WO2015171526A2 - Tricyclic pyrazolopyridine compounds - Google Patents

Tricyclic pyrazolopyridine compounds Download PDF

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WO2015171526A2
WO2015171526A2 PCT/US2015/029115 US2015029115W WO2015171526A2 WO 2015171526 A2 WO2015171526 A2 WO 2015171526A2 US 2015029115 W US2015029115 W US 2015029115W WO 2015171526 A2 WO2015171526 A2 WO 2015171526A2
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substituted
compound
optionally substituted
alkyl
aryl
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PCT/US2015/029115
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French (fr)
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WO2015171526A3 (en
Inventor
Zhe Li
Chul Yu
Calvin W. YEE
Qing Xu
Ii Stephen L. Gwaltney
Brian W. Metcalf
Matthew A. Lardy
Steven Richards
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Global Blood Therapeutics, Inc.
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Publication of WO2015171526A2 publication Critical patent/WO2015171526A2/en
Publication of WO2015171526A3 publication Critical patent/WO2015171526A3/en

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    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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

Definitions

  • This invention relates generally to compounds of Formula I and subformulas thereof, pharmaceutical compositions comprising the same, and uses thereof.
  • Plasma prekallikrein is a serine protease zymogen in blood that is converted to its catalytically active form, plasma kallikrein (PK), by coagulation factor XI la, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation.
  • the mechanisms that lead to the activation of this pathway in vivo include interactions with poly-phosphates released from activated platelets and deficiency of CI inhibitor (Cl-INH), the primary physiological inhibitor of plasma kallikrein.
  • PK-mediated cleavage of high-molecular weight kininogen generates the nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor.
  • Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability. Bradykinin and its binding to B2 receptor are reportedly responsible for many synptoms of hereditary angioedema (HAE).
  • HAE hereditary angioedema
  • Kallikrein is also associated with Hereditary Angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups. HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of CI- Inhibitor (Cl-INH), a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in the blood. If left untreated, HAE can result in a mortality rate as high as 40% primarily due to upper airway obstruction.
  • HAE Hereditary Angioedema
  • each of R A and R B independently is N or CR 10 , preferably if one of R A and R B is N, the other is
  • R 10 is hydrogen, halo, preferably fluoro, or an optionally substituted Ci-C 6 alkyl
  • X 1 is O, S, SO, S0 2 , NR 15 ;
  • R 15 is hydrogen or an amino protective group; each of L 1 and L 3 independently is -(L ) m (CO) n (L 12 ) 0 -;
  • L 11 and L 12 each independently are optionally substituted C C 6 alkylene or C C 6
  • each of R 1 and R 3 is independently optionally substituted C 6 -C 10 aryl, optionally substituted 5- 10 membered heteroaryl, an optionally substituted 4-15 membered heterocyclyl, or an optionally substituted C 3 -C 8 cycloalkyl, and/or where adjacent positions on a substitued aryl, heteroaryl, heterocyclyl, or cyckloalkyl of R 1 and R 3 are substituted with R 50 and R 51 substituents, such that, for an aryl, and R together with the intervening atoms form an optionally substituted 5- 6 membered heteroaryl, an optionally substituted heterocycle, or an optionally
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of Formula I, or sub-formulas thereof, and optionally at least one pharmaceutical excipient.
  • this invention provides a method for inhibiting plasma kallikrein activity in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a pharmaceutical composition thereof.
  • this invention provides a method for treating a disorder or a disease in a subject mediated by plasma kallikrein, by administering an effective amount of the compound of Formula I, or a pharmaceutical composition thereof, to a patient.
  • this invention provides a method of treating hereditary angiodema, comprising administering to a patient in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable composition provided herein. [0010] In yet another aspect, this invention provides a method for synthesizing the compound of Formula I, or sub-formulas thereof.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • C m -C n such as Ci-Ci 0 , Ci-C 6 , or C C 4 when used before a group refers to that group containing m to n carbon atoms.
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 25 carbon atoms (i.e., Ci-C 25 alkyl) or 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t- butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 - ), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-
  • Alkyl substituted with a substituent refers to an alkyl group that is substituted with up to 5, preferably up to 4, and still more preferably up to 3 substituents, and includes alkyl groups substituted with 1 or 2 substituents.
  • alkyl encompasses the term “cycloalkyl” described below.
  • Substituted alkyl refers to an alkyl group having from 1 to 5, prefera bly 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
  • alkylene alone or as part of another substituent means a divalent radical derived from an alkyl or cycloalkyl group as exemplified by -CH 2 CH 2 CH 2 CH 2 - For alkylene groups, no orientation of the linking group is implied.
  • alkenyl refers to monovalent aliphatic hydrocarbyl groups having from 2 to 25 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon double bond.
  • alkenyl include vinyl, allyl, dimethyl allyl, and the like.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C ⁇ C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • C x alkynyl refers to an alkynyl group having x number of carbon atoms.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 su bstituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
  • alkoxy refers to -O-alkyl, where alkyl is as defined above.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, wherein alkyl,
  • alkyi -NR 300 C(O)cycloalkyl, -N 300 C(O)su bstituted cycloalkyi, -N
  • R 300 C(O)alkenyl, -NR 300 C(O)substituted alkenyl, alkoxy, substituted
  • R 300 is hydrogen or alkyi and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and su bstituted heterocyclic are as defined herein.
  • Acyloxy refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Substituted amino refers to the group -NR 310 R 320 where R 310 and R 320 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R 310 and R 320 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 310 and R 320 are both not hydrogen, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted
  • R 310 is hydrogen and R 320 is alkyi
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 310 and R 320 are alkyi
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 310 or R 320 is hydrogen but not both.
  • R 310 nor R 320 are hydrogen.
  • Aminocarbonyl refers to the group -C(O)NR 330 R 340 where R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where 3 30 and R 340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heterocyclic and wherein
  • Aminothiocarbonyl refers to the group -C(S)NR 330 R 340 where R 330 and R 340 are
  • Aminocarbonylamino refers to the group -NR 300 C(O)NR 330 R 340 where R 300 is hydrogen or alkyi and R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 330 and R 340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, ary
  • Aminothiocarbonylamino refers to the group -NR 300 C(S)NR 330 R 340 where R 300 is hydrogen or alkyi and R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, ary
  • Aminocarbonyloxy refers to the group -O-C(O)N 330 340 where R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted substituted alky
  • Aminosulfonyl refers to the group -SO 2 NR 330 R 340 where R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, su bstituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
  • Aminosulfonyloxy refers to the group -O-SO 2 NR 330 R 340 where R 330 and R 340 are
  • Aminosulfonylamino refers to the group -NR 300 -SO 2 NR 330 R 340 where R 300 is hydrogen or alkyi and R 330 and R 340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 330 and R 340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalky
  • aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
  • aminosulfonylamino amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyi, substituted cycloalkyi, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S0 3 H, substituted sulfonyl,
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(0)0-alkyl, -C(0)0-substituted alkyi, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted
  • alkyi, su bstituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)amino refers to the group -N 300 -C(O)O-alkyl, -NR 300 -C(O)O-substituted alkyi, -NR 300 -C(O)O-alkenyl, -NR 300 -C(O)O-substituted
  • R 300 is alkyi or hydrogen, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted
  • alkyi -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyi, -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined
  • cycloalkyi refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyi, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms.
  • Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • heterocyclyl refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic.
  • Nonlimiting examples of heterocyclyl include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and
  • the condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group.
  • a heterocyclyl group For example, and without limitation, the following is a heterocyclyl group:
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are su bstituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(su bstituted heterocycyl).
  • Non-limiting examples of heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
  • phenanthridine acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide,
  • hydrolyzing refers to breaking an H -0-CO-, R H -0-CS-, or an R H -0-S0 2 - moiety to an R H -OH, preferably by adding water across the broken bond. A hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.
  • alkenylene and arylene alone or as part of another substituent means a divalent radical derived from an alkenyl or aryl group, respectively.
  • alkenylene and arylene linking groups are contemplated to be used together with, or instead of, alkylene linking groups in some embodiments; no orientation of the linking group is implied.
  • halo refers to F, CI, Br, and I.
  • nitro refers to -N0 2 .
  • cyano refers to -CN.
  • Spiro ring systems refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Substituted sulfonyl refers to the group -S0 2 -alkyl, -S0 2 -substituted
  • heteroaryl -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic, wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfonyl includes groups such as methyl-S0 2 -, phenyl-S0 2 -, and
  • Preferred substituted alkyi groups on the su bstituted alkyl-S0 2 - include halogenated alkyi groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Substituted sulfinyl refers to the group -SO-alkyl, -SO-substituted
  • heteroaryl -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and
  • substituted alkyi groups on the substituted alkyl-SO- include halogenated alkyi groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Sulfonyloxy or “substituted sulfonyloxy” refers to the group -OS0 2 -alkyl, -OS0 2 -substituted alkyl, -OS0 2 -OH, -OS0 2 -alkenyl, -OS0 2 -su bstituted
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and su bstituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted heterocyclic-C
  • Forml refers to the group -C(0)H.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • amino-protecting group is attached to a nitrogen atom.
