (d, J=8.0 Hz, IH), 7.64 (td, J=7.6, 1.5 Hz, IH), 7.54 - 7.47 (m, IH), 7.28 (s, IH), 7.25 (d, J=7.4 Hz, IH), 7.23 - 7.20 (m, IH), 7.19 - 7.16 (m, IH), 7.16 - 7.13 (m, IH), 7.01 (d, J=7.4 Hz, 3H), 4.23 (t, J=8.7 Hz, 2H), 3.88 (s, 2H), 3.18 (t, J=8.5 Hz, 2H), 2.04 (s, 3H); HPLC RT = 1.81 min (Method E), 1.80 min (Method F).
Example 265: 4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-l-yl)-2- oxo -one
Figure imgf000326_0002
According to the procedure for the preparation of Example 258, coupling of
Intermediate 1 (10 mg, 0.036 mmol), Intermediate 74 (11.5 mg, 0.036 mmol) afforded Example 265 (13.2 mg, 0.028 mmol, 78% yield). MS(ESI) m/z: 470.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.86 (s, IH), 8.39 - 8.30 (m, IH), 7.93 - 7.88 (m, 2H), 7.76 (d, J=2.5 Hz, IH), 7.73 - 7.68 (m, IH), 7.60 - 7.54 (m, J=8.3 Hz, 2H), 7.50 - 7.43 (m, J=8.3 Hz, 2H), 7.1 1 (d, J=8.3 Hz, IH), 6.57 (dd, J=8.3, 2.5 Hz, IH), 4.61 (s, IH), 4.24 (t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.63 (s, 2H), 3.10 (t, J=8.4 Hz, 2H), 1.18 (s, 6H); HPLC RT = 1.61 min (Method E), 1.61 min (Method F). Example 266: N-(4-(6-Methoxy-l-oxo-l,2-dihydroisoquinolin-4-yl)phenyl)indoline-l- carboxamide
Figure imgf000327_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (18 mg, 0.071 mmol) and Intermediate 10 (28.4 mg, 0.078 mmol) afforded 5.3 mg (17%) of Example 266. MS(ESI) m/z: 412.2 (M+H)+; ¾ NMR
(500MHz, DMSO-d6) δ 11.28 (d, J=6.1 Hz, IH), 8.64 (s, IH), 8.22 (d, J=8.8 Hz, IH), 7.89 (d, J=8.0 Hz, IH), 7.70 - 7.65 (m, 2H), 7.41 - 7.35 (m, 2H), 7.21 (d, J=7.2 Hz, IH), 7.17 - 7.11 (m, 2H), 7.05 (d, J=6.1 Hz, IH), 6.94 (d, J=2.5 Hz, IH), 6.93 - 6.88 (m, IH), 4.16 (t, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.19 (t, J=8.5 Hz, 2H); HPLC RT = 1.71 min (Method E), 1.71 min (Method F).
Example 267: 4-(6-Methoxy-l-oxo-l,2-dihydroisoquinolin-4-yl)phi
methoxyisoindoline-2-carboxylate
Figure imgf000327_0002
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (18 mg, 0.071 mmol) and Example 70B (28 mg, 0.071 mmol) afforded 1 1.9 mg (36%) of Example 267. MS(ESI) m/z: Mi.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 1 1.33 (br. s., IH), 8.23 (d, J=8.8 Hz, IH), 7.54 - 7.44 (m, 2H), 7.35 - 7.26 (m, 3H), 7.15 (dd, J=8.8, 2.5 Hz, IH), 7.14 - 7.08 (m, IH), 6.98 (s, IH), 6.94 - 6.86 (m, 2H), 4.89 (s, IH), 4.85 (s, IH), 4.71 (s, IH), 4.66 (s, IH), 3.77 (d, J=2.2 Hz, 6H); HPLC RT = 1.86 min (Method E), 1.86 min (Method F). Example 268: 6-Methoxy-N-(4-(6-methoxy-l-oxo-l,2-dihydroisoquinolin-4- yl)phenyl)indoline- 1 -carboxamide
Figure imgf000328_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (25 mg, 0.098 mmol) and Intermediate 12 (42.7 mg, 0.108 mmol) afforded 3.9 mg (9%) of Example 268. MS(ESI) m/z: 442.2 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 8.64 (s, IH), 8.22 (d, J=8.8 Hz, IH), 7.74 - 7.65 (m, J=8.8 Hz, 2H), 7.55 (d, J=2.5 Hz, IH), 7.42 - 7.34 (m, J=8.5 Hz, 2H), 7.14 (dd, J=8.8, 2.5 Hz, IH), 7.09 (d, J=8.0 Hz, IH), 7.04 (d, J=6.1 Hz, IH), 6.94 (d, J=2.5 Hz, IH), 6.48 (dd, J=8.3, 2.5 Hz, IH), 4.17 (t, J=8.5 Hz, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.11 (t, J=8.5 Hz, 2H); HPLC RT = 1.71 min (Method E), 1.71 min (Method F).
Example 269: 4-(6-Methoxy-l-oxo-l,2-dihydroisoquinolin-4-yl)phenyl isoindoline-2- carboxylate
Figure imgf000328_0002
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (18 mg, 0.071 mmol) and Example 68B (25.9 mg, 0.071 mmol) afforded 7.1 mg (23%) of Example 269. MS(ESI) m/z: 413.2 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 11.34 (d, J=5.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.44 - 7.38 (m, 2H), 7.36 - 7.33 (m, 3H), 7.16 (dd, J=8.8, 2.5 Hz, 1H), 7.10 (d, J=5.8 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.94 (s, 2H), 4.75 (s, 2H), 3.77 (s, 3H); HPLC RT = 1.88 min (Method E), 1.88 min (Method F).
The following Examples in Table 4 were made by using the same procedure as shown in Example 3. Intermediate 1 was coupled with the appropriate amine. Various coupling reagents could be used other than the one described in Example 3 such as BOP, PyBop, EDC/HOBt or HATU.
Figure imgf000330_0001
Table 4
Figure imgf000330_0002
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
Exam le 287: 4-(2-Fluoro-4-(2-(indolin-l-yl)-2-oxoethyl)phenyl)isoquinolin-l(2H)-one
Figure imgf000342_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 6 (15 mg, 0.067 mmol) and Intermediate 72 (33.2 mg, 0.087 mmol), afforded 10.6 mg (31%) of Example 287. MS(ESI) m/z: 399.2 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 11.55 (br. s., IH), 8.28 (dd, J=8.1, 1.0 Hz, IH), 8.08 (d, J=8.0 Hz, IH), 7.69 (ddd, J=8.3, 7.1, 1.4 Hz, IH), 7.58 - 7.50 (m, IH), 7.40 (t, J=7.8 Hz, IH), 7.32 - 7.27 (m, IH), 7.27 - 7.20 (m, 3H), 7.19 - 7.12 (m, 2H), 7.04 - 6.97 (m, IH), 4.23 (t, J=8.5 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=8.5 Hz, 2H); HPLC RT = 1.76 min (Method E), 1.76 min (Method F).
Example 288: 4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-l-yl)-2- - 1 (2H)-one
Figure imgf000342_0002
According to the procedure for the preparation of Example 76, coupling of
Intermediate 6 (20 mg, 0.089 mmol) and Intermediate 87 (40.3mg, 0.089 mmol), afforded 1 1.9 mg (28%) of Example 287. MS(ESI) m/z: 469.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.47 (d, J=5.5 Hz, IH), 8.33 - 8.27 (m, IH), 7.76 (d, J=1.9 Hz, IH), 7.73 - 7.67 (m, IH), 7.58 - 7.51 (m, 2H), 7.40 (s, 4H), 7.13 - 7.06 (m, 2H), 6.57 (dd, J=8.1, 2.3 Hz, IH), 4.62 (s, IH), 4.23 (t, J=8.5 Hz, 2H), 3.91 (d, J=7.2 Hz, 2H), 3.63 (s, 2H), 3.09 (t, J=8.4 Hz, 2H), 1.18 (s, 6H); HPLC RT = 1.70 min (Method E), 1.69 (Method F).
Example 289: 4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-l-yl)-2- -6-methoxyisoquinolin- 1 (2H)-one
Figure imgf000343_0001
According to the procedure for the preparation of Example 76, coupling of Intermediate 73 (22 mg, 0.087 mmol) and Intermediate 87 (39.1 mg, 0.087 mmol) afforded 12.4 mg (29%) of Example 289. MS(ESI) m/z: 499.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 11.30 (d, J=5.8 Hz, IH), 8.23 (d, J=9.1 Hz, IH), 7.76 (d, J=1.9 Hz, IH), 7.48 - 7.37 (m, 4H), 7.23 - 7.09 (m, 2H), 7.06 (d, J=5.5 Hz, IH), 6.94 (d, J=2.2 Hz, IH), 6.57 (dd, J=8.1, 2.3 Hz, IH), 4.61 (s, IH), 4.23 (t, J=8.4 Hz, 2H), 3.92 (s, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.09 (t, J=8.4 Hz, 2H), 1.17 (s, 6H); HPLC RT = 1.70 min (Method E), 1.70 min (Method F).
Example 290: 2-(( 1 -(2-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)acetyl)indolin-6- yl)oxy)acetic acid
Figure imgf000343_0002
A mixture of Example 283 (32 mg, 0.068 mmol) and 1M lithium hydroxide (0.2 mL, 0.200 mmol) in THF (2 mL) was stirred rt for 2h. The mixture was concentrated, then was purified by prep HPLC to afford Example 290 (28 mg, 90% yield). MS(ESI) m/z: 456.0 (M+H)+; 'H NMR (500MHZ, methanol-d4) δ 8.50 - 8.44 (m, IH), 7.96 - 7.84 (m, 4H), 7.63 - 7.58 (m, 2H), 7.57 - 7.52 (m, 2H), 7.11 (d, J=8.3 Hz, IH), 6.64 (dd, J=8.3, 2.5 Hz, IH), 4.62 (s, 2H), 4.27 (t, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.16 (t, J=8.3 Hz, 2H); HPLC RT = 7.44 min (Method A), 7.57 min (Method B).
Example 297: 4-(4-(2-(6-(2-Morpholino-2-oxoethoxy)indolin-l-yl)-2- - 1 (2H)-one
Figure imgf000344_0001
To a solution of Example 290 (8 mg, 0.018 mmol), morpholine (3.06 mg, 0.035 mmol), and HATU (10.02 mg, 0.026 mmol) in DMF (1 mL), was add DIEA (0.015 mL, 0.088 mmol). The mixture was stirred rt for lh, then was purified by prep HPLC to afford Example 297 (6.1 mg, 64% yield). MS(ESI) m/z: 525.3 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.86 (br. s., IH), 8.34 (d, J=6.1 Hz, IH), 7.90 (br. s., 2H), 7.73 (br. s., 2H), 7.56 (d, J=6.6 Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.12 (d, J=5.8 Hz, IH), 6.57 (d, J=8.0 Hz, IH), 4.75 (br. s., 2H), 4.24 (t, J=7.4 Hz, 2H), 3.96 (br. s., 2H), 3.59 (br. s., 2H), 3.55 (br. s., 2H), 3.44 (d, J=11.8 Hz, 4H), 3.10 (t, J=7.6 Hz, 2H); HPLC RT = 1.45 min (Method E), 1.45 min (Method F). Example 298: 2-((l-(2-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)acetyl)indolin-6- yl)oxy)acetamide ONH,
Figure imgf000345_0001
According to the procedure for the preparation of Example 297, coupling of Example 290 (8 mg, 0.018 mmol) and ammonium chloride (1.9 mg, 0.035 mmol) afforded Example 298 (5.1 mg, 63% yield). MS(ESI) m/z: 455.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.86 (br. s., 1H), 8.34 (d, J=6.3 Hz, 1H), 7.90 (br. s., 2H), 7.79 (br. s., 1H), 7.73 (d, J=6.6 Hz, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.53 - 7.45 (m, 3H), 7.35 (br. s., 1H), 7.13 (d, J=6.3 Hz, 1H), 6.65 - 6.55 (m, 1H), 4.35 (br. s., 2H), 4.24 (t, J=7.8 Hz, 2H), 3.96 (br. s., 2H), 3.10 (t, J=7.8 Hz, 2H); HPLC RT = 1.48 min (Method E), 1.49 min (Method F).
Example 299: 4-(4-(2-(6-(2-(4-Methylpiperazin-l-yl)-2-oxoethoxy)indolin-l-yl)-2- - 1 (2H)-one
Figure imgf000345_0002
According to the procedure for the preparation of Example 297, coupling of Example 290 (8 mg, 0.018 mmol) and 1-methylpiperazine (4.40 mg, 0.044 mmol) afforded Example 299 (1.2 mg, 9% yield). MS(ESI) m/z: 538.4 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.87 (br. s., 1H), 9.98 (br. s., 1H), 8.40 - 8.29 (m, 1H), 7.91 (br. s., 2H), 7.76 - 7.67 (m, 2H), 7.57 (d, J=6.9 Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.19 - 7.09 (m, 1H), 6.59 (d, J=7.7 Hz, 1H), 4.87 (br. s., 1H), 4.79 (br. s., 1H), 4.39 (br. s., 1H), 4.26 (br. s., 2H), 4.06 (br. s., 1H), 3.98 (br. s., 2H), 3.17 - 3.04 (m, 3H), 2.65 (br. s., 3H); HPLC RT = 1.30 min (Method E), 1.30 min (Method F).
Example 300: 4-(Dimethylamino)-N-(l-(2-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)acetyl)indolin-6-yl)benzamide
Figure imgf000346_0001
According to the procedure for the preparation of Example 3, coupling of
Intermediate 1 (11 mg, 0.039 mmol), and Intermediate 95 (22 mg, 0.043 mmol) afforded Example 300 (8.6 mg, 40% yield). MS(ESI) m/z: 544.3 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.84 (s, 1H), 9.81 (s, 1H), 8.38 - 8.31 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92 - 7.81 (m, 4H), 7.76 - 7.69 (m, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 3H), 6.75 (d, J=9.1 Hz, 2H), 4.24 (t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.19 (t, J=8.4 Hz, 2H), 2.99 (s, 6H); HPLC RT = 1.55 min (Method E), 1.70 min (Method F). The following Examples in Table 5 were made by using the same procedure as shown in Example 45. Intermediate 94 was coupled with the appropriate carboxylic acid. Various coupling reagents could be used other than the one described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.
Figure imgf000347_0001
Table 5
Figure imgf000347_0002
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
The following Examples in Table 6 were made by using the same procedure as shown in Example 45. Intermediate 96 was coupled with the appropriate carboxylic acid. Various coupling reagents could be used other than the one described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.
Figure imgf000355_0001
Table 6
Figure imgf000355_0002
Figure imgf000356_0001
Figure imgf000357_0001
Example 321: l-((l-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(3 -methyl -4-(4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000358_0001
To a degassed solution of Example 307 (24 mg, 0.038 mmol) in THF (2 mL), was added 10% Pd/C (5 mg). The mixture was stirred under H2 (balloon). The mixture was filtered, then was purified by prep HPLC to afford Example 321 (20 mg, 0.034 mmol, 88% yield). MS(ESI) m/z: 565.3 (M+H)+; 'H NMR (400MHZ, methanol^) δ 8.48 - 8.43 (m, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.91 - 7.86 (m, 2H), 7.85 - 7.82 (m, 1H), 7.80 (dd, J=8.3, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.45 - 7.40 (m, 1H), 7.39 - 7.32 (m, 2H), 4.60 - 4.52 (m, 2H), 3.66 - 3.56 (m, 2H), 3.41 (d, J=13.0 Hz, 1H), 3.18 - 3.07 (m, 1H), 3.05 - 2.89 (m, 2H), 2.48 (ddt, J=1 1.2, 7.5, 3.9 Hz, 1H), 2.22 - 2.14 (m, 3H), 2.03 - 1.75 (m, 4H), 1.74 - 1.51 (m, 4H); HPLC RT = 5.67 min (Method A), 6.19 min (Method B).