  • An amino protecting group is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Suitable amino protecting groups include carbamates such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), t— butyl carbamate (BOC), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc); amides such as formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide; /V-phthalimide,
  • the terms “optional” or “optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • the nitrogen atom is optionally oxidized to provide for the N-oxide (N->0) moiety means that the nitrogen atom may but need not be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.
  • the term "optionally substituted” refers to a substituted or unsubstituted group.
  • the group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
  • substituents are selected from the functional groups provided herein.
  • “optionally substituted” refers to a substituted or unsubstituted group.
  • the group may be su bstituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5
  • the substituents are selected from the group consisting of chloro, fluoro, -OCH 3 , methyl, ethyl, / ' so-propyl, cyclopropyl, vinyl, ethynyl, -C0 2 H, - C0 2 CH 3 , -OCF 3 , -CF 3, -OCHF 2 .
  • each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R and R together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • salts refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkai metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary, and non-limiting cations useful in pharmaceutically accepta ble salts include Na, K, Rb, Cs, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • such salts include, without limitation, salts of organic acids, such as caroboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • treatment means any treatment of a disease or condition in a patient, including one or more of:
  • this invention provides a compound of formula I:
  • each of A and R B independently is N or CR 10 , preferably if one of R A and R B is N, the other is
  • R 10 is hydrogen, halo, preferably fluoro, or an optionally substituted Ci-C 6 alkyl
  • X 1 is O, S, SO, S0 2 , NR 15 ;
  • R 15 is hydrogen or an amino protective group; each of L 1 and L 3 independently is -(L ) m (CO) n (L 12 ) 0 -;
  • L 11 and L 12 each independently are optionally substituted C C 3 alkylene or C C 3 heteroalkylene provided that -X 1 . 1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R 1 to the rest of the compound; each of m, n, and o is 0 or 1; each of R 1 and R 3 is independently C 6 -Ci 0 aryl, 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4-15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, or a C 3 -C 8 cycloalkyl, wherein the aryl, heteroaryl,
  • R 26 is optionally substituted C C 6 alkyl, preferably, C C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl, or N(R 25 ) 2 ; each R 25 is independently hydrogen or C C 6 alkyl optionally substituted with 1-5 halo, preferably fluoro groups, or the two R 25 groups together with the nitrogen atom they are bonded to forms a: 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; preferably, a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatoms; wherein the heterocycle is optionally substituted, preferably, with 1-3, more preferably a single, group selected from optionally substituted Ci-C 6 alkyl, preferably Ci-C 6 al
  • A is N. In some embodiments, R A is CR 10 . In some embodiments, R A is CH. In some embodiments, R B is N. In some embodiments, R B is CR 10 . In some embodiments, R B is CH. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is halo. In some embodiments, R 10 is fluoro. In some embodiments, R 10 is an optionally substituted C C 6 alkyl, such as methyl.
  • X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is SO. In some embodiments, X 1 is S0 2 . In some embodiments, X 1 is NR 15 . In some embodiments, X 1 is NH.
  • R 15 is hydrogen. In some embodiments, R 15 is an amino protective group.
  • L 1 and L 3 independently is -(L u ) m (CO) n (L 12 ) 0 -.
  • L 11 is an optionally substituted Ci-C 3 alkylene.
  • L 11 is an optionally substituted Ci-C 3 heteroalkylene.
  • -X ⁇ L 1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R 1 to the rest of the compound.
  • m is 0. In some embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, o is 0. In some embodiments, o is 1.
  • R 1 is an optionally su bstituted C 6 -Ci 0 aryl.
  • R 1 is an optionally substituted 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4- 15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • R 1 is a 4- 15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • R 1 is a C 3 -C 8 cycloalkyl.
  • R 3 is a su bstituted C 6 -Ci 0 aryl. In some embodiments, R 3 is an unsu bstituted C 6 -Ci 0 aryl.
  • R 3 is an optionally su bstituted 5-10 membered heteroaryl containing u p to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4-15 mem bered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • R 1 is a 4-15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • R 1 is a C 3 -C 8 cycloalkyl.
  • the aryl, heteroaryl, heterocyclyl, or cycloalkyl group for R 1 or R 3 is unsu bstituted.
  • the aryl, heteroaryl, heterocyclyl, or cycloalkyl grou p for R 1 or R 3 is su bstituted, preferably, with 1-3 su bstituents selected from amino or -N H 2 , halo, C C 6 alkoxy, -
  • C 3 -C 8 cycloalkyl 0- C 3 -C 8 cycloalkyl, -O-(5-10 membered heteroaryl), -O-C 6 -C 10 aryl, optionally su bstituted C C 6 alkyl preferably methyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl optionally su bstituted with a halo group, 4-15 mem bered heterocyclyl, and C 3 -C 8 cycloalkyl su bstituents.
  • R 3 is C 6 -Ci 0 aryl or 5-10 membered heteroaryl optionally su bstituted with 1-2 Ci-C 6 alkyl groups.
  • adjacent positions on a su bstitued aryl, heteroaryl, heterocyclyl, or cyckloalkyl are su bstituted with R 50 and R 51 su bstituents.
  • R 50 and R 51 together with the intervening atoms form a 5-6 mem bered heteroaryl containing up to 2 heteroatoms, prefera bly optionally su bstituted as disclosed herein.
  • the heteroaryl is su bstituted with 1-3 halo.
  • the heteroaryl is su bstituted with 1-3 Ci-C 6 alkyl groups.
  • the heteroaryl is su bstituted with an -N H 2 .
  • R 50 and R 51 together with the intervening atoms form a 5-6 membered heterocycle containing u p to 2 heteroatoms, prefera bly optionally su bstituted as d isclosed herein.
  • the heterocycle is su bstituted with 1-3 halo.
  • the heterocycle is su bstituted with 1-3 Ci-C 6 alkyl groups.
  • the heterocyclyl is su bstituted with an -N H 2 .ln some em bodiments, for an aryl, R 50 a nd R 51 together with the intervening atoms form a 5-6 mem bered cycloalkyl group, preferably optionally su bstituted as d isclosed herein.
  • the cycloalkyl is su bstituted with
  • the cycloalkyl is su bstituted with 1-3 C C 6 alkyl groups. In some embodiments, the cycloalkyl is su bstituted with an -N H 2 .
  • R 50 and R 51 together with the intervening atoms form a phenyl, prefera bly optionally su bstituted as disclosed herein.
  • R together with the intervening atoms form a a 5-6 membered heterocycle containing up to 2 heteroatoms, prefera bly optionally substituted as disclosed herein.
  • the heterocycle is substituted with 1-3 halo.
  • the heterocycle is substituted with 1-3 Ci-C 6 alkyl groups.
  • R 50 and R 51 together with the intervening atoms form a 5-6 membered cycloalkyl group, preferably optionally substituted as disclosed herein.
  • the cycloalkyl is substituted with 1-3 halo.
  • the cycloalkyl is substituted with 1-3 Ci-C 6 alkyl groups.
  • R 50 and R 51 together with the intervening atoms form a phenyl, preferably optionally substituted as disclosed herein. In some embodiments, for a heterocyclyl, R 50 and R 51 together with the intervening atoms form a 5-6 membered heteroaryl containing up to 2 heteroatoms, prefera bly optionally substituted as disclosed herein. In some embodiments, the heteroaryl is substituted with 1-3 halo. In some embodiments, the heteroaryl is substituted with 1-3 Ci-C 6 alkyl groups. In some embodiments, R 50 and R 51 together with the intervening atoms form a 5-6 membered cycloalkyl group. In some embodiments, the cycloalkyl is substituted with 1-3 halo. In some embodiments, the cycloalkyl is substituted with 1-3 Ci-C 6 alkyl groups.
  • R 50 and R 51 together with the intervening atoms form a phenyl.
  • the phenyl is substituted with 1-3 halo.
  • the phenyl is substituted with 1-3 Ci-C 6 alkyl groups.
  • R 50 and R 51 together with the intervening atoms form a 5-6 me heterocyle membered heteroaryl containing up to 2 heteroatoms.
  • the heteroaryl is substituted with 1-3 halo.
  • the heteroaryl is substituted with 1-3 Ci-C 6 alkyl groups.
  • R 50 and R 51 together with the intervening atoms form a 5-6 membered heterocyle containing up to 2 heteroatoms.
  • the heterocyle is substituted with 1-3 halo.
  • the heterocyle is substituted with 1-3 C C 6 alkyl groups.
  • ring C is a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • ring C is a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatom, wherein the heterocycle is optionally substituted.
  • the heterocycle is optionally substituted with 1, 2 or 3 substituents selected from COR 26 , C0 2 R 26 , and - S0 2 R 26 and optionally substituted Ci-C 6 alkyl, such as methyl.
  • R is optionally su bstituted Ci-C 6 alkyl.
  • R is optionally su bstituted C 6 -Ci 0 aryl.
  • R 26 is optionally su bstituted 5-6 membered heteroaryl.
  • R 26 is optionally su bstituted C 3 -C 6 cycloalkyl.
  • R 26 is N(R 25 ) 2 , such as NH 2 .
  • each R 25 is hydrogen. In some embodiments, each R 25 is Ci-C 6 alkyl optionally su bstituted with 1-5 halo, prefera bly fluoro groups. In some embod iments, two R 25 groups together with the nitrogen atom they are bonded to forms a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • two R 25 groups together with the nitrogen atom they are bonded to forms a a 4-7 mem bered heterocycle containing 2, or more preferably, a single, ring heteroatoms; wherein the heterocycle is optionally su bstituted, prefera bly, with 1-3, more prefera bly a single, group selected from optionally su bstituted Ci-Cg alkyl, prefera bly C C 6 alkyl, such as methyl.
  • ring C is C 6 -Ci 0 aryl.
  • ring C is 5-10 membered heteroaryl containing u p to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.
  • the aryl or heteroaryl is optionally su bstituted with 1-3, prefera bly, 2, more prefera bly a single su bstituent.
  • ring C is C 3 -C 8 cycloalkyl optionally su bstituted with 1, 2 or 3, preferably, 2, and more prefera bly a single su bstituent.
  • ⁇ is a dou ble bond.
  • C when C is aryl or heteroaryl, ⁇ is a dou ble bond.
  • C when C is a heterocyl or cycloalkyl, is a single bond.
  • C when C is a heterocyle or cycloalkyl, is a dou ble bond.
  • R is hydrogen or Ci-C 6 alkyl optionally su bstituted with halo, preferably fluoro, r is 1, 2, or 3, preferably, 2, more prefera bly, 1, and the remaining varia bles are defined a bove.
  • the compound of formula I is of formula l-B where any of the varia bles can be defined as described a bove for formula I:
  • ring C is a 5-6 membered heteroaryl, optionally su bstituted with 1-3, preferably, 2, more preferably, 1, substituent as defined in claim 1, and the remaining variables are defined above.
  • the compound of formula I is of formula l-C:
  • the compound of formula I is of form
  • the compound of formula I is of form l-E
  • the compound of formula I is of form
  • any of the variables can be defined as described above for formula I; and independently each p is 1, 2, or 3; independently each X 2 is O, S, SO, S0 2 , CH 22 , optionally substituted N-(C C 6 alkyl), NH, -N- CO-R 26 , -N-CO 2 -R 26 , or -NS0 2 R 26 ; independently each R 21 is hydrogen or optionally substituted Ci-C 6 alkyl; independently each R 22 is hydrogen or optionally substituted Ci-C 6 alkyl; independently each q is 1, 2, 3, or 4, preferably, 3, more preferably 1 or 2;
  • A, B, C are independently CHR 22 preferably -CH 2 -, and 1 of A, B, and C is O, S, SO, S0 2 , optionally substituted N-(C C 6 alkyl), NH, -N-CO-R 26 , -N-C0 2 -R 26 , or -NS0 2 R 26 ; where the remaining variables are defined above.
  • the compound of formula I is of formula l-G:
  • R is H, -CO-R , -C0 2 -R , or -S0 2 R , or optionally substituted C C 6 alkyl, such as methyl, and the remaining variables are defined above.
  • R 23 is H.
  • R 23 is CO-R 26 .
  • R 23 is -C0 2 -R 26 .
  • R 23 is- S0 2 R 26 .
  • R 23 is optionally substituted Ci-C 6 alkyl, such as methyl.
  • the compound of formula I is of formula l-l:
  • v 1, 2, 3 or 4;
  • R 27 is optionally substituted C C 6 alkyl, preferably substituted with 1-5 halo, more preferably fluoro; p is 1, 2, or 3, and the remaining variables are defined above. [0133] In some embodiments the compound of formula I is of formula l-J:
  • the compound of formula I is of formula l-K:
  • the compound of formula I is of formula l-L:
  • ring C is a 6-membered aryl or a 6 member heteroaryl containing a single nitrogen atom; 3 5 is methyl substituted with a 5 membered heteroaryl containing 2 nitrogen atoms, -0-(6 membered heteroaryl containing a single nitrogen atom), or -0-(6 membered heterocyclyl containing a single nitrogen atom); is hydrogen, or R and R together with the intervening carbon atoms form a 5 mem bered heteroaryl containing 1-2 nitrogen atoms, which heteroaryl ring is su bstituted with 1-2, C C 6 alkyl, prefera bly methyl groups.
  • R A is CR 10 . In some embodiments, R A is CH. In some embodiments, R A is N.
  • R B is N. In some em bodiments, R B is CR 10 . In some em bodiments, R B is CH.
  • X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is SO or S0 2 . In some embodiments, X 1 is N R 15 .
  • R 15 is hydrogen. In some em bodiments, R 15 is an amino protecting group.
  • L 1 is -CH 2 - or -CO-, prefera bly -CH 2 -.
  • R 1 is optionally su bstituted C 6 -Ci 0 aryl or optionally su bstituted 5-10 mem bered heteroaryl.
  • L 3 is -CH 2 -.
  • R 3 is optionally su bstituted C 6 -Ci 0 aryl or optionally su bstituted 5-10 membered heteroaryl.
  • ring C is:
  • R is hydrogen or Ci-C 6 alkyl, optionally su bstituted with halo, preferably fluoro, or N(R 25 ) 2 ; C C 6 alkoxy optionally su bstituted with halo, prefera bly fluoro, or N(R 25 ) 2 ; r is 1, 2, or 3, prefera bly, 2, more prefera bly, 1.
  • ring C is a 5-6 membered heteroaryl, optionally su bstituted with 1-3, preferably, 2, more preferably, 1, su bstituent, yet more preferably, ring C is a 6 mem bered heteroaryl, containing a single nitrogen atom.
  • ring C is of formula : l l-C or 11 - D
  • each p is 1, 2, or 3; independently each X 2 is O, S, SO, S0 2 , CH 22 , N-( optionally substituted C C 6 alkyl), NH, -N- CO-R 26 , -N-CO2-R 26 , or -NS0 2 R 26 ; independently each R 21 is hydrogen or optionally substituted Ci-C 6 alkyl; independently each R 22 is hydrogen or optionally substituted Ci-C 6 alkyl; and independently each q is 1,2, 3, or 4, preferably, 3, more preferably 1 or 2.
  • ring C is of formula ll-E or ll-F:
  • ring C is selected from:
  • R is, H, -CO-R , -C0 2 -R , -S0 2 R , or optionally substituted C C 6 alkyl, and R b is defined above.
  • ring C is:
  • the compound of formula I is selected from the table below.
  • Plasma kallikrein inhibitors (I) can be synthesized by a number of approaches such as the synthetic route described in Scheme 1.
  • N-P can refer to a protected nitrogen atom,which protecting groups are well known in the art and to the skilled artisan.
  • the free NH tricyclic chloride INT-1 is first reacted with reagent 1 with a leaving group such as an alkyl halide (alkylation reaction) or an alcohol (Mitsunobu reaction) to give the N-substituted tricyclic chloride INT-2.
  • alkylating reagents such as alkyl mesylate or tosylate can also be used to substitute alkyl halide; a sulfonyl chloride can also be used to react with INT-1 to form a sulfonamide INT-2.
  • Regioisomers may be generated if at least one of R A or R B is a nitrogen atom, separation of the N- regioisomers can be achieved by preparative HPLC or flash silica gel chromatography. Alternatively, the N-regioisomer mixture can be directly applied to the next reaction and separation done after the final reaction.
  • the plasma kallikrein inhibitors are prepared via the nucleophilic aromatic substitution of INT-2 chloride with the appropriate nucleophile (R ⁇ L ⁇ X 1 !-!).
  • the reaction is typically carried out in the presence of a base such as Hunig's base and/or Lewis acid or a catalyst (e.g., a palladium catalyst).
  • One way to make the tricyclic chloride intermediate INT-1 (and or INT-2) is oxidation of the nitrogen containing tricyclic scaffold (Scheme 2, step 1) with appreciate oxidation reagent such as acid peroxide (e.g., mCPBA); the reaction gives a N-oxide product, which can be transformed to the ortho hydroxyl compound (step 2) or the ortho chloride analog depending on the reaction conditions.
  • oxidation reagent such as acid peroxide (e.g., mCPBA)
  • acid peroxide e.g., mCPBA
  • the reaction gives a N-oxide product, which can be transformed to the ortho hydroxyl compound (step 2) or the ortho chloride analog depending on the reaction conditions.