Example 322: l-((l-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(4-(4-oxo-3,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000358_0002
Intermediate 3 (23.7 mg, 0.051 mmol) was coupled with Intermediate 21 (20 mg, 0.051 mmol) according to the procedure for Example 45 to afford after prep HPLC the amide product (21 mg, 67% yield). MS(ESI) m/z: 613.2 (M+H) . The residue (21 mg) was dissolved in THF (2 mL). To this mixture was added 10% Pd/C (5 mg). The mixture was stirred under H2 (balloon) for 16h. The mixture was filtered and purified by prep HPLC to afford Example 322 (15 mg, 79% yield). MS(ESI) m/z: 551.2 (M+H)+; XH NMR (400MHz, methanol-d4) δ 8.46 - 8.42 (m, IH), 8.32 (d, J=8.1 Hz, IH), 8.01 - 7.95 (m, 2H), 7.92 - 7.83 (m, 3H), 7.74 - 7.69 (m, IH), 7.66 - 7.61 (m, 2H), 7.52 (td, J=7.7, 0.9 Hz, IH), 7.37 - 7.31 (m, IH), 4.54 (dd, J=6.7, 3.2 Hz, 2H), 3.63 - 3.55 (m, 2H), 3.41 (d, J=13.0 Hz, IH), 3.18 - 3.05 (m, 2H), 3.05 - 2.87 (m, 2H), 2.55 - 2.37 (m, IH), 1.93 (d, J=14.7 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.75 - 1.53 (m, 3H); HPLC RT = 5.53 min (Method A), 6.33 min (Method B).
Example 323: N-(4-(6-Methoxy-l-oxo-l,2-dihydroisoquinolin-4-yl)-3- - 1 -carboxamide
Figure imgf000359_0001
According to the procedure for the preparation of Example 76, coupling of
Intermediate 73 (10 mg, 0.039 mmol) and Intermediate 97 (14.9 mg, 0.039 mmol), afforded 2.7 mg (15%) of Example 323. MS(ESI) m/z: 426.2 (M+H)+; 'H NMR
(500MHz, DMSO-d6) δ 11.19 (d, J=5.8 Hz, IH), 8.55 (s, IH), 8.21 (d, J=8.8 Hz, IH), 7.89 (d, J=8.3 Hz, IH), 7.57 (s, IH), 7.51 (d, J=8.0 Hz, 2H), 7.21 (d, J=7.2 Hz, IH), 7.12 (t, J=7.0 Hz, 3H), 6.96 (d, J=5.8 Hz, IH), 6.91 - 6.85 (m, IH), 6.39 (s, IH), 4.15 (t, J=8.7 Hz, 2H), 3.70 (s, 3H), 3.19 (t, J=8.5 Hz, 2H), 2.06 (s, 3H); HPLC RT = 1.77 min (Method E), 1.78 min (Method F).
Example 324: N-(3-Methyl-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)indoline-l- carboxamide
Figure imgf000360_0001
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin- 1 (2H)-one (20 mg, 0.1 1 mmol) and Intermediate 97 (46 mg, 0.12 mmol), afforded 4.4 mg (10%) of Example 324. MS(ESI) m/z: 397.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.76 (s, IH), 8.63 (s, IH), 8.37 - 8.28 (m, IH), 7.93 - 7.83 (m, 3H), 7.61 (s, IH), 7.57 (d, J=8.3 Hz, IH), 7.33 - 7.27 (m, IH), 7.21 (d, J=7.4 Hz, IH), 7.24 (d, J=8.5 Hz, IH), 7.14 (t, J=7.7 Hz, IH), 6.92 (t, J=7.3 Hz, IH), 4.17 (t, J=8.4 Hz, 2H), 3.20 (t, J=8.5 Hz, 2H), 2.07 (s, 3H); HPLC RT = 1.73 min (Method E), 1.73 min (Method F).
Example 326: 1 -(Azetidin-3 -ylmethyl)-N-(3-methyl-4-(4-oxo-3 ,4-dihydrophthalazin- 1 - yl)pheny - lH-indazole-3-carboxamide, TFA
Figure imgf000360_0002
Example 326A: tert-Butyl 3-((3-((3-methyl-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)carbamoyl)- 1 H-indazol- 1 -yl)methyl)azetidine- 1 -carboxylate
Figure imgf000361_0001
To a solution of Intermediate 94 (55 mg, 0.12 mmol), Intermediate 33 (38 mg, 0.12 mmol), and HATU (45.8 mg, 0.12 mmol) in DMF (1 mL), was added DIEA (0.1 mL, 0.57 mmol). The mixture was stirred at rt for 4h, then was concentrated. The residue was purified via preparative HPLC to afford Example 326A (45 mg, 70% yield).
MS(ESI) m/z: 565.3 (M+H)+.
Figure imgf000361_0002
Example 326A (30 mg, 0.053 mmol) was stirred with TFA (0.5 ml) in DCM (1 ml) for 10 min, then was concentrated. The residue was purified by prep HPLC to afford Example 326 (30 mg, 97% yield). MS(ESI) m/z: 465.0 (M+H)+; XH NMR (400MHz, methanol-cU) δ 8.53 - 8.42 (m, 1H), 8.35 (dt, J=8.2, 1.0 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.85 - 7.82 (m, 1H), 7.80 (dd, J=8.4, 1.8 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.39 - 7.33 (m, 2H), 4.82 - 4.79 (m, 2H), 4.27 - 4.12 (m, 4H), 3.76 - 3.61 (m, 1H), 2.19 (s, 3H); HPLC RT = 5.38 min (Method A), 5.98 min (Method B).
Example 327 : 1 -(Azetidin-3 -ylmethyl)-N- [3 -chloro-4-(4-oxo-3 ,4-dihydrophthalazin- 1 - yl)phenyl] - 1 H-indazole-3 -carboxamide, TFA
Figure imgf000362_0001
Example 316 (24 mg, 0.041 mmol) stirred with TFA (0.5 ml) and DCM (2ml) for 10 min, then was concentrated. The residue was purified via preparative HPLC to afford Example 327 (20 mg, 81% yield). MS(ESI) m/z: 485.1 (M+H)+; 'H NMR (400MHZ, methanol-cU) δ 8.49 - 8.40 (m, 1H), 8.39 - 8.31 (m, 1H), 8.24 - 8.17 (m, 1H), 7.96 - 7.85 (m, 3H), 7.74 (d, J=8.6 Hz, 1H), 7.61 - 7.48 (m, 2H), 7.46 - 7.35 (m, 2H), 4.83 - 4.81 (m, 2H), 4.31 - 4.10 (m, 4H), 3.67 (t, J=7.8 Hz, 1H); HPLC RT = 5.83 min (Method A), 6.83 min (Method B). Example 328: 2-(3- {[4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl]carbamoyl}-lH- -l-yl)acetic acid
Figure imgf000362_0002
To 4-chlorophthalazin- 1 (2H)-one (40.8 mg, 0.226 mmol), Intermediate 98 (82 mg, 0.188 mmol) and phosphoric acid, potassium salt (100 mg, 0.47 mmol), were added dioxane (5 mL) and water (0.56 mL). The mixture was degassed (evacuated and flushed with Ar (5x)). Pd(PPh3)4 (10.9 mg, 9.42 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 25 min. The product was purified by prep HPLC to afford Example 328 (20 mg, 24% yield). MS(ESI) m/z: 440.1 (M+H)+; ¾ NMR (400MHz, DMSO-d6) δ 12.82 (s, 1H), 10.60 (s, 1H), 8.40 - 8.32 (m, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.15 - 8.06 (m, J=8.6 Hz, 2H), 7.97 - 7.87 (m, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.63 - 7.56 (m, J=8.6 Hz, 2H), 7.53 (td, J=7.7, 1.1 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 5.46 (s, 2H); HPLC RT = 7.
(Method A), 6.64 min (Method B).
Example 329 : 1 -(( 1 -Acetylazetidin-3 -yl)methyl)-N-(3 -chloro-4-(4-oxo-3
dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000363_0001
Example 327 (10 mg, 0.021 mmol) was mixed with acetic anhydride (3.2 mg, 0.031 mmol) and TEA (4.17 mg, 0.041 mmol) in CH2C12 (1 mL) and stirred at rt o/n. The reaction mixture was concentrated, then was purified by prep HPLC to afford Example 329 (9.6 mg, 87% yield). MS(ESI) m/z: 527.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.89 (s, 1H), 10.62 (br. s., 1H), 8.38 - 8.31 (m, 2H), 8.26 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.92 - 7.85 (m, 2H), 7.60 - 7.50 (m, 2H), 7.37 (t, J=7.2 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 7.00 (s, 1H), 4.83 (br. s., 2H), 4.21 (t, J=8.3 Hz, 1H), 4.05 (br. s., 1H), 3.96 - 3.86 (m, 1H), 3.79 (br. s., 1H), 3.25 (br. s., 2H), 2.55 (br. s., 2H), 1.74 (s, 3H); HPLC RT = 1.55 min (Method E), 1.55 min (Method F).
Example 330: N-(3 -Methyl-4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(( 1 - -3-yl)methyl)-l H-indazole-3 -carboxamide
Figure imgf000363_0002
To a solution of Example 326 (10 mg, 0.017 mmol) in (¾(¾ (1 mL), were added TEA (1.7 mg, 0.017 mmol), followed by formaldehyde (2.8 mg, 0.035 mmol), acetic acid (5.2 mg, 0.086 mmol), and Na(OAc)3BH (7.3 mg, 0.035 mmol). The mixture was stirred rt for 16h, then was concentrated and purified by prep HPLC to afford
Example 330 (3.8 mg, 46% yield). MS(ESI) m/z: 479.2 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.79 (s, 1H), 10.30 (s, 1H), 8.34 (d, J=4.7 Hz, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.92 - 7.77 (m, 4H), 7.52 (t, J=7.4 Hz, 1H), 7.39 - 7.21 (m, 3H), 4.76 (d, J=6.9 Hz, 2H), 3.14 (br. s., 4H), 3.05 - 2.96 (m, 1H), 2.25 (br. s., 3H), 2.10 (s, 3H); HPLC RT = 1.35 min (Method E), 1.35 min (Method F).
Example 331 : 3-(3-((4-(4-Pxo-3,4-dihydrophthalazin- 1 -yl)phenyl)carbamoyl)- 1H- indazol-l-yl)propanoic acid
Example 332: Methyl 3-(3-((4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)carbamoyl)- -indazol- 1 -yl)propanoate
Figure imgf000364_0001
Example 331 Example 332
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin-l(2H)-one (40.7 mg, 0.225 mmol) and Intermediate 99 (92 mg, 0.205 mmol), afforded Example 331 (8 mg, 8.5% yield) and Example 332 (42 mg, 43% yield).
Example 331: MS(ESI) m/z: 454.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, 1H), 12.45 (br. s., 1H), 10.45 (s, 1H), 8.41 - 8.31 (m, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.13 - 8.05 (m, 2H), 8.00 - 7.83 (m, 3H), 7.82 - 7.73 (m, 1H), 7.65 - 7.57 (m, 2H), 7.52 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.39 - 7.29 (m, 1H), 4.77 (t, J=6.7 Hz, 2H), 3.04 (t, J=6.9 Hz, 2H)); HPLC RT = 7.51 min (Method A), 6.78 min (Method B).
Example 332: MS(ESI) m/z: 468.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, 1H), 10.45 (s, 1H), 8.42 - 8.28 (m, 1H), 8.26 - 8.20 (m, 1H), 8.12 - 8.03 (m, 2H), 7.97 - 7.83 (m, 3H), 7.83 - 7.73 (m, 1H), 7.67 - 7.59 (m, 2H), 7.53 (ddd, J=8.5, 7.1, 1.0 Hz, 1H), 7.41 - 7.28 (m, 1H), 4.81 (t, J=6.7 Hz, 2H), 3.58 (s, 3H), 3.13 (t, J=6.7 Hz, 2H); HPLC RT = 8.90 min (Method A), 7.84 min (Method B). Example 333: l-(3-Hydroxy-3-methylbutyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000365_0001
According to the procedure for the preparation of Example 76, coupling of 4- chlorophthalazin-l(2H)-one (22.6 mg, 0.1 13 mmol) and Intermediate 100 (51 mg, 0.125 mmol), afforded Example 333 (5.2 mg, 9.7% yield). MS(ESI) m/z: 468.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, IH), 10.48 (s, IH), 8.35 (dd, J=7.7, 1.4 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 8.09 (d, J=8.5 Hz, 2H), 7.97 - 7.90 (m, 2H), 7.81 - 7.74 (m, 2H), 7.60 (s, IH), 7.57 - 7.48 (m, IH), 7.34 (t, J=7.6 Hz, IH), 4.69 - 4.63 (m, 2H), 4.57 (br. s., IH), 2.55 (t, J=5.0 Hz, IH), 2.09 - 2.00 (m, 2H), 1.21 (s, 6H); HPLC RT = 1.68 min (Method E), 1.68 min (Method F).
Example 334: 1 -(2-((2-Hydroxy-2-methylpropyl)amino)-2-oxoethyl)-N-(4-(4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000365_0002
To Example 328 (8 mg, 0.018 mmol), 1 -amino-2-methylpropan-2-ol (3.3 mg, 0.036 mmol), and HATU (7.6 mg, 0.020 mmol) in DMF (1 mL), was added DIEA (0.016 mL, 0.091 mmol). The mixture was stirred at rt for 16h, then was purified by prep HPLC to afford Example 334 (6 mg, 64% yield). MS(ESI) m/z: 51 1.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, IH), 10.55 (s, IH), 8.39 - 8.34 (m, IH), 8.27 (d, J=8.0 Hz, IH), 8.18 (t, J=6.1 Hz, IH), 8.12 - 8.03 (m, 2H), 7.98 - 7.86 (m, 2H), 7.83 - 7.76 (m, IH), 7.73 (d, J=8.5 Hz, IH), 7.63 - 7.56 (m, 2H), 7.51 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.42 - 7.32 (m, IH), 5.36 (s, 2H), 3.10 (d, J=6.1 Hz, 2H), 1.10 (s, 6H); HPLC RT = 1.42 min (Method E), 1.41 min (Method F). Example 335: l-(2-(((l-Hydroxycyclobutyl)methyl)amino)-2-oxoethyl)-N-(4-(4-oxo- -dihydrophthalazin- 1 -yl)phenyl)- lH-indazole-3-carboxamide
Figure imgf000366_0001
According to the procedure for the preparation of Example 334, coupling of Example 328 (8 mg, 0.018 mmol) and 1 -(aminomethyl)cyclobutanol (3.7 mg, 0.036 mmol) afforded Example 335 (2.7 mg, 26% yield). MS(ESI) m/z: 523.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.81 (s, IH), 10.57 (s, IH), 8.41 - 8.32 (m, IH), 8.29 - 8.21 (m, 2H), 8.14 - 8.06 (m, 2H), 7.98 - 7.86 (m, 3H), 7.78 (dd, J=7.8, 1.0 Hz, IH), 7.75 - 7.71 (m, IH), 7.63 - 7.55 (m, 2H), 7.53 - 7.47 (m, IH), 7.40 - 7.31 (m, IH), 5.36 (s, 2H), 3.90 (s, IH), 3.26 (d, J=5.8 Hz, 2H), 2.00 - 1.86 (m, 4H), 1.70 - 1.55 (m, IH), 1.42 (dt, J=l 1.2, 9.0 Hz, IH); HPLC RT = 1.47 min (Method E), 1.46 min (Method F).