  • treating the N-oxide with or phosphorus trichloride or phosphorus oxychloride under heating gives the tricyclic chloride INT-2 product directly via mechanism shown in scheme 3 (Meiseheimer reaction).
  • NH analog (2a) is converted to N-substituted analog (2b) via similar conditions described in scheme 1 (INT-1 to INT-2).
  • Suzuki coupling of the bromide with a 2-amino (or 2-nitro) aryl/heteroaryl boronic acid derivative (step 2) and subsequent cyclization produces the tricyclic hydroxyl analog 3.
  • Reacting the hydroxyl analog with phosphorus oxychloride furnishes the key chloride INT-2, which is transformed to the kallikrein inhibitor (I) via similar conditions described in Schemel.
  • NR refers to an N-L 2 -R 2 moety or a protected nitrogen atom N-P.
  • step 5 mesylation or tosylation of the hydroxyl intermediate 4 followed by reaction with ammonia (NH 3 , or NH 4 OH, or NH 4 CI etc.) (step 5) gives compound 6 with partially unsaturated B-ring (dotted line).
  • Compound 6 can also be obtained from compound 3 via amino intermediate 4a by conditions shown in scheme 5.
  • Final conversion of compound 6 to chloride INT-2 and plasma kallikrein inhibitors (I) can be achieved by methods similar to these described in scheme 1 for heteroaromatic tricyclic analogs.
  • INT-2 by general method A - alkylation reaction.
  • a base such as Cs 2 C0 3 (2-5 eq.
  • reaction mixture was then heated by either conventional methods or in a microwave reactor at elevated temperatures between 100 and 250 °C for up to 24 hrs.
  • workup A the reaction mixture was concentrated on a rotavap to remove all volatiles, and the resulting residue was purified by preparative HPLC or flash silica gel chromatography.
  • workup B water was added to the reaction mixture, the precipitated product was collected, washed with water, and then, if necessary, subjected to preparative HPLC or flash silica gel chromatography purification.
  • a pharmaceutical composition comprising a compound of Formula (I) as provided herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or
  • physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • the concentration of the excipient is one that can readily be determined to be effective by those skilled in the art, and can vary depending on the particular excipient used.
  • the total concentration of the excipients in the solution can be from about 0.001% to about 90% or from about 0.001% to about 10%.
  • the concentration of compounds provided herein and/or utilized herein can be from about 1 to about 99% by weight in the pharmaceutical compositions provided herein.
  • the concentration of compounds provided herein and/or utilized herein in the pharmaceutical composition is about 5% by weight, or alternatively, about 10%, or about 20%, or about 1%, or about 2%, or about 3%, or about 4%, or about 6%, or about 7%, or about 8%, or about 9%, or about 11%, or about 12%, or about 14%, or a bout 16%, or about 18%, or about 22%, or about 25%, or about 26%, or about 28%, or about 30%, or about 32%, or about 34%, or about 36%, or about 38%, or about 40%, or about 42%, or about 44%, or about 46%, or about 48%, or about 50%, or about 52%, or about 54%, or about 56%, or about 58%, or about 60%, or about 64%, or about 68%, or about 72%, or
  • Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds.
  • the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
  • co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
  • co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • a compound of this invention can be used as an adjunct to conventional drug therapy of the conditions described herein.
  • compositions can be formulated for different routes of administration, including oral delivery and other routes such as intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, transdermal, intracranial, and subcutaneous routes.
  • Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 th ed., A. Oslo editor, Easton Pa. 1980).
  • this invention provides a method for inhibiting plasma kallikrein activity in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a subformula thereof, or a pharmaceutical composition of any thereof.
  • Plasma kallikrein is contemplated to have implications in disorders such as (HAE) , retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, CM E following vascular occlusion (e.g.
  • central retina vein occlusion branch retinal vein occlusion, or hemiretinal vein occlusion
  • retinal edema complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet aged-related macular degeneration (AM D), ischemic reperfusion injuries, e.g.
  • tissue and/or organ transplantation surgically-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma- associated edema, spinal cord injury, pain, ischemia, focal brain ischemia, neurological and cognitive deficits, deep vein thrombosis, stroke, myocardial infarction, acquired angioedema drug-related (ACE-inhibitors), edema, high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation induced edema, lymph edema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral stroke or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, cerebral trauma associate with injury or surgery, brain aneurysm, arterio-venous malformation, reduction of blood losses during surgical procedures (e.g.cardiothoracic surgery,
  • osteoarthritis infection arthritis
  • lupus e.g., lupus, gout, psoriasis, blood loss during cardiopulmonary bypass, inflammatory bowel, diabetes, diabetic complications, infectious diseases, astrocyte- activation related diseases (e.g. Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, stroke, epilepsy andtrauma (e.g. brain trauma).
  • astrocyte- activation related diseases e.g. Alzheimer's disease or multiple sclerosis
  • Parkinson's disease e.g. Alzheimer's disease or multiple sclerosis
  • amyotrophic lateral sclerosis e.g. Creutzfeld-Jacob disease
  • stroke e.g. brain trauma.
  • Plasma kallikrein inhibitors are also contemplated to be useful in the treatment of a wide range of disorders, in particular retinopathy or edema-associated diseases, such as hereditary angioedema, macular edema and brain edema.
  • Plasma kallikrein inhibitors are also contemplated to be useful in the treatment of retinopathy, e.g. retinopathy associated with diabetes and/or hypertension; hereditary angioedema; edema formation in diseases, e.g. edema formation related to ischemic reperfusion injuries; macular edema, e.g. macular edema associated with diabetes and/or hypertension; .in the prevention and treatment of thrombosis; in the treatment of intracerebral hemorrhage induced by hyperglycemia in diabetic patients.
  • a therapeutically effective amount of the compound of Formula I, or a subformula thereof reduces protease activity, such as kallikrein activity, for up to 12, 24, 26 or 48 hours after administration.
  • an effective amount of the compound of Formula I is the amount of the compound of Formula I required to produce a therapeutic effect in vitro or in vivo. In some embodiments the effective amount in vitro is about from 0.1 nM to about 1 mM. In some embodiments the effective amount in vitro is from a bout 0.1 nM to about 0.5 nM or from about 0.5 nM to about 1.0 nM or from about 1.0 nM to about 5.0 nM or from a bout 5.0 nM to about 10 nM or from about 10 nM to about 50 nM or from about 50 nM to about 100 nM or from about 100 nM to about 500 nM or from about 500 nM to about 1 mM.
  • the effective amount for an effect in vivo is about 0.1 mg to about 100 mg, or preferably, from about 1 mg to about 50 mg, or more preferably, from about 1 mg to about 25 mg per kg/day. In some other embodiments, the effective amount in vivo is from about 10 mg/kg/day to about 100 mg/kg/day, about 20 mg/kg/day to about 90 mg/kg/day, about 30 mg/kg/day to about 80 mg/kg/day, about 40 mg/kg/day to about 70 mg/kg/day, or about 50 mg/kg/day to about 60 mg/kg/day. In still some other embodiments, the effective amount in vivo is from about 100 mg/kg/day to about 1000 mg/kg/day.
  • Routes of administration refer to the method for administering a compound of Formula I or a composition thereof to a mammal. Administration can be achieved by a variety of methods. These include but are not limited to subcutaneous, intravenous, transdermal, su blingual, or intraperitoneal injection or oral administration.
  • the methods described herein relate to administering the compound of Formula I or compositions thereof in vitro.
  • the administration is in vivo.
  • the in vivo administration is to a mammal. Mammals include but are not limited to humans and common laboratory research animals such as, for example, mice, rats, dogs, pigs, cats, and rabbits.
  • Amine-1 Synthesis of 6-(aminomethyl)isoquinolin-l-amine:
  • Step 1 Into a 500-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of l,4-dibromo-2-methyl benzene (15 g, 60.02 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL). CuCN (20.4 g, 227.77 mmol, 3.80 equiv) was added to the reaction. The resulting solution was heated to reflux for 6 h, and then diluted with 200 mL of ammonia. The solids were filtered. The filtrate was extracted with 2x200 mL of ethyl acetate.
  • Step 2 Into a 250-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-methylbenzene-l,4-dicarbonitrile (4 g, 28.14 mmol, 1.00 equiv), [(tert-butoxy)(dimethylamino)methyl]dimethylamine (9.8 g, 56.23 mmol, 2.00 equiv) in N,N-dimethylformamide (50 mL). The resulting solution was stirred overnight at 75 °C, and then concentrated under vacuum. The resulting mixture was washed with 50 mL of hexane. The solids were collected by filtration. This provided 5.3 g (95%) of 2-[(E)-2- (dimethylamino)ethenyl]benzene-l,4-dicarbonitrile as a yellow solid.
  • Step 3 Into a 250-mL round-bottom flask, was placed a mixture of 2-[(E)-2- (dimethylamino)ethenyl]benzene-l,4-dicarbonitrile (5.4 g, 27.38 mmol, 1.00 equiv), DMPU (15 mL), and (2,4-dimethoxyphenyl)methanamine (7.58 mL). The resulting solution was stirred for 3 h at 140 °C, and then cooled with an ice bath. The resulting solution was diluted with 200 mL of hexane/EA (2/1). The precipitates were collected by filtration. The solid was dried in an oven under reduced pressure.
  • Step 4 Into a 250-m L round-bottom flask, was placed a solution of 2-[(2,5- dimethoxyphenyl)methyl]-l-imino-l,2-d ihydroisoquinoline-6-carbonitrile (7.55 g, 23.64 mmol, 1.00 equiv) and anisole (3.9 m L, 1.50 equiv) in trifluoroacetic acid (100 mL).
  • the resulting solution was stirred for 2 days at 70 °C.
  • the resulting mixture was concentrated under vacuum.
  • the pH value of the solution was adjusted to 8 with sodium bicarbonate (sat. aq.), and then the mixture was extracted with 3x200 mL of ethyl acetate.
  • the com bined organic layers were dried over anhydrous sodiu m sulfate and concentrated under vacuum.
  • the residue was applied onto a silica gel column with dichlorometha ne/methanol (50/1-30/1) as eluent to yield 2.5 g (63%) of l-aminoisoquinoline-6- carbonitrile as a yellow solid.
  • Step 5 6-(aminomethyl)isoquinolin-l-amine.
  • 6-isocyanoisoquinolin-l-amine 7.9 g, 46.70 mmol, 1.00 equiv
  • methanol 100 mL
  • ammonia 100 mL
  • Raney-Ni 10 g
  • Step 1 Into a 500-m L round-bottom flask, was placed 4-chloroaniline (20 g, 156.77 mmol, 1.00 equiv) in toluene (172 mL). This was followed by the addition of BCI 3 in d ichloromethane (1M, 172.4 mL, 1.10 equiv) dropwise with stirring. To this was added CICH 2 CN (12 m L, 1.20 equiv), AICI 3 (23 g, 1.10 equiv). The resulting solution was stirred for 24 h at 120 °C in an oil bath. The reaction was then quenched by the addition of 240 mL of 2M hydrogen chloride.
  • Step 2 Into a 500-m L round-bottom flask, was placed l-(2-amino-5-chlorophenyl)-2- chloroethan-l-one (9.8 g, 48.03 mmol, 1.00 equiv) and hydrogen chloride in H 2 0 (37%, 146.3 m L). This was followed by the addition of a solution of Na N0 2 (3.651 g, 52.91 mmol, 1.10 equiv) in water (22.5 m L) d ropwise with stirring at -10 °C. The mixture was stirred for 2 h. To this was added SnCI 2 2H 2 0 (26 g, 2.40 equiv).
  • Step 3 Into a 250-m L round-bottom flask, was placed 5-chloro-3-(chloromethyl)-lH- indazole hydrochloride (10.8 g, 45.47 mmol, 1.00 equ iv), N, N-dimethylformamide (91 m L), water (9.4 mL), and NaN 3 (3.8 g, 58.45 mmol, 1.30 equiv). The resulting solution was stirred for 1 h at 90 °C. The resulting mixture was concentrated under vacuum. The residue was diluted with 500 m L of water/ice. The resulting solution was extracted with 3x500 mL of dichloromethane and the organic layers combined and concentrated. This resulted in 9.3 g of 3-(azidomethyl)-5-chloro-lH-indazole as a crude solid.
  • Step 4 (5-chloro-lH-indazol-3-yl)methanamine.
  • 3-(azidomethyl)-5- chloro-lH-indazole (9.3 g, 44.79 mmol, 1.00 equiv)
  • methanol 147.8 mL
  • Pt0 2 790 mg, 0.08 equiv.
  • hydrogen (1 atm) was introduced.
  • the resulting mixture was stirred for 1 day at room temperature.
  • the solids were filtered.
  • the filtrate was concentrated under vacuum.
  • Step 1 Into a 500-mL three neck round-bottom flask, was placed PPA (300 g). This was followed by the addition of (2E)-3-aminobut-2-enenitrile (30 g, 365.39 mmol, 1.00 equiv) at 100 °C. The resulting solution was stirred for 3 h at 165 °C. The reaction mixture was cooled to 90 °C. The reaction was then quenched by the addition of 500 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10%). The resulting solution was extracted with 3x1500 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12.4 g (23%) of 6-amino-2,4-dimethylpyridine-3- carbonitrile as a yellow solid.
  • Step 2 Into a 500-mL round-bottom flask, was placed 6-amino-2,4-dimethylpyridine-3- carbonitrile (12.4 g, 84.25 mmol, 1.00 equiv), 4-dimethylaminopyridine (1.03 g, 8.43 mmol, 0.10 equiv), and tetrahydrofuran (100 mL). This was followed by the addition of a solution of Boc 2 0 (55.0 g, 252.00 mmol, 3.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature.
  • Step 3 Into a 250-mL round-bottom flask, was placed tert-butyl N-[(tert-butoxy)carbonyl]- N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate (7.1 g, 20.44 mmol, 1.00 equiv), methanol (70 mL), and dichloromethane (20 mL). This was followed by the addition of H 2 0 2 (2.69 mL, 1.50 equiv) dropwise with stirring. To this was added a solution of sodium hydroxide (1.228 g, 30.70 mmol, 1.50 equiv) in water (10 mL) dropwise with stirring.
  • sodium hydroxide 1.228 g, 30.70 mmol, 1.50 equiv
  • Step 4 tert-butyl (5-(aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate.
  • tert-butyl N-(5-cyano-4,6-d imethylpyridin-2-yl)carbamate (3.8 g, 15.37 mmol, 1.00 equiv)
  • N H 3 /MeOH 10 m L
  • methanol 20 mL
  • a ney-Ni 3.8 g
  • Step 1 Into a 500-m L 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed lH-pyrazole (6.2 g, 91.07 mmol, 1.00 equiv) in N, N- dimethylformamide (100 mL). This was followed by the addition of Na H (60%) (5.5 g, 137.50 mmol, 1.51 equiv) in several batches at 0 °C. The mixture was stirred for 1 h at 0 °C.
  • Step 2 (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol.
  • methyl 4-(lH-pyrazol-l-ylmethyl)benzoate (8 g, 37.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL).
  • LiAIH 4 (1.69 g, 44.53 mmol, 1.20 equiv) in several batches at 0 °C.
  • the resulting solution was stirred for 30 min at 0 °C and for an additional 3 h at room temperature.
  • Step 3a l-(4-(chloromethyl)benzyl)-lH-pyrazole.
  • thionyl chloride (0.13 mL, 1.00 equiv) dropwise with stirring at 0 °C.
  • the resulting solution was stirred for 0.5 h at room temperature and thenconcentrated under vacuum. This resulted in 360 mg (100%) of l-[[4-(chloromethyl)phenyl]methyl]-lH-pyrazole as a brown oil.
  • Step 3b l-(4-(bromomethyl)benzyl)-lH-pyrazole.
  • Step 1 To a suspension of ethyl 3-bromo-lH-pyrazole-4-carboxylate (219.00 mg; 1.00 mmol; 1.00 eq.) and l- ⁇ [4-(bromomethyl)phenyl]methyl ⁇ -lH-pyrazole (263.64 mg; 1.05 mmol; 1.05 eq.) in AcCN (3 mL) was added potassium carbonate (275.95 mg). The mixture was stirred at room temperature for 1 h, diluted with water, and extracted with EtOAc.
  • Step 2 To a solution of l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-bromo-lH-pyrazole-4- carboxylate (120.00 mg; 0.31 mmol; 1.00 eq.) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (74.30 mg; 0.34 mmol; 1.10 eq.) in Toluene (2 mL), iPrOH (0.5 mL), and water (0.5 mL) was added disodium carbonate (65.35 mg; 0.62 mmol; 2.00 eq.). The mixture was degassed for 5 min.
  • Step 3 A suspension of 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2,5-dihydro-4H-pyrazolo[4,3- c]quinolin-4-one (84.00 mg; 0.24 mmol; 1.00 eq.) in POCI 3 (1 mL) was heated at 100 °C for 2 h. The reaction mixture was then cooled and concentrated. The residue was diluted with ice water and sat. NaHC0 3 and the aqueous layer was extracted with DCM.
  • Human plasma kallikrein was purchased from Enzyme Research Labs (South Bend, IN, USA, batch HPKa 2830). A stock solution of 7 ⁇ in 50% glycerol was stored at -20°C.
  • Enzyme reactions were conducted in "assay buffer" comprised of 20mM HEPES at pH 7.4, 150 mM NaCI, 0.1% PEG-8000 and 0.01% Triton X-100.
  • the assays were performed at room temperature in 96-well plates with a total assay volume of 85 ⁇ per well.
  • the test compound was dissolved in 100% DMSO.
  • the compounds were serially diluted in DMSO in a 7 point dose response.