Example 336: 1 -(3-((2-Hydroxy-2-methylpropyl)amino)-3-oxopropyl)-N-(4-(4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000366_0002
According to the procedure for the preparation of Example 334, coupling of
Example 331 (9 mg, 0.02 mmol) and l-amino-2-methylpropan-2-ol (3.5 mg, 0.040 mmol) afforded Example 336 (7.4 mg, 65% yield). MS(ESI) m/z: 525.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.82 (s, IH), 10.44 (s, IH), 8.35 (dd, J=7.8, 1.2 Hz, IH), 8.23 (d, J=8.3 Hz, 1H), 8.12 - 8.05 (m, J=8.5 Hz, 2H), 7.98 - 7.84 (m, 3H), 7.82 (d, J=8.5 Hz, 1H), 7.78 (dd, J=7.8, 1.0 Hz, 1H), 7.63 - 7.58 (m, J=8.5 Hz, 2H), 7.53 - 7.47 (m, 1H), 7.33 (t, J=7.4 Hz, 1H), 4.79 (t, J=6.7 Hz, 2H), 2.98 (d, J=6.1 Hz, 2H), 2.93 - 2.86 (m, 2H), 0.92 (s, 6H); HPLC RT = 1.46 min (Method E), 1.46 min (Method F).
Example 337: l-(3-Morpholino-3-oxopropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- - 1 H-indazole-3 -carboxamide
Figure imgf000367_0001
According to the procedure for the preparation of Example 334, coupling of Example 331 (9 mg, 0.02 mmol) and morpholine (3.5 mg, 0.040 mmol) afforded
Example 337 (7.3 mg, 70% yield). MS(ESI) m/z: 523.2 (M+H)+; ¾ NMR 12.82 (s, 1H), 10.46 (s, 1H), 8.40 - 8.30 (m, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.98 - 7.83 (m, 3H), 7.81 - 7.73 (m, 1H), 7.62 - 7.58 (m, 2H), 7.51 (ddd, J=8.3, 7.1, 0.8 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.80 (t, J=7.0 Hz, 2H), 3.52 - 3.37 (m, 8H), 3.09 (t, J=6.9 Hz, 2H); HPLC RT = 1.55 min (Method E), 1.51 min (Method F).
Example 338: l-(Azetidin-3-ylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-
Figure imgf000367_0002
According to the procedure for the preparation of Example 326, coupling of Intermediate 3 and Intermediate 33, followed by TFA deprotection afforded Example 338. MS(ESI) m/z: 451.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.83 (s, 1H), 10.40 (s, 1H), 8.68 (br. s., 1H), 8.52 (br. s., 1H), 8.40 - 8.34 (m, 1H), 8.29 - 8.23 (m, 1H), 8.09 - 8.03 (m, 2H), 7.97 - 7.85 (m, 3H), 7.80 - 7.72 (m, 1H), 7.67 - 7.60 (m, 2H), 7.57 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.41 - 7.35 (m, 1H), 4.81 (d, J=6.9 Hz, 2H), 4.14 - 4.02 (m, 2H), 3.99 - 3.87 (m, 2H); HPLC RT = 5.09 min (Method A), 5.73 min (Method B).
Example 339: l-((l-Acetylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- - 1 H-indazole-3 -carboxamide
Figure imgf000368_0001
According to the procedure for the preparation of Example 329, acylation of Example 338 (9 mg, 0.016 mmol) with acetic anhydride afforded Example 339 (5.0 mg, 63% yield). MS(ESI) m/z: 493.3 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.85 (s, 1H), 10.46 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.11 - 8.06 (m, J=8.3 Hz, 2H), 7.97 - 7.90 (m, 3H), 7.78 (d, J=7.7 Hz, 1H), 7.64 - 7.58 (m, J=8.5 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.36 (t, J=7.4 Hz, 1H), 4.83 (dd, J=6.9, 4.7 Hz, 2H), 4.21 (t, J=8.4 Hz, 1H), 4.05 (dd, J=8.1, 5.6 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.79 (dd, J=9.4, 5.5 Hz, 1H), 3.30 - 3.19 (m, 1H), 1.74 (s, 3H); HPLC RT = 1.48 min (Method E), 1.47 min (Method F).
Example 340: l-((l-Methylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- - 1 H-indazole-3 -carboxamide
Figure imgf000368_0002
According to the procedure for the preparation of Example 330, reductive amination of Example 339 (12 mg, 0.021 mmol) afforded Example 340 (9.1 mg, 90% yield). MS(ESI) m/z: 465.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.86 (s, IH), 10.41 (d, J=13.5 Hz, IH), 9.82 (br. s., IH), 8.36 (d, J=7.7 Hz, IH), 8.30 - 8.24 (m, IH), 8.11 - 8.03 (m, J=8.3 Hz, 2H), 7.98 - 7.87 (m, 3H), 7.77 (d, J=7.7 Hz, IH), 7.65 - 7.60 (m, J=8.3 Hz, 2H), 7.57 (t, J=7.6 Hz, IH), 7.38 (t, J=7.4 Hz, IH), 4.84 (t, J=7.3 Hz, 2H), 4.31 (d, J=5.5 Hz, IH), 4.27 - 4.14 (m, IH), 4.03 (d, J=6.9 Hz, 2H), 2.85 (dd, J=16.4, 4.5 Hz, 3H); HPLC RT = 1.33 min (Method E), 1.36 min (Method F). Example 341: Methyl 3-((3-((4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)carbamoyl)- -indazol- 1 -yl)methyl)azetidine- 1 -carboxylate
Figure imgf000369_0001
According to the procedure for the preparation of Example 329, acylation of Example 338 (8 mg, 0.014 mmol) with methyl chloroformate afforded Example 341 (5.1 mg, 67% yield). MS(ESI) m/z: 509.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.85 (s, IH), 10.46 (s, IH), 8.35 (d, J=7.7 Hz, IH), 8.25 (d, J=8.0 Hz, IH), 8.12 - 8.04 (m, J=8.0 Hz, 2H), 7.97 - 7.88 (m, 3H), 7.78 (d, J=7.7 Hz, IH), 7.63 - 7.59 (m, J=8.0 Hz, 2H), 7.53 (t, J=7.7 Hz, IH), 7.35 (t, J=7.6 Hz, IH), 4.82 (d, J=7.2 Hz, 2H), 4.01 (br. s., 2H), 3.93 - 3.84 (m, 2H), 3.54 (s, 3H), 3.27 - 3.14 (m, IH); HPLC RT = 1.74 min (Method E), 1.74 min (Method F).
Example 342 : N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(piperidin-4- ylmethyl)-lH-indazole-3-carboxamide, TFA
Figure imgf000370_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 3 (95 mg, 0.20 mmol) and Intermediate 101 (88 mg, 0.245 mmol), afforded after TFA deprotection Example 342 (78 mg, 79% yield). MS(ESI) m/z: 479.4 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.83 (s, IH), 10.49 (s, IH), 8.48 (d, J=9.9 Hz, IH), 8.38 - 8.34 (m, IH), 8.27 (d, J=8.0 Hz, IH), 8.15 (d, J=1 1.3 Hz, IH), 8.1 1 - 8.07 (m, 2H), 7.94 - 7.88 (m, 3H), 7.79 - 7.74 (m, IH), 7.64 - 7.59 (m, 2H), 7.54 (ddd, J=8.4, 7.0, 1.1 Hz, IH), 7.39 - 7.33 (m, IH), 4.55 (d, J=6.6 Hz, 2H), 3.27 (d, J=12.4 Hz, 2H), 2.93 - 2.80 (m, 2H), 2.39 - 2.27 (m, IH), 1.71 (d, J=13.8 Hz, 2H), 1.54 - 1.39 (m, 2H); HPLC RT = 8.74 min (Method A), 9.34 min (Method B).
Example 343: l-((l-Acetylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- -lH-indazole-3-carboxamide
Figure imgf000370_0002
According to the procedure for the preparation of Example 329, acylation of
Example 342 (12 mg, 0.020 mmol) with acetic anhydride afforded Example 343 (8.9 mg, 84% yield). MS(ESI) m/z: 521.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.85 (s, IH), 10.52 (s, IH), 8.35 (d, J=7.4 Hz, IH), 8.25 (d, J=8.0 Hz, IH), 8.14 - 8.04 (m, J=8.0 Hz, 2H), 7.98 - 7.87 (m, 3H), 7.78 (d, J=7.4 Hz, IH), 7.62 - 7.58 (m, J=7.7 Hz, 2H), 7.52 (t, J=7.6 Hz, IH), 7.34 (t, J=7.2 Hz, IH), 4.49 (d, J=6.6 Hz, 2H), 4.37 (d, J=12.4 Hz, IH), 3.80 (d, J=13.5 Hz, IH), 2.96 (t, J=12.9 Hz, IH), 2.30 (br. s., IH), 1.97 (s, 3H), 1.50 (t, J=15.5 Hz, 2H), 1.37 - 1.25 (m, 1H), 1.18 (d, J=12.1 Hz, 1H); HPLC RT = 1.61 min (Method E), 1.61 min (Method F).
Example 344: Methyl 4-((3-((4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)carbamoyl)- -indazol- 1 -yl)methyl)piperidine- 1 -carboxylate
Figure imgf000371_0001
According to the procedure for the preparation of Example 329, acylation of Example 342 (10 mg, 0.017 mmol) with methyl chloroformate afforded Example 344 (4.7 mg, 52% yield). MS(ESI) m/z: 537.3 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.85 (s, 1H), 10.51 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.12 - 8.05 (m, J=8.0 Hz, 2H), 7.95 - 7.87 (m, 3H), 7.78 (d, J=7.7 Hz, 1H), 7.63 - 7.57 (m, J=7.7 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 4.48 (d, J=6.9 Hz, 2H), 3.96 (br. s., 2H), 3.57 (s, 3H), 2.73 (br. s., 2H), 2.25 (br. s., 1H), 1.47 (br. s., 2H), 1.32 - 1.19 (m, 2H); HPLC RT = 1.83 min (Method E), 1.83 min (Method F).
Example 345: l-(2-Hydroxy-2-methylpropyl)-N-(3-methoxy-4-(4-oxo-3,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000371_0002
According to the procedure for the preparation of Example 45, coupling of
Intermediate 102 (16 mg, 0.042 mmol) and Intermediate 15 (9.8 mg, 0.042 mmol), afforded Example 345 (14.8 mg, 73% yield). MS(ESI) m/z: 484.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.75 (br. s., 1H), 10.37 (br. s., 1H), 8.35 - 8.28 (m, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.90 - 7.80 (m, 4H), 7.70 (d, J=7.2 Hz, 1H), 7.48 (br. s., 1H), 7.40 - 7.28 (m, 3H), 4.79 (br. s., 1H), 4.49 (br. s., 2H), 3.72 (br. s., 3H), 1.20 (br. s., 6H); HPLC RT = 1.65 min (Method E), 1.66 min (Method F). Example 346: N-(3-Ethoxy-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(2-hydroxy- -methylpropyl)- 1 H-indazole-3 -carboxamide
Figure imgf000372_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 103 (14 mg, 0.050 mmol) and Intermediate 15 (11.7 mg, 0.050 mmol), afforded Example 346 (22.9 mg, 92% yield). MS(ESI) m/z: 498.3 (M+H)+; XH NMR
(500MHz, DMSO-d6) δ 12.74 (br. s., 1H), 10.35 (br. s., 1H), 8.33 - 8.27 (m, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.92 - 7.81 (m, 4H), 7.69 (d, J=8.0 Hz, 1H), 7.48 (br. s., 1H), 7.42 - 7.37 (m, 1H), 7.33 (d, J=7.7 Hz, 2H), 4.77 (br. s., 1H), 4.49 (br. s., 2H), 4.06 (br. s., 2H), 1.20 (br. s., 6H), 1.06 (br. s., 3H); HPLC RT = 1.76 min (Method E), 1.76 min (Method F).
Example 347: N-(3 -Ethoxy-4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 - ((tetrahydrofuran-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000372_0002
According to the procedure for the preparation of Example 45, coupling of
Intermediate 103 (11 mg, 0.039 mmol) and Intermediate 24 (9.6 mg, 0.039 mmol), afforded Example 347 (17.6 mg, 87% yield). MS(ESI) m/z: 510.4 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.74 (s, IH), 10.40 (s, IH), 8.34 - 8.24 (m, 2H), 7.90 (s, IH), 7.86 - 7.82 (m, 3H), 7.71 (dd, J=8.3, 1.7 Hz, IH), 7.53 (ddd, J=8.3, 7.1, 1.1 Hz, IH), 7.43 - 7.29 (m, 3H), 4.58 (d, J=7.7 Hz, 2H), 4.14 - 4.00 (m, 2H), 3.87 - 3.81 (m, IH), 3.72 - 3.64 (m, 2H), 3.58 (dd, J=8.8, 5.5 Hz, IH), 2.96 (s, IH), 1.94 (s, IH), 1.72 (d, J=7.4 Hz, IH), 1.06 (t, J=7.0 Hz, 3H); HPLC RT = 1.81 min (Method E), 1.81 min (Method F).
Example 348: N-(3-Methoxy-4-(4-oxo-3,4-dihydrophthalazin- 1 -yl)phenyl)-l - ((tetrahydrofuran-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000373_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 102 (15 mg, 0.039 mmol) and Intermediate 24 (9.7 mg, 0.039 mmol), afforded Example 348 (19.1 mg, 97% yield). MS(ESI) m/z: 496.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.79 (br. s., IH), 10.48 (br. s., IH), 8.28 (br. s., 2H), 7.90 (d, J=7.2 Hz, IH), 7.88 - 7.81 (m, 3H), 7.73 (br. s., IH), 7.53 (br. s., IH), 7.35 (d, J=8.8 Hz, 3H), 4.58 (br. s., 2H), 3.86 (br. s., IH), 3.72 (br. s., 3H), 3.68 (br. s., 2H), 3.59 (br. s., IH), 2.96 (br. s., IH), 1.94 (br. s., IH), 1.77 - 1.65 (m, IH); HPLC RT = 1.71 min (Method E), 1.71 min (Method F).
Example 349: Propan-2-yl 4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl]carbamoyl} - lH-indazol- 1 -yl)methyl]piperidine- 1 -carboxylate
Figure imgf000373_0002
According to the procedure for the preparation of Example 329, acylation of Example 342 (10 mg, 0.017 mmol) with isopropyl chloroformate afforded Example 349 (8 mg, 84% yield). MS(ESI) m/z: 565.2 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.82 (s, IH), 10.47 (s, IH), 8.35 (dd, J=7.7, 1.4 Hz, IH), 8.25 (d, J=8.3 Hz, IH), 8.13 - 8.06 (m, J=8.8 Hz, 2H), 7.97 - 7.85 (m, 3H), 7.81 - 7.73 (m, IH), 7.63 - 7.58 (m, J=8.5 Hz, 2H), 7.55 - 7.48 (m, IH), 7.34 (t, J=7.4 Hz, IH), 4.75 (quin, J=6.2 Hz, IH), 4.48 (d, J=7.2 Hz, 2H), 4.07 - 3.93 (m, 2H), 2.82 - 2.66 (m, 2H), 2.25 (ddd, J=l l. l, 7.4, 3.7 Hz, IH), 1.48 (d, J=11.0 Hz, 2H), 1.30 - 1.22 (m, 2H), 1.20 - 1.10 (m, 6H); HPLC RT = 2.04 min (Method E), 2.04 min (Method F).
Example 350: 2-Fluoroethyl 4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl]carbamoyl} - lH-indazol- 1 -yl)methyl]piperidine- 1 -carboxylate
Figure imgf000374_0001
According to the procedure for the preparation of Example 329, acylation of Example 342 (10 mg, 0.017 mmol) with 2-fluoroethyl chloroformate afforded Example 350 (8.5 mg, 86% yield). MS(ESI) m/z: 569.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.82 (br. s., IH), 10.48 (s, IH), 8.35 (dd, J=7.7, 1.4 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 8.12 - 8.05 (m, J=8.5 Hz, 2H), 7.96 - 7.84 (m, 3H), 7.77 (d, J=7.7 Hz, IH), 7.65 - 7.56 (m, J=8.5 Hz, 2H), 7.55 - 7.48 (m, IH), 7.34 (t, J=7.6 Hz, IH), 4.66 - 4.61 (m, IH), 4.55 - 4.51 (m, IH), 4.49 (d, J=7.2 Hz, 2H), 4.27 - 4.23 (m, IH), 4.23 - 4.15 (m, IH), 3.99 (d, J=13.2 Hz, 2H), 2.77 (br. s., IH), 2.73 (s, IH), 2.27 (ddd, J=l l. l, 7.4, 3.7 Hz, IH), 1.51 (d, J=l 1.0 Hz, 2H), 1.27 (qd, J=12.4, 4.1 Hz, 2H); HPLC RT = 1.93 min (Method E), 1.95 min (Method F).
Example 351: 2,2,2-Trifluoroethyl 4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl]carbamoyl} - lH-indazol- 1 -yl)methyl]piperidine- 1 -carboxylate
Figure imgf000375_0001
According to the procedure for the preparation of Example 329, acylation of Example 342 (10 mg, 0.017 mmol) with 2,2,2-trifluoroethyl chloroformate afforded Example 351 (6.6 mg, 62% yield). MS(ESI) m/z: 605.2 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.82 (br. s., IH), 10.47 (s, IH), 8.35 (dd, J=7.7, 1.4 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 8.13 - 8.06 (m, J=8.5 Hz, 2H), 7.98 - 7.85 (m, 3H), 7.81 - 7.72 (m, IH), 7.64 - 7.56 (m, J=8.5 Hz, 2H), 7.56 - 7.48 (m, IH), 7.34 (t, J=7.6 Hz, IH), 4.68 (q, J=9.1 Hz, 2H), 4.50 (d, J=7.2 Hz, 2H), 3.97 (br. s., 2H), 2.95 - 2.80 (m, 2H), 2.29 (ddt, J=l 1.2, 7.5, 3.9 Hz, IH), 1.65 - 1.47 (m, 2H), 1.28 (qd, J=12.3, 4.3 Hz, 2H); HPLC RT = 2.02 min (Method E), 2.02 min (Method F).
Example 352 : N-(2-Methoxy-4-(4-oxo-3,4-dihydrophthalazin- 1 -yl)phi
((tetrahydrofuran-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000375_0002
According to the procedure for the preparation of Example 45, coupling of
Intermediate 104 (15 mg, 0.056 mmol) and Intermediate 24 (13.8 mg, 0.056 mmol), afforded Example 352 (19.4 mg, 68% yield). MS(ESI) m/z: 496.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.84 (s, IH), 9.58 (s, IH), 8.55 (d, J=8.3 Hz, IH), 8.35 (dd, J=7.8, 1.5 Hz, IH), 8.27 (d, J=8.3 Hz, IH), 7.95 - 7.88 (m, 3H), 7.86 - 7.80 (m, IH), 7.59 - 7.51 (m, IH), 7.38 (t, J=7.4 Hz, IH), 7.34 (d, J=1.7 Hz, IH), 7.25 (dd, J=8.1, 1.8 Hz, IH), 4.65 - 4.52 (m, 2H), 4.00 (s, 3H), 3.89 - 3.84 (m, IH), 3.75 (dd, J=8.5, 6.9 Hz, IH), 3.72 - 3.66 (m, IH), 3.59 (dd, J=8.5, 5.8 Hz, IH), 2.99 - 2.86 (m, IH), 2.05 - 1.92 (m, IH), 1.72 (dd, J=12.9, 6.6 Hz, IH); HPLC RT = 1.82 min (Method E), 1.82 min
F).
Example 353: l-(2-Hydroxy-2-methylpropyl)-N-(2-hydroxy-4-(4-oxo-3,
dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000376_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 105 (8 mg, 0.032 mmol) and Intermediate 15 (7.4 mg, 0.032 mmol), afforded Example 353 (0.9 mg, 6% yield). MS(ESI) m/z: 470.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.80 (s, IH), 9.59 (s, IH), 8.53 (d, J=8.3 Hz, IH), 8.35 (d, J=7.4 Hz, IH), 8.26 (d, J=8.3 Hz, IH), 7.98 - 7.80 (m, 4H), 7.49 (t, J=7.7 Hz, IH), 7.34 (t, J=7.6 Hz, IH), 7.22 - 7.16 (m, IH), 7.1 1 (dd, J=8.3, 1.4 Hz, IH), 4.76 (s, IH), 4.56 - 4.43 (m, 2H), 1.28 - 1.15 (m, 6H); HPLC RT = 1.60 min (Method E), 1.56 min (Method F).
Example 354 : N-(2-Hydroxy-4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phi
-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000376_0002
According to the procedure for the preparation of Example 45, coupling of
Intermediate 105 (16 mg, 0.063 mmol) and Intermediate 24 (15.6 mg, 0.063 mmol), afforded Example 354 (4 mg, 13% yield). MS(ESI) m/z: 482.4 (M+H)+; XH NMR
(400MHz, DMSO-d6) δ 12.80 (s, IH), 10.63 (s, IH), 9.59 (s, IH), 8.51 (d, J=8.4 Hz, IH), 8.37 - 8.32 (m, 1H), 8.31 - 8.26 (m, 1H), 7.96 - 7.87 (m, 3H), 7.86 - 7.80 (m, 1H), 7.54 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.12 (dd, J=8.3, 1.9 Hz, 1H), 4.67 - 4.54 (m, 2H), 3.95 - 3.82 (m, 1H), 3.75 (dd, J=8.6, 7.0 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.63 - 3.50 (m, 1H), 2.96 - 2.82 (m, 1H), 2.06 - 1.91 (m, 1H), 1.72 (dt, J=13.5, 6.6 Hz, 1H); HPLC RT = 9.20 min (Method A), 8.67 min (Method B).
Example 355: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l- -3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000377_0001
Example 355A: Methyl 2-(4-oxo-3,4-dihydrophthalazin-l-yl)-5-(l-((tetrahydrofuran-3- yl)methyl)-l H-indazole-3 -carboxamido)benzoate
Figure imgf000377_0002
To a mixture of Intermediate 106 (34 mg, 0.12 mmol), Intermediate 24 (28 mg, 0.12 mmol), and HATU (48.2 mg, 0.127 mmol) in DMF (2 mL), was added DIEA (0.100 mL, 0.58 mmol). The reaction mixture was stirred at rt for 16h, the was concentrated. The residue was purified by preparative HPLC to afford Example 355A (39 mg, 64% yield). MS(ESI) m/z: 524.4 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 10.71 (s, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.39 - 8.31 (m, 1H), 8.28 (td, J=5.5, 2.8 Hz, 2H), 7.90 (d, J=8.5 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.61 - 7.51 (m, 2H), 7.42 - 7.34 (m, 1H), 7.32 - 7.25 (m, 1H), 4.68 - 4.52 (m, 2H), 3.86 (td, J=8.0, 5.6 Hz, 1H), 3.77 - 3.63 (m, 2H), 3.63 - 3.58 (m, 1H), 3.55 (s, 3H), 3.06 - 2.92 (m, 1H), 2.03 - 1.87 (m, 1H), 1.78 - 1.67 (m, 1H).
E
Figure imgf000378_0001
To a solution of Example 355A (13.2 mg, 0.025 mmol) in THF (1 mL) was added lithium borohydride (2M in THF, 0.684 mL, 1.37 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h, then was diluted with MeOH and DMSO and the solution was purified by preparative HPLC to afford Example 355 (7.6 mg, 58% yield). MS(ESI) m/z: 496.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) δ 12.77 (s, 1H), 10.40 (s, 1H), 8.39 - 8.30 (m, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.93 (dd, J=8.3, 2.2 Hz, 1H), 7.91 - 7.83 (m, 3H), 7.55 - 7.49 (m, 1H), 7.39 - 7.28 (m, 3H), 4.65 - 4.52 (m, 2H), 4.35 (br. s., 2H), 3.87 - 3.81 (m, 1H), 3.73 - 3.65 (m, 2H), 3.59 (dd, J=8.8, 5.5 Hz, 1H), 3.04 - 2.93 (m, 1H), 2.04 - 1.89 (m, 1H), 1.80 - 1.68 (m, 1H); HPLC RT = 1.55 min (Method E), 1.55 min (Method F).
Example 356: l-((l-Methylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000378_0002
According to the procedure for the preparation of Example 330, reductive amination of Example 342 (12 mg, 0.021 mmol) afforded Example 356 (6.4 mg, 64% yield). MS(ESI) m/z: 493.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.82 (s, IH), 10.47 (s, IH), 8.42 - 8.32 (m, IH), 8.25 (d, J=8.3 Hz, IH), 8.13 - 8.05 (m, J=8.5 Hz, 2H), 7.99 - 7.84 (m, 3H), 7.78 (d, J=8.3 Hz, IH), 7.65 - 7.55 (m, J=8.8 Hz, 2H), 7.51 (t, J=7.7 Hz, IH), 7.34 (t, J=7.4 Hz, IH), 4.47 (d, J=7.2 Hz, 2H), 2.83 - 2.66 (m, 2H), 2.14 (s, 3H), 2.05 - 1.96 (m, IH), 1.81 (t, J=l l . l Hz, 2H), 1.52 - 1.30 (m, 4H); HPLC RT = 1.30 min (Method E), 1.28 min (Method F).
Example 357: l-(2-Hydroxy-2-methylpropyl)-N-(2-methoxy-4-(4-oxo-3,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000379_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 104 (16 mg, 0.060 mmol) and Intermediate 15 (14 mg, 0.060 mmol), afforded Example 357 (6.1 mg, 20% yield). MS(ESI) m/z: 484.3 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.83 (s, IH), 9.59 (s, IH), 8.57 (d, J=8.3 Hz, IH), 8.35 (dd, J=7.7, 1.4 Hz, IH), 8.25 (d, J=8.0 Hz, IH), 7.98 - 7.78 (m, 4H), 7.54 - 7.46 (m, IH), 7.39 - 7.31 (m, 2H), 7.25 (dd, J=8.1, 1.8 Hz, IH), 4.77 (s, IH), 4.47 (s, 2H), 3.99 (s, 3H), 1.21 (s, 6H); HPLC RT = 1.69 min (Method E), 1.70 min (Method F).
Example 358: N-(2-Fluoro-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(2-hydroxy- -methylpropyl)- 1 H-indazole-3 -carboxamide
Figure imgf000379_0002
To a solution of Intermediate 107 (15 mg, 0.041 mmol), Intermediate 15 (10.5 mg, 0.045 mmol) and DIEA (0.035 mL, 0.20 mmol) in DMF (1 mL) at rt, was added HATU (17 mg, 0.045 mmol). The mixture was stirred at rt for 5 days. The reaction mixture was diluted with MeOH (1 mL), then was filtered and purified by prep HPLC to afford Example 358 (6.0 mg, 30% yield). MS(ESI) m/z: 472.2 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ 12.90 (s, IH), 9.85 (s, IH), 8.29-8.44 (m, IH), 8.17-8.29 (m, 2H), 7.89-7.99 (m, 2H), 7.88 (d, J=8.80 Hz, IH), 7.78 (d, J=7.43 Hz, IH), 7.60 (dd, J=1.65, 1 1.28 Hz, IH), 7.46-7.53 (m, 2H), 7.33 (t, J=7.43 Hz, IH), 4.48 (s, 2H), 1.20 (s, 6H); HPLC RT = 1.67 min (Method E), 1.66 min (Method F).
Example 359: l-(2-Hydroxyethyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4- dihydrophthalazi - 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000380_0001
According to the procedure of the preparation of Example 355, substituting
Intermediate 35 for Intermediate 24 afforded Example 359. MS(ESI) m/z: 456.2
(M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.80 (s, IH), 10.45 (s, IH), 8.36 - 8.30 (m, IH), 8.27 - 8.19 (m, 2H), 7.93 - 7.84 (m, 3H), 7.81 (d, J=8.4 Hz, IH), 7.49 (t, J=7.6 Hz, IH), 7.38 - 7.28 (m, 3H), 4.61 (t, J=5.0 Hz, 2H), 4.34 (br. s., 2H), 3.94 (d, J=5.4 Hz, 2H); HPLC RT = 1.31 min (Method E), 1.31 min (Method F).
Example 360: 1 -(2-Hydroxy-2-methylpropyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000381_0001
According to the procedure of the preparation of Example 355, substituting Intermediate 15 for Intermediate 24 afforded Example 360. MS(ESI) m/z: 484.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.80 (s, IH), 10.39 (s, IH), 8.38 - 8.28 (m, IH), 8.23 (d, J=8.1 Hz, IH), 8.18 (s, IH), 7.99 - 7.80 (m, 4H), 7.48 (t, J=7.6 Hz, IH), 7.38 - 7.20 (m, 3H), 5.17 (t, J=5.4 Hz, IH), 4.84 (s, IH), 4.48 (s, 2H), 4.34 (br. s., 2H), 3.89 (s, IH), 1.19 (s, 6H); HPLC RT = 1.39 min (Method E), 1.40 min (Method F).
Example 361: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phi
-2H-pyran-4-yl)ethyl)- 1 H-indazole-3 -carboxamide
Figure imgf000381_0002
According to the procedure for the preparation of Example 45, coupling of Intermediate 108 (12.5 mg, 0.047 mmol) and Intermediate 15 (14 mg, 0.051 mmol), afforded Example 361 (13.4 mg, 53% yield). MS(ESI) m/z: 484.3 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.77 (s, IH), 10.40 (s, IH), 8.34 - 8.29 (m, IH), 8.28 - 8.19 (m, 2H), 7.97 - 7.80 (m, 4H), 7.52 (td, J=7.7, 1.1 Hz, IH), 7.40 - 7.27 (m, 3H), 5.11 (t, J=5.4 Hz, IH), 4.61 (t, J=7.4 Hz, 2H), 4.34 (br. s., 2H), 3.85 - 3.79 (m, 2H), 3.29 - 3.19 (m, 3H), 1.96 - 1.85 (m, 2H); HPLC RT = 1.63 min (Method E), 1.64 min (Method F). Example 362: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide
Figure imgf000382_0001
According to the procedure for the preparation of Example 45, coupling of Intermediate 108 (13 mg, 0.049 mmol) and pyrazolo[l,5-a]pyridine-3-carboxylic acid (7.9 mg, 0.049 mmol), afforded Example 362 (4.1 mg, 20% yield). MS(ESI) m/z: 412.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.78 (br. s., 1H), 10.16 (br. s., 1H), 8.90 - 8.77 (m, 2H), 8.43 - 8.24 (m, 2H), 8.04 (br. s., 1H), 7.96 - 7.81 (m, 3H), 7.55 (t, J=7.5 Hz, 1H), 7.39 - 7.26 (m, 2H), 7.14 (t, J=6.4 Hz, 1H), 4.33 (br. s., 2H); HPLC RT = 1.28 min (Method E), 1.16 min (Method F). Example 363: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l- - 1 H-indazole-3 -carboxamide
Figure imgf000382_0002
According to the procedure for the preparation of Example 45, coupling of Intermediate 108 (8 mg, 0.030 mmol) and 1 -methyl- 1 H-indazole-3 -carboxylic acid (5.3 mg, 0.030 mmol), afforded Example 363 (7 mg, 55% yield). MS(ESI) m/z: 426.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.77 (s, 1H), 10.49 (s, 1H), 8.37 - 8.29 (m, 1H), 8.28 - 8.20 (m, 2H), 7.92 - 7.83 (m, 3H), 7.80 (d, J=8.5 Hz, 1H), 7.53 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.41 - 7.25 (m, 3H), 5.10 (t, J=5.4 Hz, 1H), 4.34 (br. s., 2H), 4.23 (s, 3H); HPLC RT = 1.40 min (Method E), 1.41 min (Method F). Example 364: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phi
- 1 H-indazole-3 -carboxamide
Figure imgf000383_0001
According to the procedure for the preparation of Example 45, coupling of Intermediate 108 (8 mg, 0.030 mmol) and 1 -isopropyl- 1 H-indazole-3 -carboxylic acid (6.1 mg, 0.030 mmol), afforded Example 364 (6.9 mg, 51% yield). MS(ESI) m/z: 454.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.78 (s, IH), 10.25 (s, IH), 8.37 - 8.30 (m, IH), 8.25 (d, J=8.0 Hz, IH), 8.19 (d, J=1.9 Hz, IH), 8.01 - 7.92 (m, IH), 7.91 - 7.83 (m, 3H), 7.50 (td, J=7.7, 0.8 Hz, IH), 7.38 - 7.28 (m, 3H), 5.25 - 5.06 (m, 2H), 4.35 (br. s., 2H), 1.62 (d, J=6.6 Hz, 6H); HPLC RT = 1.81 min (Method E), 1.69 min (Method F).