  • 66.5 ⁇ of protease solution prote in assay buffer
  • the final assay concentration of the human plasma kallikrein was 250 pM.
  • the reactions were started by the addition of ⁇ substrate solution (in assay buffer, final assay concentration was 600 uM).
  • the curve fitting was conducted with the non-linear regression routine of the analysis software Xlfit (IDBS, version 5.3.1).

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Abstract

In one aspect this invention relates generally to compounds of Formula I and sub-formulas thereof, or a tautomer of each thereof, a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, where Formula I is shown below: I and where C, X1, L1, L3, RA, RB, R1 and R3 are described herein.

Description

TRICYCLIC PYRAZOLOPYRIDINE COMPOUNDS
REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to US provisional application No. 61/988,544, filed May 5, 2015, the content of which is incorporated herein in its entirety by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to compounds of Formula I and subformulas thereof, pharmaceutical compositions comprising the same, and uses thereof.
BACKGROUND
[0003] Plasma prekallikrein (PK) is a serine protease zymogen in blood that is converted to its catalytically active form, plasma kallikrein (PK), by coagulation factor XI la, and contributes to the innate inflammatory response and intrinsic cascade of blood coagulation. The mechanisms that lead to the activation of this pathway in vivo include interactions with poly-phosphates released from activated platelets and deficiency of CI inhibitor (Cl-INH), the primary physiological inhibitor of plasma kallikrein. PK-mediated cleavage of high-molecular weight kininogen generates the nonapeptide bradykinin (BK), which activates the bradykinin 2 receptor. Su bsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the Bl receptor. Both Bl and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers. Activation of Bl and B2 receptors causes vasodilation and increases vascular permeability. Bradykinin and its binding to B2 receptor are reportedly responsible for many synptoms of hereditary angioedema (HAE).
[0004] Kallikrein is also associated with Hereditary Angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. Prevalence for HAE is uncertain but is estimated to be approximately 1 case per 50,000 persons without known differences among ethnic groups. HAE is caused by deficient (Type I) or dysfunctional (Type II) levels of CI- Inhibitor (Cl-INH), a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in the blood. If left untreated, HAE can result in a mortality rate as high as 40% primarily due to upper airway obstruction. SUMMARY OF THE INVENTION
[0005] In various aspects, provided herein are compounds of Formula I and sub-formulas thereof, a tautomer of each thereof, a pharmaceutically acceptable salt of each the a bove, or a
pharmaceutically acceptable solvate of each of the foregoing, where Formula I is shown below:
Figure imgf000004_0001
and where C, X1, L1, L3, A, RB, R1 and R3 are described herein. In some embodiments, each of RA and RB independently is N or CR10, preferably if one of RA and RB is N, the other is
CR10;
R10 is hydrogen, halo, preferably fluoro, or an optionally substituted Ci-C6 alkyl;
X1 is O, S, SO, S02, NR15;
R15 is hydrogen or an amino protective group; each of L1 and L3 independently is -(L )m(CO)n(L12)0-;
L11 and L12 each independently are optionally substituted C C6 alkylene or C C6
heteroalkylene provided that -X1 .1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R1 to the rest of the compound; each of m, n, and o is 0 or 1; each of R1 and R3 is independently optionally substituted C6-C10 aryl, optionally substituted 5- 10 membered heteroaryl, an optionally substituted 4-15 membered heterocyclyl, or an optionally substituted C3-C8 cycloalkyl, and/or where adjacent positions on a substitued aryl, heteroaryl, heterocyclyl, or cyckloalkyl of R1 and R3 are substituted with R50 and R51 substituents, such that, for an aryl, and R together with the intervening atoms form an optionally substituted 5- 6 membered heteroaryl, an optionally substituted heterocycle, or an optionally substituted cycloalkyl; for a heteroaryl, R50 and R51 together with the intervening atoms form an optionally substituted C6-Ci0 aryl, an optionally substituted heterocycle, or an optionally substituted cycloalkyl; for a heterocyclyl, R50 and R51 together with the intervening atoms form an optionally substituted C6-Ci0 aryl, an optionally substituted heteroaryl, or an optionally su bstituted cycloalkyl; for a cycloalkyl, R50 and R51 together with the intervening atoms form an optionally substituted C6-Ci0 aryl, an optionally substituted heteroaryl, or an optionally su bstituted heterocyle; ring C is an optionally substitued 4-15 membered heterocycle; or ring C is optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl; or ring C is optionally substituted C3-C8 cycloalkyl;
Figure imgf000005_0001
is a double or a single bond, provided that when C is aryl or heteroaryl it is a double bond, and when C is a heterocyle or cycloalkyl it can be a double bond or a single bond.
[0006] In one aspect, this invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, or sub-formulas thereof, and optionally at least one pharmaceutical excipient.
[0007] In another aspect, this invention provides a method for inhibiting plasma kallikrein activity in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a pharmaceutical composition thereof.
[0008] In another aspect, this invention provides a method for treating a disorder or a disease in a subject mediated by plasma kallikrein, by administering an effective amount of the compound of Formula I, or a pharmaceutical composition thereof, to a patient.
[0009] In another aspect, this invention provides a method of treating hereditary angiodema, comprising administering to a patient in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable composition provided herein. [0010] In yet another aspect, this invention provides a method for synthesizing the compound of Formula I, or sub-formulas thereof.
DETAILED DESCRIPTION
[0011] It is to be understood that this invention is not limited to particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Definitions
[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.
[0013] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a plurality of excipients.
[0014] As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of" when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
"Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0015] The term "about" when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10 %, 5 % or 1 %.
[0016] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations. Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. [0017] As used herein, Cm-Cn, such as Ci-Ci0, Ci-C6 , or C C4 when used before a group refers to that group containing m to n carbon atoms.
[0018] The term "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 25 carbon atoms (i.e., Ci-C25 alkyl) or 1 to 6 carbon atoms (i.e., Ci-C6 alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t- butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2- ), and neopentyl ((CH3)3CCH2-). Alkyl substituted with a substituent refers to an alkyl group that is substituted with up to 5, preferably up to 4, and still more preferably up to 3 substituents, and includes alkyl groups substituted with 1 or 2 substituents. The term "alkyl" encompasses the term "cycloalkyl" described below.
[0019] "Substituted alkyl" refers to an alkyl group having from 1 to 5, prefera bly 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,
aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0020] The terms "alkylene" alone or as part of another substituent means a divalent radical derived from an alkyl or cycloalkyl group as exemplified by -CH2CH2CH2CH2- For alkylene groups, no orientation of the linking group is implied.
[0021] The term "alkenyl" refers to monovalent aliphatic hydrocarbyl groups having from 2 to 25 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon double bond. Examples of alkenyl include vinyl, allyl, dimethyl allyl, and the like.
[0022] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,
aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
[0023] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CH2C≡CH). Cx alkynyl refers to an alkynyl group having x number of carbon atoms.
[0024] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 su bstituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,
aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.
[0025] The term "alkoxy" refers to -O-alkyl, where alkyl is as defined above.
[0026] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein. Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
[0027] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and su bstituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CH3C(0)-.
[0028] "Acylamino" refers to the groups -N 300C(O)alkyl, -N 300C(O)substituted
alkyi, -NR300C(O)cycloalkyl, -N 300C(O)su bstituted cycloalkyi, -N
R300C(O)alkenyl, -NR300C(O)substituted alkenyl, alkoxy, substituted
alkoxy-NR300C(O)alkynyl, -NR300C(O)substituted alkynyl, -NR300C(O)aryl, -NR300C(O)substituted aryl, -NR300C(O)heteroaryl, -NR300C(O)substituted heteroaryl, -NR300C(O)heterocyclic,
and -NR300C(O)substituted heterocyclic wherein R300 is hydrogen or alkyi and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and su bstituted heterocyclic are as defined herein.
[0029] "Acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0030] "Substituted amino" refers to the group -NR310R320 where R310 and R320 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R310 and R320 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R310 and R320 are both not hydrogen, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R310 is hydrogen and R320 is alkyi, the substituted amino group is sometimes referred to herein as alkylamino. When R310 and R320 are alkyi, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R310 or R320 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R310 nor R320 are hydrogen.
[0031] "Aminocarbonyl" refers to the group -C(O)NR330R340 where R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where 330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0032] "Aminothiocarbonyl" refers to the group -C(S)NR330R340 where R330 and R340 are
independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0033] "Aminocarbonylamino" refers to the group -NR300C(O)NR330R340 where R300 is hydrogen or alkyi and R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0034] "Aminothiocarbonylamino" refers to the group -NR300C(S)NR330R340 where R300 is hydrogen or alkyi and R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0035] "Aminocarbonyloxy" refers to the group -O-C(O)N 330 340 where R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and su bstituted heterocyclic are as defined herein.