Example 365: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide
Figure imgf000383_0002
According to the procedure for the preparation of Example 45, coupling of
Intermediate 108 (10 mg, 0.037 mmol) and imidazo[l,2-a]pyridine-3 -carboxylic acid (6.7 mg, 0.041 mmol), afforded Example 365 (10.7 mg, 68% yield). MS(ESI) m/z: 412.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 9.51 (d, J=7.0 Hz, IH), 8.66 (s, IH), 8.41 - 8.23 (m, IH), 8.05 (s, IH), 7.93 (s, IH), 7.92 - 7.83 (m, 3H), 7.78 (d, J=8.9 Hz, IH), 7.54 (t, J=7.8 Hz, IH), 7.32 (d, J=7.9 Hz, 2H), 7.21 (t, J=6.7 Hz, IH), 4.34 (br. s., 2H), 3.11 (d, J=7.3 Hz, IH); HPLC RT = 0.95 min (Method E), 1.14 min (Method F). Example 366: 5-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)- 1 -((tetrahydrofuran-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000384_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 108 (10 mg, 0.037 mmol) and Intermediate 49 (10.9 mg, 0.041 mmol), afforded Example 366 (8.6 mg, 45% yield). MS(ESI) m/z: 514.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 10.43 (s, IH), 8.32 (d, J=5.2 Hz, IH), 8.15 (s, IH), 7.99 - 7.77 (m, 6H), 7.42 (t, J=9.0 Hz, IH), 7.36 - 7.26 (m, 2H), 4.54 (d, J=7.3 Hz, 2H), 4.33 (br. s., 2H), 3.91 - 3.76 (m, IH), 3.61 - 3.51 (m, IH), 2.99 - 2.90 (m, IH), 1.99 - 1.88 (m, IH), 1.69 (dq, J=12.7, 6.6 Hz, IH); HPLC RT = 1.52 min (Method E), 1.48 min (Method F).
Example 367: N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phi
-2-yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000384_0002
According to the procedure for the preparation of Example 45, coupling of Intermediate 108 (9.5 mg, 0.036 mmol) and Intermediate 109 (9.6 mg, 0.039 mmol), afforded Example 367 (13.7 mg, 74% yield). MS(ESI) m/z: 496.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 10.46 (s, IH), 8.41 - 8.30 (m, IH), 8.29 - 8.18 (m, 2H), 8.00 - 7.78 (m, 4H), 7.50 (t, J=7.6 Hz, IH), 7.38 - 7.26 (m, 3H), 4.62 (d, J=5.4 Hz, 2H), 4.41 (quin, J=6.1 Hz, 1H), 4.34 (br. s., 2H), 3.73 (q, J=6.8 Hz, 1H), 3.68 - 3.56 (m, 1H), 3.44 - 3.33 (m, 1H), 2.08 - 1.94 (m, 1H), 1.86 - 1.71 (m, 3H); HPLC RT = 1.54 min (Method E), 1.66 min (Method F).
Example 368: 6-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-l- - 1 -((tetrahydrofuran-3 -yl)methyl)- 1 H-indazole-3 -carboxamide
Figure imgf000385_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 108 (9.5 mg, 0.036 mmol) and Intermediate 50 (10.3 mg, 0.039 mmol), afforded Example 368 (8.6 mg, 47% yield). MS(ESI) m/z: 514.2 (M+H)+; (500MHz,
DMSO-d6) δ 10.47 (s, 1H), 8.39 - 8.30 (m, 1H), 8.30 - 8.17 (m, 2H), 7.96 - 7.77 (m, 4H), 7.39 - 7.31 (m, 2H), 7.24 (t, J=8.9 Hz, 1H), 4.63 - 4.49 (m, 2H), 4.34 (br. s., 2H), 3.88 - 3.80 (m, 1H), 3.76 - 3.64 (m, 2H), 3.58 (dd, J=8.6, 5.6 Hz, 1H), 2.95 (dt, J=13.7, 6.8 Hz, 1H), 2.07 - 1.89 (m, 1H), 1.71 (dq, J=12.9, 6.6 Hz, 1H); HPLC RT = 1.55 min (Method E), 1.76 min (Method F).
Example 369: 1 -(2-Hydroxy-2-methylpropyl)-N-(4-(6-methoxy-4-oxo- dihydrophthalazin- 1 -yl)phenyl)- 1 H-indazole-3 -carboxamide
Figure imgf000385_0002
Intermediate 110 (15 mg, 0.039 mmol) and Intermediate 15 (1 1 mg, 0.047 mmol), afforded Example 369 (0.9 mg, 6% yield). MS(ESI) m/z: 484.2 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.75 (s, IH), 10.40 (s, IH), 8.23 (d, J=8.3 Hz, IH), 8.06 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, IH), 7.76 - 7.69 (m, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.53 - 7.42 (m, 2H), 7.32 (t, J=7.6 Hz, IH), 4.79 (s, IH), 4.49 (s, 2H), 3.97 (s, 3H), 1.20 (s, 6H); HPLC RT = 1.76 min (Method E), 1.64 min (Method F).
Example 370: N-(4-(6-Methoxy-4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)imidazo[l,2- a]pyridine-2-carboxamide
Figure imgf000386_0001
According to the procedure for the preparation of Example 45, coupling of
Intermediate 110 (15 mg, 0.039 mmol) and Intermediate 15 (7.7 mg, 0.047 mmol), afforded Example 370 (0.5 mg, 3% yield). MS(ESI) m/z: 412.2 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.74 (s, IH), 10.51 (s, IH), 8.64 (d, J=6.6 Hz, IH), 8.57 (s, IH), 8.09 (d, J=8.3 Hz, 2H), 7.76 - 7.64 (m, 3H), 7.56 (d, J=8.5 Hz, 2H), 7.49 (dd, J=9.1, 2.8 Hz, IH), 7.43 - 7.36 (m, IH), 7.04 (t, J=6.7 Hz, IH), 3.96 (s, 3H); HPLC RT = 1.18 min (Method E), 1.37 min (Method F).
Example 371: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)spiro[indoline-3,4'- - 1 -carboxamide
Figure imgf000386_0002
2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (50 mg, 0.204 mmol) and tert-butyl spiro[indoline-3,4'-piperidine]-l'-carboxylate (58.8 mg, 0.204 mmol) were dissolved in THF (3 mL), and DIEA (0.053 mL, 0.31 mmol) was added. The reaction mixture was stirred at rt for 1 h. THF was removed under reduced pressure. To the obtained residue were added 4-chlorophthalazin-l(2H)-one (18.4 mg, 0.102 mmol) and phosphoric acid, potassium salt (54.1 mg, 0.255 mmol), followed by dioxane (3 mL) and water (0.333 mL). The mixture was degassed (evacuated and flushed with Ar (3x)). Pd(PPh3)4 (11.8 mg, 10.2 μιηοΐ) was added, then the mixture was degassed (2x). The reaction vial was sealed and heated in a microwave reactor at 150 °C for 30 min. The solvent was removed under reduced pressure, and the residue was treated with TFA (2 mL). The reaction mixture was stirred for 15 min. TFA was removed under reduced pressure. The residue was purified by prep HPLC to afford Example 371 (1 1.9 mg, 25% yield). MS(ESI) m/z: 452.3 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 8.90 (br. s., 1H), 8.81 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.02 - 7.85 (m, 4H), 7.76 (d, J=8.4 Hz, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.06 - 6.95 (m, 1H), 4.18 (s, 2H), 3.48 - 3.33 (m, 1H), 3.02 (br. s., 2H), 2.1 1 - 1.99 (m, 2H), 1.88 (d, J=13.8 Hz, 2H); HPLC RT = 1.13 min (Method E), 1.09 min (Method F).
Example 372 : N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(piperidin-4-yl)- 1 H- l,2,3-triazole-4-carboxamide
Figure imgf000387_0001
To a mixture of Intermediate 12 (20 mg, 0.084 mmol), \-(\-(tert- butoxycarbonyl)piperidin-4-yl)-lH-l,2,3-triazole-4-carboxylic acid (25 mg, 0.084 mmol), HATU (38.5 mg, 0.101 mmol) in DMF (1.5 mL), was added DIEA (0.074 mL, 0.42 mmol). The mixture was stirred rt for 16h, then was concentrated. The residue was stirred with TFA (0.5 mL) in DCM (1 mL) for 30 min, then was concentrated and purified by prep HPLC to afford Example 372 (9.6 mg, 27% yield). MS(ESI) m/z: 416.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.88 - 12.81 (m, 1H), 10.71 (s, 1H), 8.88 (s, 1H), 8.34 (d, J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.95 - 7.85 (m, 2H), 7.75 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 4.94 (br. s., 1H), 3.46 (d, J=12.1 Hz, 1H), 3.18 - 3.04 (m, 2H), 2.38 (d, J=12.8 Hz, 2H), 2.23 (d, J=10.8 Hz, 2H); HPLC RT = 0.78 min (Method E), 0.75 min (Method F).
Example 373 : 1 -Cyclohexyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 H- pyrazole-4-carboxamide, TFA
Figure imgf000388_0001
Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry MeCN (1.5 mL), then bromocyclohexane (0.072 mL, 0.588 mmol) was added, followed by cesium carbonate (96 mg, 0.294 mmol) and the reaction mixture was heated under microwave irradiation at 150 °C for 30 min. The reaction mixture was cooled to rt, and most of MeCN was removed under reduced pressure. The obtained residue was treated TFA (2 mL), and the reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure. The crude product was purified by preparative HPLC to afford 17.6 mg (57%) of Example 373. MS(ESI) m/z: 414.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ ppm 12.81 (s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 8.36 - 8.30 (m, 1H), 8.05 (s, 1H), 7.93 - 7.84 (m, 4H), 7.75 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 4.27 - 4.14 (m, 1H), 2.10 - 2.00 (m, 2H), 1.82 (d, J=13.4 Hz, 2H), 1.77 - 1.60 (m, 3H), 1.41 (q, J=12.9 Hz, 2H), 1.22 (q, J=13.0 Hz, IH); HPLC RT = 1.61 min (Method E), 1.62 min (Method F).
Example 374 : 1 -Cyclopentyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 H- -4-carboxamide, TFA
Figure imgf000389_0001
According to the procedure for the preparation of Example 373, substituting bromocyclopentane for bromocyclohexane afforded Example 374. MS(ESI) m/z: 400.1 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.82 (s, IH), 10.04 (s, IH), 8.39 (s, IH), 8.35 - 8.31 (m, IH), 8.04 (s, IH), 7.94 - 7.88 (m, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.3 Hz, IH), 7.55 (d, J=8.5 Hz, 2H), 4.74 (quin, J=6.9 Hz, IH), 2.17 - 2.05 (m, 2H), 1.91 (dd, J=12.8, 7.0 Hz, 2H), 1.84 - 1.74 (m, 2H), 1.71 - 1.60 (m, 2H); HPLC RT = 1.50 min (Method E), 1.51 min (Method F). Example 375: l-(Cyclopropylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- -pyrazole-4-carboxamide, TFA
Figure imgf000389_0002
According to the procedure for the preparation of Example 373, substituting (bromomethyl)cyclopropane for bromocyclohexane afforded Example 375. MS(ESI) m/z: 386.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.82 (s, IH), 10.08 (s, IH), 8.40 (s, 1H), 8.33 (d, J=7.0 Hz, 1H), 8.06 (s, 1H), 7.95 - 7.82 (m, 4H), 7.74 (d, J=7.3 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 4.02 (d, J=7.3 Hz, 2H), 1.32 - 1.22 (m, 1H), 0.59 - 0.52 (m, 2H), 0.42 - 0.34 (m, 2H); HPLC RT = 1.36 min (Method E), 1.36 min (Method F). Example 376: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(2,2,2-trifluoroethyl)- -pyrazole-4-carboxamide, TFA
Figure imgf000390_0001
According to the procedure for the preparation of Example 373, substituting 2,2,2-trifluoroethyl trifluoromethanesulfonate for bromocyclohexane afforded Example 376. MS(ESI) m/z: 386.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.23 (s, 1H), 8.50 (s, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 7.95 - 7.82 (m, 4H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.2 Hz, 2H), 5.20 (q, J=9.1 Hz, 2H); HPLC RT = 1.34 min (Method E), 1.35 min (Method F). Example 377: l-(2-Hydroxy-2-methylpropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- -lH-pyrazole-4-carboxamide
Figure imgf000390_0002
According to the procedure for the preparation of Example 373, substituting 2,2- dimethyloxirane for bromocyclohexane afforded Example 377. MS(ESI) m/z: 404.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.84 (s, 1H), 10.10 (s, 1H), 8.36 - 8.28 (m, 2H), 8.05 (s, 1H), 7.95 - 7.84 (m, 4H), 7.75 (d, J=7.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 4.91 (s, 1H), 4.07 (s, 2H), 1.08 (s, 6H); HPLC RT = 0.98 min (Method E), 0.98 min (Method F).
Example 378: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(3,3,3-trifluoro-2- - 1 H-pyrazole-4-carboxamide
Figure imgf000391_0001
According to the procedure for the preparation of Example 373, substituting 2- (trifluoromethyl)oxirane for bromocyclohexane afforded Example 378. MS(ESI) m/z: 440.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.36 - 8.30 (m, 1H), 8.14 (s, 1H), 7.99 - 7.84 (m, 5H), 7.75 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 4.53 - 4.40 (m, 2H), 4.39 - 4.27 (m, 1H); HPLC RT = 1.11 min (Method E), 1.1 1 min (Method F). Example 379: l-(2-Hydroxy-3-methoxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- -lH-pyrazole-4-carboxamide
Figure imgf000391_0002
According to the procedure for the preparation of Example 373, substituting 2- (methoxymethyl)oxirane for bromocyclohexane afforded Example 379. MS(ESI) m/z: 420.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 10.07 (s, 1H), 8.38 - 8.29 (m, 2H), 8.06 (s, 1H), 7.96 - 7.84 (m, 4H), 7.75 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 4.23 (dd, J=13.8, 3.7 Hz, 1H), 4.13 - 4.04 (m, 1H), 3.98 (br. s., 1H), 3.31 - 3.25 (m, 5H); HPLC RT = 0.91 min (Method E), 1.00 min (Method F). Example 380: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(3,3,3-trifluoro-2- -2-(trifluoromethyl)propyl)-lH-pyrazole-4-carboxamide
Figure imgf000392_0001
According to the procedure for the preparation of Example 373, substituting 2,2- bis(trifluoromethyl)oxirane for bromocyclohexane afforded Example 380. MS(ESI) m/z: 512.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.17 (s, 1H), 8.40 (s, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.1 1 (s, 1H), 7.97 - 7.81 (m, 4H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 4.81 (s, 2H); HPLC RT = 1.48 min (Method E), 1.50 min (Method F).
Example 381: 1 -(tert-Butyl)-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phi
-4-carboxamide
Figure imgf000392_0002
Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry MeCN (1.5 mL), then 2-bromo-2-methylpropane (0.066 mL, 0.59 mmol) was added, followed by silver carbonate (81 mg, 0.29 mmol) and the reaction mixture stirred at 150 °C for 15 min under microwave irradiation. The reaction mixture was cooled to rt, and most of MeCN was removed under reduced pressure. The obtained residue was treated with TFA (2 mL), and the reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure, the residue was diluted with DMF (2 mL), filtered and purified by prep HPLC to afford Example 381 (2.6 mg, 11% yield). MS(ESI) m/z: 388.2 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.82 (s, 1H), 10.03 (s, 1H), 8.46 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.05 (s, 1H), 7.95 - 7.88 (m, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 1.55 (s, 9H); HPLC RT = 1.42 min (Method E), 1.44 min (Method F).