[0036] "Aminosulfonyl" refers to the group -SO2NR330R340 where R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R33 and R34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, su bstituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0037] "Aminosulfonyloxy" refers to the group -O-SO2NR330R340 where R330 and R340 are
independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and su bstituted heterocyclic are as defined herein.
[0038] "Aminosulfonylamino" refers to the group -NR300-SO2NR330R340 where R300 is hydrogen or alkyi and R330 and R340 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0039] "Amidino" refers to the group -C(=N 350)N 330 340 where R330, R340, and R350 are
independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R330 and R340 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0040] The term "aryl" refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:
Figure imgf000012_0001
[0041] "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyi, substituted cycloalkyi, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, S03H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said su bstituents are defined herein.
[0042] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy. [0043] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
[0044] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.
[0045] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
[0046] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=0)-.
[0047] "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
[0048] "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl, -C(0)0-substituted alkyi, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted
alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted
cycloalkyi, -C(0)0-heteroaryl, -C(0)0-su bstituted heteroaryl, -C(0)0-heterocyclic,
and -C(0)0-substituted heterocyclic wherein alkyi, su bstituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0049] "(Carboxyl ester)amino" refers to the group -N 300-C(O)O-alkyl, -NR300-C(O)O-substituted alkyi, -NR300-C(O)O-alkenyl, -NR300-C(O)O-substituted
alkenyl, -NR300-C(O)O-alkynyl, -NR300-C(O)O-substituted
alkynyl, -NR300-C(O)O-aryl, -NR300-C(O)O-substituted
aryl, -NR300-C(O)O-cycloalkyl, -NR300-C(O)O-substituted
cycloalkyi, -NR300-C(O)O-heteroaryl, -NR300-C(O)O-substituted heteroaryl, -NR300-C(O)O-heterocyclic, and -NR300-C(O)O-substituted heterocyclic wherein R300 is alkyi or hydrogen, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0050] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted
alkyi, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyi, -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0051] The term "cycloalkyi" refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms. While cycloalkyi, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon-carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like. The condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom. For example, and without limitation, the following is a cycloalkyl group:
Figure imgf000014_0001
defined herein.
[0052] "Cycloalkyloxy" refers to -O-cycloalkyl.
[0053] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).
[0054] "Cycloalkylthio" refers to -S-cycloalkyl.
[0055] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[0056] "Guanidino" refers to the group -NHC(=NH)NH2.
[0057] "Substituted guanidino" refers to -N 360C(=N 360)N( 360)2 where each R360 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R360 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R360 is not hydrogen, and wherein said substituents are as defined herein.
[0058] The term "heteroaryl" refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2-16 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms. Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like. The condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom. For example, and without limitation, the following is a heteroaryl group:
Figure imgf000014_0002
[0059] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
[0060] "Heteroaryloxy" refers to -O-heteroaryl.
[0061] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryl). [0062] "Heteroarylthio" refers to the group -S-heteroaryl.
[0063] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).
[0064] The term "heterocyclyl" or heterocycle refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-12 ring carbon atoms and 1-8 ring heteroatoms selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that the ring is non-aromatic. Nonlimiting examples of heterocyclyl include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and
tetrahydropyranyl. The condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocyclyl group. For example, and without limitation, the following is a heterocyclyl group:
Figure imgf000015_0001
[0065] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl groups that are su bstituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[0066] "Heterocyclyloxy" refers to the group -O-heterocycyl.
[0067] "Substituted heterocyclyloxy" refers to the group -0-(substituted heterocycyl).
[0068] "Heterocyclylthio" refers to the group -S-heterocycyl.
[0069] "Substituted heterocyclylthio" refers to the group -S-(su bstituted heterocycyl).
[0070] Non-limiting examples of heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide,
1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
[0071] The term "hydrolyzing" refers to breaking an H-0-CO-, RH-0-CS-, or an RH-0-S02- moiety to an RH-OH, preferably by adding water across the broken bond. A hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis. [0072] The terms "alkenylene" and "arylene" alone or as part of another substituent means a divalent radical derived from an alkenyl or aryl group, respectively. For, alkenylene and arylene linking groups are contemplated to be used together with, or instead of, alkylene linking groups in some embodiments; no orientation of the linking group is implied. [0073] The term "halo" refers to F, CI, Br, and I.
[0074] The term "nitro" refers to -N02.
[0075] The term "cyano" refers to -CN.
[0076] The term "oxo" refers to a C=0 group, and to a substitution of 2 geminal hydrogen atoms with a C=0 group.
[0077] "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
[0078] "Sulfinyl" refers to the divalent group -SO-.
[0079] "Sulfonyl" refers to the divalent group -S(0)2-.
[0080] "Substituted sulfonyl" refers to the group -S02-alkyl, -S02-substituted
alkyi, -S02-OH, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted
cylcoalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted
heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-S02-, phenyl-S02-, and
4-methylphenyl-S02-. Preferred substituted alkyi groups on the su bstituted alkyl-S02- include halogenated alkyi groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
[0081] "Substituted sulfinyl" refers to the group -SO-alkyl, -SO-substituted
alkyi, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted
cylcoalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-su bstituted
heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and
4-methylphenyl-SO-. Preferred substituted alkyi groups on the substituted alkyl-SO- include halogenated alkyi groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
[0082] "Sulfonyloxy" or "substituted sulfonyloxy" refers to the group -OS02-alkyl, -OS02-substituted alkyl, -OS02-OH, -OS02-alkenyl, -OS02-su bstituted
alkenyl, -OS02-cycloalkyl, -OS02-substituted cylcoalkyl, -OS02-aryl, -OS02-substituted
aryl, -OS02-heteroaryl, -OS02-substituted heteroaryl, -OS02-heterocyclic, -OS02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0083] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and su bstituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0084] "Mercapto" or "thiol" refers to the group -SH.
[0085] "Formyl" refers to the group -C(0)H.
[0086] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
[0087] "Thione" refers to the atom (=S).
[0088] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.
[0089] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
[0090] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0091] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0092] An "amino-protecting group," as used herein, is attached to a nitrogen atom. An amino protecting group is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable amino protecting groups include carbamates such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), t— butyl carbamate (BOC), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc); amides such as formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide; /V-phthalimide, /V-dithiasuccinimide (Dts), /V-2,3-diphenylmaleimide, /V-2,5-dimethylpyrrole, /V-benzylamine, /V-triphenylmethylamine (Tr); eneamines such as /V-l,l-dimethylthiomethyleneamine, /V-benzylideneamine, N-p- methoxybenzylideneamine; enamides such as benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide; and sulfonamides such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr).
[0093] The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "the nitrogen atom is optionally oxidized to provide for the N-oxide (N->0) moiety" means that the nitrogen atom may but need not be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.
[0094] The term "optionally substituted" refers to a substituted or unsubstituted group. The group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.
Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, "optionally substituted" refers to a substituted or unsubstituted group. The group may be su bstituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5
substituents. Preferably, the substituents are selected from the group consisting of oxo, halo, -CN, N02, -N2+, -C02 100, -OR100, -SR100, -SOR100, -SO2R10°, -NR101R102, -CONR101R102, -SO2NR101R102, C C6 alkyl, C C6 haloalkyl, C C6 alkoxy, -CR100=C(R100)2, -CCR100, C3-C10 cycloalkyl, C3-C10 heterocyclyl, C6-C12 aryl and C2-C12 heteroaryl, wherein each R100 independently is hydrogen or C C8 alkyl; C3-C12 cycloalkyl; C3-Ci0 heterocyclyl; C6-Ci2 aryl; or C2-Ci2 heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 Ci-C6 alkyl, 1-3 Ci-C6 haloalkyl or 1-3 C C6 alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, /'so-propyl, cyclopropyl, vinyl, ethynyl, -C02H, - C02CH3, -OCF3, -CF3, -OCHF2.
[0095] R101 and R102 independently is hydrogen; C C8 alkyl, optionally substituted with -C02H or an ester thereof, C C6 alkoxy, oxo, -CR103=C(R103)2, -CCR, C3-Ci0 cycloalkyl, C3-Ci0 heterocyclyl, C6-Ci2 aryl, or C2-Ci2 heteroaryl, wherein each R103 independently is hydrogen or Ci-C8 alkyl; C3-Ci2
cycloalkyl; C3-Ci0 heterocyclyl; C6-Ci2 aryl; or C2-Ci2 heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R and R together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
[0096] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the su bstituent "alkoxycarbonylalkyl" refers to the group (alkoxy)-C(0)-(alkyl)-.
[0097] It is understood that in all su bstituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -su bstituted aryl-(substituted aryl)-substituted aryl.
[0098] It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[0099] The term "pharmaceutically acceptable" refers to safe and non-toxic for in vivo, preferably, human administration. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable. The term "salt" refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkai metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, and non-limiting cations useful in pharmaceutically accepta ble salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as caroboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
[0100] As used herein, the term "treatment" or "treating" means any treatment of a disease or condition in a patient, including one or more of:
• preventing or protecting against the disease or condition, that is, causing the clinical
symptoms not to develop, for example, in a subject at risk of suffering from such a disease or condition, thereby substantially averting onset of the disease or condition; • inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or
• relieving the disease or condition that is, causing the regression of clinical symptoms.