Example 382 : N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -propyl- 1 H-pyrazole-4-
Figure imgf000393_0001
According to the procedure for the preparation of Example 373, substituting 1- bromopropane for bromocyclohexane afforded Example 382. MS(ESI) m/z: 374.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.82 (s, 1H), 10.09 (s, 1H), 8.32 (s, 2H), 8.05 (s, 1H), 7.94 - 7.87 (m, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H), 1.79 (sxt, J=7.2 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); HPLC RT = 1.30 min (Method E), 1.32 min (Method F).
Example 383: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(2,2,3,3- tetrafluoropropyl)- lH-pyrazole-4-carboxamide, TFA
Figure imgf000394_0001
According to the procedure for the preparation of Example 373, substituting 2,2,3,3 -tetrafluoropropyl trifluoromethanesulfonate for bromocyclohexane afforded
Example 383. MS(ESI) m/z: 446.1 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.22 (s, 1H), 8.46 (s, 1H), 8.33 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.95 - 7.87 (m, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.73 - 6.25 (m, 1H), 4.99 (t, J=15.0 Hz, 2H); HPLC RT = 1.40 min (Method E), 1.40 min (Method F). Example 384: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(tetrahydro-2H-pyran- -yl)- 1 H-pyrazole-4-carboxamide
Figure imgf000394_0002
According to the procedure for the preparation of Example 373, substituting 4- bromotetrahydro-2H-pyran for bromocyclohexane afforded Example 384. MS(ESI) m/z: 416.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, 1H), 10.01 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.10 (s, 1H), 7.98 - 7.85 (m, 4H), 7.76 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 4.49 (t, J=l 1.3 Hz, 1H), 3.98 (d, J=10.1 Hz, 2H), 3.49 (t, J=11.4 Hz, 1H), 2.10 - 1.89 (m, 4H); HPLC RT = 1.22 min (Method E), 1.22 min (Method F). Example 385: 1 -(Cyclopropylmethyl)-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- -pyrazole-4-carboxamide, TFA
Figure imgf000395_0001
According to the procedure for the preparation of Example 373, substituting bromocyclobutane for bromocyclohexane afforded Example 385. MS(ESI) m/z: 386.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, IH), 10.02 (s, IH), 8.46 (s, IH), 8.34 (d, J=7.3 Hz, IH), 8.09 (s, IH), 7.94 - 7.84 (m, 4H), 7.75 (d, J=7.6 Hz, IH), 7.56 (d, J=8.5 Hz, 2H), 4.90 (quin, J=8.3 Hz, IH), 2.49 - 2.37 (m, 4H), 1.87 - 1.76 (m, 2H); HPLC RT = 1.39 min (Method E), 1.39 min (Method F).
Example 386: l-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- -pyrazole-4-carboxamide
Figure imgf000395_0002
According to the procedure for the preparation of Example 373, substituting 2,2- difluoroethyl trifluoromethanesulfonate for bromocyclohexane afforded Example 386. MS(ESI) m/z: 396.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, IH), 10.14 (s, IH), 8.46 (s, IH), 8.34 (d, J=7.1 Hz, IH), 8.16 (s, IH), 7.97 - 7.85 (m, 4H), 7.76 (d, J=7.4 Hz, IH), 7.57 (d, J=8.8 Hz, 2H), 6.42 (t, J=54.2 Hz, IH), 4.73 (td, J=15.2, 3.2 Hz, 2H); HPLC RT = 1.17 min (Method E), 1.17 min (Method F).
Example 387: l-(2-Hydroxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- lH-pyrazole-4-carboxamide
Figure imgf000396_0001
According to the procedure for the preparation of Example 373, substituting 2- methyloxirane for bromocyclohexane afforded Example 387. MS(ESI) m/z: 396.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.06 (s, 1H), 8.37 - 8.31 (m, 2H), 8.06 (s, 1H), 7.95 - 7.86 (m, 4H), 7.75 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 5.06 (d, J=4.7 Hz, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 3.95 (m, 2H), 1.07 (d, J=6.1 Hz, 3H); HPLC RT = 0.99 min (Method E), 0.99 min (Method F).
Example 388: l-(4-Chlorophenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phi
-4-carboxamide
Figure imgf000396_0002
Intermediate 111 (20 mg, 0.047 mmol), 1 -chloro-4-iodobenzene (34 mg, 0.141 mmol), salicylaldoxime (6.5 mg, 0.047 mmol) and cesium carbonate (46 mg, 0.14 mmol) were suspended in DMF (1.5 mL). The obtained suspension was degassed (3x vacuum/Ar), then copper(I) oxide (1.7 mg, 0.012 mmol) was added. The reaction mixture was degassed again (2x vacuum/Ar) and was stirred under microwave irradiation at 200 °C for 30 min. The reaction mixture was cooled to rt, and most of DMF was evaporated. The obtained residue was treated TFA (2 mL), and the reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure, the residue was purified by prep HPLC to afford Example 388 (2.2 mg, 10% yield). MS(ESI) m/z: 442.2 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.82 (s, IH), 10.22 (s, IH), 9.13 (s, IH), 8.37 (s, IH), 8.34 (d, J=7.6 Hz, IH), 8.02 - 7.84 (m, 6H), 7.76 (d, J=7.6 Hz, IH), 7.61 (dd, J=13.9, 8.4 Hz, 4H); HPLC RT = 1.77 min (Method E), 1.76 min (Method F). Example 389: l-(Oxetan-3-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-lH- -4-carboxamide
Figure imgf000397_0001
According to the procedure for the preparation of Example 373, substituting 3- bromooxetane for bromocyclohexane afforded Example 389. MS(ESI) m/z: 388.0 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.84 (s, IH), 10.12 (s, IH), 8.54 (s, IH), 8.37 - 8.30 (m, IH), 8.21 (s, IH), 7.96 - 7.85 (m, 4H), 7.75 (d, J=7.4 Hz, IH), 7.57 (d, J=8.4 Hz, 2H), 5.65 (quin, J=6.9 Hz, IH), 5.00 - 4.93 (m, 2H), 4.93 - 4.87 (m, 2H); HPLC RT = 1.03 min (Method E), 0.94 min (Method F). Example 390: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(tetrahydrofuran-3-yl)- -pyrazole-4-carboxamide
Figure imgf000397_0002
According to the procedure for the preparation of Example 373, substituting 3- bromotetrahydrofuran for bromocyclohexane afforded Example 390. MS(ESI) m/z: 402.1 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, IH), 10.07 (s, IH), 8.45 (s, IH), 8.34 (d, J=7.1 Hz, IH), 8.09 (s, IH), 7.97 - 7.85 (m, 4H), 7.75 (d, J=7.7 Hz, IH), 7.57 (d, J=8.1 Hz, 2H), 5.10 (br. s., IH), 4.06 - 3.97 (m, 2H), 3.97 - 3.90 (m, IH), 3.88 - 3.78 (m, IH), 2.48 - 2.36 (m, IH), 2.27 (d, J=3.7 Hz, IH); HPLC RT = 1.10 min (Method E), 1.02 min (Method F).
Example 391 : N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 H-pyrazole-4- carboxamide, TFA
Figure imgf000398_0001
Intermediate 111 (20 mg, 0.047 mmol) was treated with TFA (2 mL). The reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure, then the residue was purified by prep HPLC to afford Example 391 (1 1.6 mg, 53% yield). MS(ESI) m/z: 332.0 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, IH), 10.02 (s, IH), 8.41 (br. s., IH), 8.34 (d, J=7.3 Hz, IH), 8.10 (br. s., IH), 7.96 - 7.84 (m, 4H), 7.76 (d, J=7.6 Hz, IH), 7.56 (d, J=7.9 Hz, 2H); HPLC RT = 1.01 min (Method E), 1.01 min (Method F).
Example 392: l-(Bicyclo[2.2. l]heptan-7-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)-lH-pyrazole-4-carboxamide
Example 393: l-((l S,2S,4R)-Bicyclo[2.2.1]heptan-2-yl)-N-(4-(4-oxo-3,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-pyrazole-4-carboxamide
Figure imgf000398_0002
Intermediate 111 (20 mg, 0.047 mmol) was suspended in dry MeCN (1.5 mL), then (lR,4S)-7-bromobicyclo[2.2.1]heptane (0.060 mL, 0.470 mmol) was added, followed by cesium carbonate (153 mg, 0.470 mmol) and the reaction mixture was heated under microwave irradiation at 150 °C for 15 min. The reaction mixture was heated at 175 °C for 30 min (3x). The reaction mixture was cooled to rt, and most of MeCN was removed under reduced pressure. The obtained residue was treated TFA (2 mL), and the reaction mixture was stirred at rt for 15 min. TFA was removed under reduced pressure, the residue was purified by prep HPLC to afford Example 392 (7.8 mg, 38% yield) and Example 393 (2.5 mg, 13% yield).
Example 392: MS(ESI) m/z: 426.0 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, 1H), 9.98 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.98 - 7.87 (m, 4H), 7.76 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 2H), 4.38 - 4.29 (m, 1H), 2.47 (br. s., 1H), 2.39 (br. s., 1H), 2.05 (d, J=13.4 Hz, 1H), 1.91 - 1.83 (m, 1H), 1.75 (d, J=9.8 Hz, 1H), 1.65 - 1.46 (m, 2H), 1.38 - 1.30 (m, 1H), 1.21 (d, J=9.2 Hz, 2H); HPLC RT = 1.51 min (Method E), 1.52 min (Method F).
Example 393: MS(ESI) m/z: 426.0 (M+H)+; XH NMR (500 MHz, DMSO-d6) δ ppm 12.81 (br. s., 1H), 9.99 (br. s., 1H), 8.51 - 8.40 (m, 1H), 8.34 (d, J=7.0 Hz, 1H), 8.07 (br. s., 1H), 7.89 (d, J=7.9 Hz, 4H), 7.76 (d, J=7.0 Hz, 1H), 7.57 (d, J=7.3 Hz, 2H), 4.73 (br. s., 1H), 2.34 (br. s., 1H), 2.08 (d, J=14.3 Hz, 1H), 1.90 (br. s., 1H), 1.78 (br. s., 1H), 1.65 - 1.47 (m, 2H), 1.46 - 1.27 (m, 4H); HPLC RT = 1.49 min (Method E), 1.49 min (Method F).
Example 394: 5-Methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-l-yl)phi
- lH-pyrazole-4-carboxamide
Figure imgf000399_0001
Intermediate 94 (50 mg, 0.137 mmol) was dissolved in dry DMF (2 mL), then 5- methyl-1 -phenyl- lH-pyrazole-4-carboxylic acid (55.4 mg, 0.274 mmol) and DIEA (0.143 mL, 0.821 mmol) were added. After stirring for 5 min at rt, HATU (52 mg, 0.137 mmol) was added, and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was quenched with MeOH (0.1 mL) was purified by preparative HPLC to afford
Example 394 (18 mg, 29% yield) as an off-white solid. MS(ESI) m/z: 436.0 (M+H)+; XH NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1H), 9.97 (s, 1H), 8.37 (s, 1H), 8.35 - 8.29 (m, 1H), 7.91 - 7.84 (m, 2H), 7.79 (d, J=1.8 Hz, 1H), 7.74 (dd, J=8.4, 2.0 Hz, 1H), 7.63 - 7.54 (m, 4H), 7.54 - 7.46 (m, 1H), 7.32 - 7.26 (m, 2H), 2.58 (s, 3H), 2.09 (s, 3H); HPLC RT = 8.43 min (Method A), 8.11 min (Method B). Example 395: 5-(tert-Butyl)-l-methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000400_0001
According to the procedure for the preparation of Example 394, coupling of Intermediate 94 (40 mg, 0.109 mmol) with 5 -(tert-butyl)-l -methyl- lH-pyrazole-3- carboxylic acid (31.9 mg, 0.175 mmol) 60 °C for 2 days afforded Example 395 (18.2 mg 39% yield). MS(ESI) m/z: 416.1 (M+H)+; 'H NMR xH-NMR: (500 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 10.00 (s, 1H), 8.35 - 8.29 (m, 1H), 7.91 - 7.83 (m, 3H), 7.79 (dd, J=8.4, 2.0 Hz, 1H), 7.31 - 7.24 (m, 2H), 6.59 (s, 1H), 4.05 (s, 3H), 2.07 (s, 3H), 1.39 (s, 9H); HPLC RT = 13.24 min (Method A), 1 1.79 min (Method B).
Example 396 : 1 -( 1 , 1 -Dioxidotetrahydrothiophen-3 -yl)-N-(4-(4-oxo-3 ,4- dihydrophthalazin- 1 -yl)phenyl)- 1 H-pyrazole-4-carboxamide, TFA
Figure imgf000401_0001
According to the procedure for the preparation of Example 373, substituting 3- bromotetrahydrothiophene 1,1 -dioxide for bromocyclohexane afforded Example 396. MS(ESI) m/z: 450.1 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 12.81 (s, IH), 10.09 (s, IH), 8.54 (s, IH), 8.34 (d, J=7.3 Hz, IH), 8.19 (s, IH), 7.98 - 7.84 (m, 4H), 7.76 (d, J=7.6 Hz, IH), 7.58 (d, J=7.9 Hz, 2H), 5.35 (t, J=7.3 Hz, IH), 3.78 (dd, J=13.6, 8.4 Hz, IH), 3.51 (dd, J=13.9, 7.5 Hz, IH), 3.49 - 3.38 (m, IH), 2.73 - 2.65 (m, IH), 2.64 - 2.55 (m, IH); HPLC RT = 1.13 min (Method E), 1.14 min (Method F).
Example 397 : N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(pyrrolidin-3 -yl)- 1 H- -4-carboxamide
Figure imgf000401_0002
According to the procedure for the preparation of Example 373, substituting tert- butyl 3-bromopyrrolidine-l-carboxylate for bromocyclohexane afforded Example 397. MS(ESI) m/z: 401.3 (M+H)+; ¾ NMR (500 MHz, DMSO-d6) δ ppm 10.09 (s, IH), 8.45 (s, IH), 8.34 (d, J=7.1 Hz, IH), 8.09 (s, IH), 7.95 - 7.83 (m, 5H), 7.74 (d, J=7.4 Hz, IH), 7.56 (d, J=8.4 Hz, 2H), 4.96 (br. s., IH), 3.29 (dd, J=12.1, 7.1 Hz, IH), 3.17 - 3.06 (m, 2H), 3.03 - 2.93 (m, IH), 2.32 - 2.22 (m, IH), 2.15 - 2.01 (m, IH); HPLC RT = 0.85 min (Method E), 0.85 min (Method F). Example 398: N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(3 ,3 ,3 - - 1 H-pyrazole-4-carboxamide
Figure imgf000402_0001
According to the procedure for the preparation of Example 373, substituting 3- bromo- 1,1,1 -trifluoropropane for bromocyclohexane afforded Example 398. MS(ESI) m/z: 428.2 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.84 (s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.13 (s, 1H), 7.95 - 7.83 (m, 4H), 7.75 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 4.46 (t, J=6.6 Hz, 2H), 2.98 - 2.89 (m, 2H); HPLC RT = 1.35 min (Method E), 1.35 min (Method F).
Example 399: N-(4-(4-Oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -(3 -(pyrrolidin- 1 - - 1 H-pyrazole-4-carboxamide
Figure imgf000402_0002
According to the procedure for the preparation of Example 373, substituting l-(3- bromopropyl)pyrrolidine, HCl for bromocyclohexane afforded Example 399. MS(ESI) m/z: 443.3 (M+H)+; 'H NMR (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.02 (s, 1H), 8.39 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.08 (s, 1H), 7.97 - 7.85 (m, 4H), 7.76 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 4.21 (t, J=6.9 Hz, 2H), 2.43 (br. s., 4H), 2.37 (t, J=7.1 Hz, 2H), 1.97 (quin, J=6.9 Hz, 2H), 1.69 (br. s., 4H); HPLC RT = 0.91 min (Method E), 0.90 min (Method F). Example 400: 5 -Methyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- 1 -phenyl- 1 H- -triazole-4-carboxamide
Figure imgf000403_0001
To a mixture of Intermediate 12 (15 mg, 0.043 mmol), Intermediate 112 (9.5 mg, 0.047 mmol), and HATU (18 mg, 0.047 mmol) in DMF (1.5 mL), was added DIEA (0.037 mL, 0.21 mmol). The mixture was stirred rt for 3h, then 50 °C overnight. The mixture was purified by prep PHLC to afford Example 400 (4.6 mg, 24% yield).
MS(ESI) m/z: 423.1 (M+H)+; ¾ NMR (500MHz, DMSO-d6) d 12.82 (s, IH), 10.73 (s, IH), 8.35 (d, J=6.7 Hz, IH), 8.09 - 8.03 (m, J=7.9 Hz, 2H), 7.97 - 7.87 (m, 2H), 7.76 (d, J=7.3 Hz, IH), 7.67 (br. s., 5H), 7.61 - 7.55 (m, J=7.9 Hz, 2H), 2.60 (s, 3H); HPLC RT = 1.70 min (Method E), 1.71 min (Method F).
Example 401 : 1 -(4-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 - - 1 H- 1 ,2,3 -triazole-4-carboxamide
Figure imgf000403_0002
According to the procedure for the preparation of Example 400, coupling of Intermediate 12 (12 mg, 0.034 mmol) and Intermediate 113 (8.8 mg, 0.038 mmol) afforded Example 401 (1.8 mg, 11% yield). MS(ESI) m/z: 453.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.82 (s, IH), 10.70 (s, IH), 8.34 (d, J=7.6 Hz, IH), 8.05 (d, J=7.9 Hz, 2H), 7.91 (t, J=7.6 Hz, 2H), 7.76 (d, J=7.9 Hz, IH), 7.58 (d, J=8.2 Hz, 4H), 7.19 (d, J=8.2 Hz, 2H), 3.86 (s, 3H), 2.56 (s, 3H); HPLC RT = 1.69 min (Method E), 1.70 min (Method F).
Example 402 : 1 -(4-Methoxyphenyl)-4-methyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 - l hen l -lH-l 2 3-triazole-5-carboxamide
Figure imgf000404_0001
According to the procedure for the preparation of Example 400, coupling of Intermediate 12 (12 mg, 0.034 mmol) and Intermediate 114 (8.8 mg, 0.038 mmol) afforded Example 402 (2.5 mg, 16% yield). MS(ESI) m/z: 453.2 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.83 (s, IH), 10.98 (s, IH), 8.33 (d, J=7.6 Hz, IH), 7.89 (d, J=4.3 Hz, 2H), 7.76 (d, J=7.9 Hz, 2H), 7.70 (d, J=7.0 Hz, IH), 7.58 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 3.80 (s, 3H), 2.45 (s, 3H); HPLC RT = 1.44 min (Method E), 1.45 min (Method F). Example 403: 5-(Difluoromethoxy)-l-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000404_0002
Example 403A: Methyl 5 -(difluoromethoxy)-l -methyl- lH-pyrazole-3-carboxylate
Figure imgf000405_0001
Methyl 5 -hydroxy- 1 -methyl- lH-pyrazole-3-carboxylate (J. Med. Chem., 54:8174 (2011)) (0.35 g, 2.24 mmol), K2C03 (0.62 g, 4.48 mmol), and sodium
chlorodifluoroacetate (0.684 g, 4.48 mmol) were dissolved in DMF (10 ml) and water (1 ml). The reaction was heated to 130 °C for 20 min. The reaction was diluted with water (100 mL) and EtO Ac (200 mL). The organic phase was separated, washed with water (5x), brine and dried ( a2S04). EtO Ac was removed under reduced pressure and the residue was purified by flash chromatography: (40 g) 0-80% EtO Ac/Hex. Fractions were combined and concentrated under reduced pressure to give Example 403A (0.373 g, 81% yield) as a colorless syrup. MS(ESI) m/z: 207.0 (M+H)+; XH-NMR: (400 MHz, CDC13) δ ppm 6.44 (t, J=1.0 Hz, 1H), 6.46 (t, J=72.2 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H); 19F-NMR: (376 MHz, CDC13) δ ppm -84.02 (s, 2F).
Example 403B: 5 -(Difluoromethoxy)-l -methyl- lH-pyrazole-3-carboxylic acid
Figure imgf000405_0002
Example 403A (0.373 g, 1.809 mmol) was dissolved in THF (7.5 ml) and MeOH (1.5 ml), then LiOH (1 M in water) (5.43 ml, 5.43 mmol) was added. The reaction was heated to 50 °C for 2 h. The reaction mixture was quenched with TFA (0.418 ml, 5.43 mmol), and concentrated under reduced pressure. The residue was diluted with
DMSO/MeOH/water and was purified by preparative HPLC. Fractions were combined and concentrated to afford Example 403B (0.230 g, 66% yield) as a white solid. MS(ESI) m/z: 192.9 (M+H)+; XH-NMR: (500 MHz, DMSO-d6) δ ppm 7.30 (t, J=70.4 Hz, 1H), 6.42 (s, 1H), 3.74 (s, 3H); 19F-NMR: (376 MHz, DMSO-d6) δ ppm -84.72 (s, 2F) Example 403:
Figure imgf000406_0001
According to the procedure for the preparation of Example 400, coupling of Intermediate 12 (30 mg, 0.064 mmol) and Example 403B (24.8 mg, 0.129 mmol) afforded Example 403 (14.7 mg, 55% yield). MS(ESI) m/z: 412.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ XH-NMR: (500 MHz, DMSO-d6) δ ppm 12.83 (s, 1H), 10.37 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.93 - 7.84 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.52 - 7.14 (m, 1H), 6.58 (s, 1H), 3.81 (s, 3H); HPLC RT = 1.45 min (Method E), 1.45 min (Method F). Example 404: l-(3-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)-
1 H- 1 ,2,3 -triazole-4-carboxamide
Figure imgf000406_0002
Example 404A: Ethyl l-(3-methoxyphenyl)-lH-l,2,3-triazole-4-carboxylate
Figure imgf000406_0003
To the solution of 3 -methoxy aniline (0.3 g, 2.44 mmol) in acetonitrile (6 mL) at 0 °C was added isoamyl nitrite (0.327 mL, 2.44 mmol), followed by azidotrimethylsilane (0.320 niL, 2.44 mmol) dropwise. After 5 min, the ice bath removed, and the reaction mixture was stirred at rt for 10 min, then ethyl propiolate (0.494 mL, 4.87 mmol) added. The reaction mixture stirred in a sealed tube at 80 °C for 20 h, then was cooled to rt. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-40% EtOAc/Hexanes) to afford Example 404A. MS(ESI) m/z: 248.0 (M+H)+; XH NMR (400MHz, chloroform-d) δ 8.48 (s, 1H), 7.42 - 7.32 (m, 1H), 7.28 (t, J=2.2 Hz, 1H), 7.26 - 7.19 (m, 1H), 6.99 - 6.88 (m, 1H), 4.38 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).
Example 404B: l- -Methoxyphenyl)-lH-l,2,3-triazole-4-carboxylic acid
Figure imgf000407_0001
Example 404A (120 mg, 0.485 mmol) mixed with 1M lithium hydroxide (1.2 mL, 1.2 mmol) in THF (2 mL) and THF (2 mL). The reaction mixture was stirred at rt for 2h, then was concentrated. The residue was purified by flash chromatography (0-20% MeOH/DCM) to afford Example 404B (100 mg, 94% yield) as a yellow solid. MS(ESI) m/z: 220.0 (M+H)+; 'H NMR (400MHZ, DMSO-d6) d 9.03 (s, 1H), 7.59 - 7.43 (m, 3H), 7.08 - 7.00 (m, 1H), 3.86 (s, 3H).
Example 404:
Figure imgf000407_0002
According to the procedure for the preparation of Example 400, coupling of Intermediate 12 (10 mg, 0.028 mmol) and Example 404B (6.9 mg, 0.031 mmol) afforded Example 404 (1.9 mg, 15% yield). MS(ESI) m/z: 439.15 (M+H)+; 'H NMR (500MHz, DMSO-d6) δ 12.90 (s, IH), 10.88 (s, IH), 9.59 (s, IH), 8.42 (d, J=7.6 Hz, IH), 8.13 (d, J=7.9 Hz, 2H), 7.98 (t, J=7.6 Hz, 2H), 7.83 (d, J=7.3 Hz, IH), 7.73 - 7.64 (m, 4H), 7.61 (d, J=7.0 Hz, IH), 7.19 (d, J=8.2 Hz, IH), 3.95 (s, 3H); HPLC RT = 1.66 min (Method E), 1.66 min (Method F).
Example 405: l-(2-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-l- yl)phenyl)- - 1 ,2,3 -triazole-4-carboxamide
Figure imgf000408_0001
-(2-methoxyphenyl)-5-methyl-lH-l,2,3-triazole-4-carboxylate
Figure imgf000408_0002
Example 405A
To the solution of 2-methoxyaniline (0.30 g, 2.44 mmol) in acetonitrile (3 mL) at 0 °C was added isoamyl nitrite (0.360 mL, 2.68 mmol), followed by azidotrimethylsilane (0.352 mL, 2.68 mmol) dropwise. After 5 min, the cold bath removed, and the reaction mixture was stirred at rt for 10 min, then ethyl but-2-ynoate (0.546 g, 4.87 mmol) added, and the reaction mixture was stirred in a sealed tube at 80 °C for 20 h, then cooled to rt. The reaction mixture was concentrated and the residue was purified by flash
chromatography (0-40% EtOAc/Hexanes) to afford 1st peak at 30% EtOAc and 2nd peak at 35% EtOAc.
1st peak: Ethyl l-(2-methoxyphenyl)-4-methyl-lH-l,2,3-triazole-5-carboxylate
(55 mg, 8.6% yield) yellow solid. MS(ESI) m/z: 262.2 (M+H)+; ¾ NMR (400MHz, chloroform-d) d 7.47 (ddd, J=8.3, 7.6, 1.8 Hz, IH), 7.40 (dd, J=7.7, 1.8 Hz, IH), 7.08 (td, j=7.6, 1.2 Hz, IH), 7.01 (dd, J=8.4, 1.1 Hz, IH), 4.21 (q, j=7.3 Hz, 2H), 3.74 (s, 3H), 2.62 (s, 3H), 1.16 (t, j=7.2 Hz, 3H). 2nd peak: Example 405A (0.177 g, 28% yield) yellow solid. MS(ESI) m/z: 262.2 (M+H)+; XH NMR δ 7.57 - 7.50 (m, IH), 7.36 (dd, J=7.8, 1.7 Hz, IH), 7.16 - 7.07 (m, 2H), 4.46 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 2.42 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). Example -(2-Methoxyphenyl)-5-methyl-lH-l,2,3-triazole-4-carboxylic acid
Figure imgf000409_0001
Example 405A (177 mg, 0.677 mmol) stirred with 1M LiOH in THF (2 mL) at rt for 3h. The reaction mixture was acidified with TFA, then was concentrated. The residue was purified via preparative HPLC to afford Example 405B. MS(ESI) m/z: 234.1 (M+H)+; 'H NMR (400MHZ, methanol^) δ 7.64 - 7.57 (m, IH), 7.40 (dd, J=7.7, 1.5 Hz, IH), 7.31 - 7.25 (m, IH), 7.16 (td, J=7.6, 1.1 Hz, IH), 3.83 (s, 3H), 2.38 (s, 3H).
Figure imgf000409_0002
Intermediate 12 (12 mg, 0.051 mmol), Example 405B (13 mg, 0.056 mmol),
HATU (21 mg, 0.056 mmol) were mixed in DMF (1.5 mL), add DIEA (0.044 mL, 0.253 mmol), stirred 45 °C for 4h. The reaction mixture was purified by preparative HPLC to afford Example 405 (7.1 mg, 31% yield). MS(ESI) m/z: 453.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 10.68 (s, IH), 8.35 (d, J=7.4 Hz, IH), 8.03 (d, J=8.4 Hz, 2H), 7.95 - 7.91 (m, 2H), 7.77 (d, J=8.1 Hz, IH), 7.66 (t, J=7.6 Hz, IH), 7.59 (d, J=8.4 Hz, 2H), 7.50 (d, J=7.4 Hz, IH), 7.36 (d, J=8.4 Hz, IH), 7.21 (t, J=7.6 Hz, IH), 3.82 (s, 3H), 2.39 (s, 3H); HPLC RT = 1.67 min (Method E), 1.58 min (Method F). Example 406: 1 -(2-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin- 1 -yl)phenyl)-
1 H- 1 ,2,3 -triazole-4-carboxamide
Figure imgf000410_0001
According to the procedure for the preparation of Example 404, substituting 2- methoxyaniline for 3-methoxyaniline afforded Example 406. MS(ESI) m/z: 439.2
(M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.87 (s, 1H), 10.77 (s, 1H), 9.04 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.95 - 7.90 (m, 2H), 7.76 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.64 - 7.56 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 3.88 (s, 3H); HPLC RT = 1.51 min (Method E), 1.51 min (Method F).
Example 407: 3-Cyclopropyl-l-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- -pyrazole-5-carboxamide
Figure imgf000410_0002
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then 3-cyclopropyl-l-methyl-lH-pyrazole-5-carboxylic acid (21.4 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (37 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 407 (21.7 mg, 87% yield). MS(ESI) m/z: 386.2 (M+H)+; XH NMR (500MHz, DMSO-d6) δ 12.85 (s, 1H), 10.33 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.97 - 7.83 (m, 4H), 7.73 (d, J=7.7 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 3.99 (s, 3H), 1.97 - 1.83 (m, 1H), 0.96 - 0.82 (m, 2H), 0.67 (d, J=3.7 Hz, 2H); HPLC RT = 1.47 min (Method E), 1.48 min (Method F).
Example 408: 1 -Methyl-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phi
- 1 H-pyrazole-5-carboxamide
Figure imgf000411_0001
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (25.0 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 408 (19.6 mg, 73% yield). MS(ESI) m/z: 414.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.86 (s, 1H), 10.64 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.98 - 7.84 (m, 4H), 7.73 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 4.18 (s, 3H); HPLC RT = 1.68 min (Method E), 1.68 min (Method F).
Example 409: N-(4-(4-Oxo-3,4-dihydrophthalazin-l-yl)phenyl)-l-(2,2,2-trifluoroethyl)- lH-pyrazole-3-carboxamide
Figure imgf000411_0002
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then l-(2,2,2-trifluoroethyl)-lH-pyrazole-3-carboxylic acid (25.0 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 409 (21.2 mg, 79% yield). MS(ESI) m/z: 414.1 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.82 (s, 1H), 10.32 (s, 1H), 8.34 (d, J=7.3 Hz, 1H), 8.03 (br. s., 1H), 7.98 (d, J=7.6 Hz, 2H), 7.90 (t, J=7.6 Hz, 2H), 7.75 (d, J=7.3 Hz, 1H), 7.57 (d, J=7.9 Hz, 2H), 6.95 (br. s., 1H), 5.28 (q, J=8.5 Hz, 2H);
HPLC RT = 1.46 min (Method E), 1.47 min (Method F).
Example 410: l-(Difluoromethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- pyrazole-3-carboxamide
Figure imgf000412_0001
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then l-(difluoromethyl)-lH-pyrazole-3-carboxylic acid (20.9 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 410 (16.6 mg, 67% yield). MS(ESI) m/z: 382.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.84 (s, 1H), 10.58 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.09 - 7.80 (m, 5H), 7.75 (d, J=7.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H); HPLC RT = 1.34 min (Method E), 1.25 min (Method F).
Example 411: 1 -(2,2-Difluoroethyl)-N-(4-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)phenyl)- lH-pyrazole-5-carboxamide
Figure imgf000413_0001
Example 411A: Methyl l-(2,2-difluoroethyl)-lH-pyrazole-3-carboxylate
-(2,2-difluoroethyl)-lH-pyrazole-5-carboxylate
Figure imgf000413_0002
Example 411 A Example 411 B peak 1 , eluted at -25% EtOAc peak 2, eluted at -45% EtOAc
Methyl lH-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved in dry MeCN (30 mL), then 2,2-difluoroethyl trifluoromethanesulfonate (0.633 mL, 4.76 mmol) was added, followed by cesium carbonate (1.94 g, 5.95 mmol) and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc. Then CELITE® was added, and solvent was removed under reduced pressure. The residue was purified by flash chromatography (solid loading on CELITE®): 0-60% EtO Ac/Hex affording two products.
Example 411A (0.271 g, 1.425 mmol, 35.9% yield) as a colorless syrup: peak 1 eluted at -25% EtOAc. MS(ESI) m/z: 190.9 (M+H)+; ¾-NMR: (400 MHz, CDC13) δ ppm 7.57 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.31 - 5.95 (m, 1H), 4.98 (td, J=13.1, 4.4 Hz, 2H), 3.91 (s, 3H); 19F-NMR: (376 MHz, CDC13) δ ppm -122.87 (s, 2F).
Example 411B: (0.398 g, 2.093 mmol, 52.8% yield) as a colorless syrup: peak 2 eluted at -45% EtOAc. MS(ESI) m/z: 190.9 (M+H)+; ¾-NMR: (400 MHz, CDC13) δ ppm 7.51 (d, J=2.4 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.29 - 5.94 (m, 1H), 4.55 (td, J=13.4, 4.3 Hz, 2H), 3.94 (s, 3H); 19F-NMR: (376 MHz, CDC13) δ ppm -122.42 (s, 2F). Example 411 -(2,2-Difluoroethyl)-lH-pyrazole-5-carboxylic acid
Figure imgf000414_0001
Example 411A (0.398 g, 2.093 mmol) was dissolved in THF (8.7 ml) and MeOH (1.7 ml), then LiOH (1 M in water) (6.28 ml, 6.28 mmol) was added. The reaction was heated to 50 °C for 2 h. The reaction mixture was quenched with TFA (0.484 ml, 6.28 mmol), and concentrated under reduced pressure. The residue was diluted with
DMSO/MeOH/water, and was purified by preparative to afford Example 411C (0.173 g, 46.9% yield) as a white solid. MS(ESI) m/z: 176.9 (M+H)+; XH NMR (400MHz, DMSO- d6) δ 13.59 (br. s., IH), 7.64 (d, J=2.0 Hz, IH), 6.90 (d, J=2.0 Hz, IH), 6.60 - 6.12 (m, IH), 4.98 (td, J=14.5, 4.0 Hz, 2H).
Example 411:
Figure imgf000414_0002
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then Example 411C (22.7 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 411 (16.6 mg, 67% yield). MS(ESI) m/z: 396.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.85 (s, IH), 10.56 (s, IH), 8.35 (d, J=7.1 Hz, IH), 7.98 - 7.85 (m, 4H),
7.74 (d, J=8.1 Hz, IH), 7.71 (d, J=1.7 Hz, IH), 7.61 (d, J=8.4 Hz, 2H), 7.20 (d, J=1.7 Hz, IH), 6.56 - 6.25 (m, IH), 5.03 (td, J=14.6, 3.5 Hz, 2H); HPLC RT = 1.38 min (Method E), 1.28 min (Method F).
Example 412: l-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-l-yl)phenyl)- lH-pyrazole-3-carboxamide
Figure imgf000415_0001
Example 412A: -(2,2-Difluoroethyl)-lH-pyrazole-3-carboxylic acid
Figure imgf000415_0002
Example 411B (0.271 g, 1.43 mmol) was dissolved in THF (5.9 ml) and MeOH
(1.2 ml), then LiOH (1 M in water) (4.28 ml, 4.28 mmol) was added. The reaction was heated to 50 °C for 2 h. The reaction mixture was quenched with TFA (0.329 ml, 4.28 mmol), and concentrated under reduced pressure. The residue was diluted with
DMSO/MeOH/water, and was purified by preparative HPLC to afford Example 412A (0.177 g, 71% yield) as a white solid. MS(ESI) m/z: 176.9 (M+H)+; XH NMR (400MHz, DMSO-d6) δ 12.76 (s, IH), 7.88 (d, J=2.4 Hz, IH), 6.75 (d, J=2.4 Hz, IH), 6.59 - 6.19 (m, IH), 4.72 (td, J=15.2, 3.7 Hz, 2H).
Example 412:
Figure imgf000416_0001
O
Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1 mL), then Example 412A (22.7 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 412 (23.3 mg, 91% yield). MS(ESI) m/z: 396.2 (M+H)+; 'H NMR (500MHZ, DMSO-d6) δ 12.79 (s, IH), 10.26 (s, IH), 8.30 (d, J=7.1 Hz, IH), 7.99 - 7.81 (m, 5H), 7.71 (d, J=7.7 Hz, IH), 7.53 (d, J=8.4 Hz, 2H), 6.86 (d, J=2.0 Hz, IH), 6.58 - 6.30 (m, IH), 4.74 (td, J=15.1, 3.2 Hz, 2H); HPLC RT = 1.31 min (Method E), 1.31 min (Method F).

Claims

WHAT IS CLAIMED IS:
A compound of Formula I):
Figure imgf000417_0001
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
M is selected from N and CR10;
L is selected from -CRVC(O)-, -0C(0)-, -NR6C(0)-, and -NR6-;
R1 is selected from NR5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R2, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -OH, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci-4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci-4 alkyl), -CO(Ci-4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, Ci_4 alkoxy, Ci_4 alkylthio, Ci_4 haloalkyl, -CH2OH, -OCH2F, -OCHF2, -OCF3, CN, -NH2, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, -C02H, -CH2C02H, -C02(Ci_4 alkyl), -CO(Ci_4 alkyl), -CH2NH2, -CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -OCH2C02H, -NHCO(Ci_4 alkyl), -NHC02(Ci_4 alkyl), -NHS02(Ci_4 alkyl), -S02NH2, -C(=NH)NH2, carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9; R4, at each occurrence, is independently selected from H, OH, NH2, CH2NH2, C1-4 haloalkyl, OCH2F, OCHF2, OCF3, -NH(Ci_4 alkyl), -N(C1-4 alkyl)2, Ci_4 alkoxy, CH2OH, CH20(Ci_4 alkyl), CH2C02H, CH2C02(Ci_4 alkyl), Ci_4 alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and -(CR6R6)n- 4-10 membered heterocycle comprising carbon atoms and 1 -4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1 -4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1 -4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, N02, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -(CH2)n-C(0)Ci_4alkyl, -(CH2)n-C(0)carbocycle, -(CH2)n-C(0)heterocycle, -(CH2)n -C(0)NRaRa, -(CH2)n-C(0)0-alkyl, -(CH2)n-C(0)0-carbocycle,
-(CH2)n-C(0)0-heterocycle, -(CH2)n-S02alkyl, -(CH2)n S02carbocycle,
-(CH2)n-S02heterocycle, -(CH2)n-S02NRaRa, -(CH2)n-carbocycle, and
-(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, CO(Ci_4 alkyl), C02H, C02(Ci_4 alkyl),
-(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)ncarbocycle, -0(CH2)nheterocycle,
-0(CH2)nNRaRa, -(CR10R10)n- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
R10 is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, OH, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2;
provided NHC(O), R1 is other than
Figure imgf000420_0001
, and
Figure imgf000420_0002
, wherein X is N or a substituted or unsubstituted carbon atom;
when L is NR6, R1 is heterocycle substituted with 1-4 R7; 2. The compound of claim 1, wherein:
M is CR10;
L is selected from -CRVC(O)-, -0C(0)-, and -NR6C(0)-;
R1 is selected from NR5R5, C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R3, at each occurrence, is independently selected from halogen, Ci_6 alkyl, C1-4 alkoxy;
R4 is H;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle and 4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 15-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, C1-4 alkyl, C1-4 alkoxy,
-NR8R8, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H and C1-4 alkyl;
R9, at each occurrence, is independently selected from halogen, OH, C1-4 alkyl,
Ci-4 alkoxy;
R10 is selected from H and C1-4 alkyl;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2. compound of claim 1, having Formula (II)
Figure imgf000421_0001
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
M is selected from N and CR10;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci-4 alkyl), -S02NH2, -S02NH(Ci-4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci-4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)„ C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, NO2, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
R10 is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl,
Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3-6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p;
n, at each occurrence, is independently selected from 0, 1,
2,
3, and 4;
p, at each occurrence, is independently selected from 0, 1, and 2.
4. The compound of claim 3, wherein: R is selected from H, C1-4 alkyl, -(CH2)n- -10 carbocycle, -(CH2)n-aryl,
-(CH2)n-4- 10 membered heterocycle selected from
Figure imgf000423_0001
5
Figure imgf000423_0002
wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R7.
5. The compound of claim 3, wherein:
R5 and R5 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
Figure imgf000423_0003
Figure imgf000424_0001
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(C1_4 alkyl), -(CH2)n-NR8R8, -CH2NH2, -NHCO(Ci-4 alkyl), -NHCOCF3, -NHC02(Ci-4 alkyl), -NHC(0)NH2,
-NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2,
-S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci_4 alkyl), -(CH2)n-CONR8R8, -0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci-4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)„-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci-4 alkyl, C1-4 alkoxy, CH2OH, C02H, C02(Ci-4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4- 10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH, CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl,
-(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, Ci_4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p.
6. The compound of claim 1, having Formula (III):
Figure imgf000425_0001
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
M is selected from N and CR10;
R5, at each occurrence, is independently selected from H, Ci_4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and Ci_4 alkyl; R7, at each occurrence, is independently selected from H, =0, NO2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(C!_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(d_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from 0, 1, and 2.
7. The compound of claim 1, wherein:
L is -NR6-;
R1 is heteroaryl substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, halogen, Ci_4 alkyl, Ci_4 alkoxy, CN, OH, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9.
8. The compound of claim 7, wherein: L is -NR6-: and 1 is selected fro
Figure imgf000427_0001
Figure imgf000427_0002
9. The compound of claim 2, having Formula (IV):
Figure imgf000427_0003
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from NR5R5, C3-10 carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R7;
R5, at each occurrence, is independently selected from H, C1-4 alkyl,
-(CR6R6)n-C3_io carbocycle, and -(CR6R6)n-4-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R7;
alternatively, R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R6, at each occurrence, is independently selected from H and C1-4 alkyl;
R7, at each occurrence, is independently selected from H, =0, NO2, halogen, Ci_4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl), -(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci_4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci_4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, C2_4 alkenyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, alkenyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2,
CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb;
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; p, at each occurrence, is independently selected from 0, 1, and 2.
10. The com ound of claim 9, wherein:
Figure imgf000428_0001
Figure imgf000429_0001
R7, at each occurrence, is independently selected from H, =0, O2, halogen, C1-4 alkyl, Ci_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH2)n-C02(Ci_4 alkyl),
-(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl),
-NHC02(CH2)20(d_4 alkyl), -NHC02(CH2)30(C1_4 alkyl), -NHC02(CH2)2OH,
-NHC02(CH2)2NH2, -NHC02(CH2)2N(Ci-4 alkyl)2, -NHC02CH2C02H, -CH2NHC02(Ci-4 alkyl), -NHC(0)NR8R8, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci_4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(C!_4 alkyl), -(CH2)n-CONR8R8,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, -NHCO-carbocycle, -NHCO-heterocycle, -(CH2)n-carbocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(0)p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, SC^carbocycle, S02heterocycle,
S02 RaRa, -(CH2)n-carbocycle, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, O2, CHF2,
CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2-4)NRaRa, -(CR10R10)n- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with
0- 4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, -(CH2)nOH,
CO(Ci_4 alkyl), COCF3, C02(Ci_4 alkyl), -CONH2, -CONH-Ci_4 alkylene-C02(Ci_4 alkyl), Ci_4 alkylene-C02(Ci_4 alkyl), Rc, C02Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form 4- to
10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from =0, halogen, C1-4 alkyl, Ci_4 alkoxy, OCF3, NH2, N02, N(Ci_4 alkyl)2, CO(Ci_4 alkyl), CO(Ci_4 haloalkyl), C02(Ci_4 alkyl), CONH2, -CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-0(Ci_4 alkyl), -CONH-Ci_4 alkylene-N(Ci_4 alkyl)2, -CONH-Ci_4 alkylene-N (Ci_4 alkyl)2, -C1-4 alkylene-0-P(0)(OH)2, -NHC02(Ci_4 alkyl), -Rc, CORc, C02Rc, and CONHRc;
Rc, at each occurrence, is independently selected from -(CH2)n-C3_6 cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-5- to 6- membered heterocycle containing carbon atoms and
1- 4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(0)p; wherein each ring moiety is substituted with 0-2 Rd; and
Rd, at each occurrence, is independently selected from =0, halogen, -OH, C1-4 alkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, Ci_4 alkoxy, and -NHCO(Ci_4 alkyl), and heterocycle containing carbon atoms and 1 -4 heteroatoms selected from the group consisting of: N, NH, N(Ci_4 alkyl), O, and S(0)p.
11. The compound of claim 9, wherein:
R1 is NR5R5;
R5 and R5 are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, =0, halogen, C1-4 alkyl, d_4 alkoxy, CN, OH, CF3, -(CH2)n-C02H, -(CH^-CO^C^ alkyl), -(CH2)n-NR8R8, -NHCO(Ci_4 alkyl), -NHCOCF3, -NHC02(Ci_4 alkyl), -NHC(0)NH2, -NHC(0)NH(Ci_4 alkyl), -NHC(0)N(Ci_4 alkyl)2, -NHS02(Ci_4 alkyl), -S02NH2, -S02NH(Ci_4 alkyl), -S02N(Ci-4 alkyl)2, -S02NH(CH2)2OH, -S02NH(CH2)20(Ci-4 alkyl), -CONH2,
-CONH(Ci_4 alkyl), -CON(Ci_4 alkyl)2, -CH2CONH2, -(CH2)n-carbocycle,
-0(CH2)n-carbocycle, -0(CH2)n-heterocycle, and -(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from , NR8, O, and S(0)p, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl,
C(0)Ci_4alkyl, C(0)carbocycle, C(0)heterocycle, -(CH2)n-C(0)NRaRa, C(0)0-alkyl, C(0)0-carbocycle, C(0)0-heterocycle, S02alkyl, S02carbocycle, S02heterocycle, S02NRaRa, -(CH2)n-cycloalkyl, -(CH2)n-phenyl, and -(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9; and
R9, at each occurrence, is independently selected from halogen, OH, N02, CHF2, CF3, Ci_4 alkyl, Ci_4 alkoxy, CH2OH, C02H, C02(Ci_4 alkyl), CONH2, -(CH2)nNRaRa, -(CH2)nCONRaRa, -0(CH2)nheterocycle, -0(CH2)(2_4)NRaRa, -(CR10R10)„- 4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 Rb.
12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-11 and a pharmaceutically acceptable carrier or diluent.
13. A compound according to any one of claims 1-11 for use in therapy.
14. Use of a compound according to any one of claims 1-11 for prophylaxis and/or treatment of disorders associated with aberrant Rho kinase activity.
15. The use of claim 14, wherein said disorder is selected from the group consisting of a cardiovascular disorder, a smooth muscle related disorder, a fibrotic disease, an inflammatory disease, neuropathic disorders, oncologic disorders, and an autoimmune disorder.
16. The use of claim 15, wherein said cardiovascular disorder is selected from the group consisting of angina, atherosclerosis, stroke, cerebrovascular disease, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stenosis, vasospasm, hypertension and pulmonary hypertension.
17. The use of claim 15, wherein said smooth muscle related disorder is selected from the group consisting of glaucoma, erectile dysfunction, and bronchial asthma.
18. The use of claim 15, wherein said autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, irritable bowel syndrome, and systemic sclerosis.
19. A method for inhibiting Rho kinase activity, comprising (a) providing target cells and a composition comprising a compound described in claim 1 ; and (b) exposing said target cells to said composition under conditions such that said composition binds to said target cells so as to inhibit Rho kinase activity within said target cells.
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