Compounds
[0101] In one aspect, this invention provides a compound of formula I:
Figure imgf000020_0001
or a tautomer thereof, a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, wherein each of A and RB independently is N or CR10, preferably if one of RA and RB is N, the other is
CR10;
R10 is hydrogen, halo, preferably fluoro, or an optionally substituted Ci-C6 alkyl;
X1 is O, S, SO, S02, NR15;
R15 is hydrogen or an amino protective group; each of L1 and L3 independently is -(L )m(CO)n(L12)0-;
L11 and L12 each independently are optionally substituted C C3 alkylene or C C3 heteroalkylene provided that -X1 .1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R1 to the rest of the compound; each of m, n, and o is 0 or 1; each of R1 and R3 is independently C6-Ci0 aryl, 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4-15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, or a C3-C8 cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted, preferably, with 1-3 substituents selected from amino, halo, Ci-C6 alkoxy, -O- C3-C8 cycloalkyl, -O-(5-10 membered heteroaryl), -O-C6-Ci0 aryl, optionally substituted C C6 alkyl, preferably, methyl, C6-Ci0 aryl, 5-10 membered heteroaryl, 4-15 membered heterocyclyl, and C3-C8 cycloalkyl substituents; and/or where adjacent positions on a substitued aryl, heteroaryl, heterocyclyl, or cyckloalkyl of 1 and R3 are substituted with R50 and R51 substituents, such that, for an aryl, R50 and R51 together with the intervening atoms form a 5-6 membered heteroaryl containing up to 2 heteroatoms, a 5-6 membered heterocycle containing up to 2 heteroatoms, or a 5-6 membered cycloalkyl group each optionally substituted with 1-3 halo and/or Ci-C6 alkyl group; for a heteroaryl, R50 and R51 together with the intervening atoms form a phenyl, a 5-6 membered heterocycle containing up to 2 heteroatoms, or a 5-6 membered cycloalkyl group each optionally substituted with 1-3 halo and/or C C6 alkyl group; for a heterocyclyl, R50 and R51 together with the intervening atoms form a phenyl, a 5-6 membered heteroaryl containing up to 2 heteroatoms, or a 5-6 membered cycloalkyl group each optionally substituted with 1-3 halo and/or Ci-C6 alkyl group; for a cycloalkyl, R50 and R51 together with the intervening atoms form a phenyl, a 5-6 membered heteroaryl containing up to 2 heteroatoms, or a 5-6 membered heterocyle containing up to 2 heteroatoms each optionally substituted with 1-3 halo and/or Ci-C6 alkyl group; ring C is a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;
preferably, a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatom; wherein the heterocycle is optionally substituted, preferably, with 1-3, more preferably with a single substituent, selected from COR26, C02R26, and -S02R26, and optionally substituted C C6 alkyl;
R26 is optionally substituted C C6 alkyl, preferably, C C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or N(R25)2; each R25 is independently hydrogen or C C6 alkyl optionally substituted with 1-5 halo, preferably fluoro groups, or the two R25 groups together with the nitrogen atom they are bonded to forms a: 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; preferably, a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatoms; wherein the heterocycle is optionally substituted, preferably, with 1-3, more preferably a single, group selected from optionally substituted Ci-C6 alkyl, preferably Ci-C6 alkyl; or ring C is C6-Ci0 aryl or 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the aryl or heteroaryl is optionally substituted with 1-3, preferably, 2, more preferably a single substituent; or ring C is C3-C8 cycloalkyl optionally substituted with 1-3, preferably, 2, more preferably a single substituent; ^ is a double or a single bond, provided that when C is aryl or heteroaryl it is a double bond, and when C is a heterocyle or cycloalkyl it can be a double bond or a single bond. [0102] In some embodiments, A is N. In some embodiments, RA is CR10. In some embodiments, RA is CH. In some embodiments, RB is N. In some embodiments, RB is CR10. In some embodiments, RB is CH. In some embodiments, R10 is hydrogen. In some embodiments, R10 is halo. In some embodiments, R10 is fluoro. In some embodiments, R10 is an optionally substituted C C6 alkyl, such as methyl.
[0103] In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SO. In some embodiments, X1 is S02. In some embodiments, X1 is NR15. In some embodiments, X1 is NH.
[0104] In some embodiments, R15 is hydrogen. In some embodiments, R15 is an amino protective group.
[0105] Each of L1 and L3 independently is -(Lu)m(CO)n(L12)0-. In some embodiments, L11 is an optionally substituted Ci-C3 alkylene. In some embodiments, L11 is an optionally substituted Ci-C3 heteroalkylene. In each of these embodiments, it is provided that -X^L1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R1 to the rest of the compound.
[0106] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, o is 0. In some embodiments, o is 1.
[0107] In some embodiments, R1 is an optionally su bstituted C6-Ci0 aryl. In some embodiments, R1 is an optionally substituted 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4- 15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some embodiments, R1 is a 4- 15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some embodiments, R1 is a C3-C8 cycloalkyl. [0108] In some embodiments, R3 is a su bstituted C6-Ci0 aryl. In some embodiments, R3 is an unsu bstituted C6-Ci0 aryl. In some embodiments, R3 is an optionally su bstituted 5-10 membered heteroaryl containing u p to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4-15 mem bered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some em bodiments, R1 is a 4-15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some em bodiments, R1 is a C3-C8 cycloalkyl.
[0109] In some embodiments, the aryl, heteroaryl, heterocyclyl, or cycloalkyl group for R1 or R3 is unsu bstituted. In some embodiments, the aryl, heteroaryl, heterocyclyl, or cycloalkyl grou p for R1 or R3 is su bstituted, preferably, with 1-3 su bstituents selected from amino or -N H2, halo, C C6 alkoxy, -
0- C3-C8 cycloalkyl, -O-(5-10 membered heteroaryl), -O-C6-C10 aryl, optionally su bstituted C C6 alkyl preferably methyl, C6-Ci0 aryl, and 5-10 membered heteroaryl optionally su bstituted with a halo group, 4-15 mem bered heterocyclyl, and C3-C8 cycloalkyl su bstituents.
[0110] In some embodiments, R3 is C6-Ci0 aryl or 5-10 membered heteroaryl optionally su bstituted with 1-2 Ci-C6 alkyl groups.
[0111] In some embodiments, adjacent positions on a su bstitued aryl, heteroaryl, heterocyclyl, or cyckloalkyl are su bstituted with R50 and R51 su bstituents.
[0112] In some embodiments, for an a ryl, R50 and R51 together with the intervening atoms form a 5-6 mem bered heteroaryl containing up to 2 heteroatoms, prefera bly optionally su bstituted as disclosed herein. In some embodiments, the heteroaryl is su bstituted with 1-3 halo. In some embodiments, the heteroaryl is su bstituted with 1-3 Ci-C6 alkyl groups. In some em bodiments, the heteroaryl is su bstituted with an -N H2. In some embodiments, for an aryl, R50 and R51 together with the intervening atoms form a 5-6 membered heterocycle containing u p to 2 heteroatoms, prefera bly optionally su bstituted as d isclosed herein. In some em bodiments, the heterocycle is su bstituted with 1-3 halo. In some embodiments, the heterocycle is su bstituted with 1-3 Ci-C6 alkyl groups. In some embodiments, the heterocyclyl is su bstituted with an -N H2.ln some em bodiments, for an aryl, R50 a nd R51 together with the intervening atoms form a 5-6 mem bered cycloalkyl group, preferably optionally su bstituted as d isclosed herein. In some em bodiments, the cycloalkyl is su bstituted with
1- 3 halo. In some em bodiments, the cycloalkyl is su bstituted with 1-3 C C6 alkyl groups. In some embodiments, the cycloalkyl is su bstituted with an -N H2.
[0113] In some embodiments, for a heteroaryl, R50 and R51 together with the intervening atoms form a phenyl, prefera bly optionally su bstituted as disclosed herein. In some embodiments, for a heteroaryl, and R together with the intervening atoms form a a 5-6 membered heterocycle containing up to 2 heteroatoms, prefera bly optionally substituted as disclosed herein. In some embodiments, the heterocycle is substituted with 1-3 halo. In some embodiments, the heterocycle is substituted with 1-3 Ci-C6 alkyl groups. In some embodiments, for a heteroaryl, R50 and R51 together with the intervening atoms form a 5-6 membered cycloalkyl group, preferably optionally substituted as disclosed herein. In some embodiments, the cycloalkyl is substituted with 1-3 halo. In some embodiments, the cycloalkyl is substituted with 1-3 Ci-C6 alkyl groups.
[0114] In some embodiments, for a heterocyclyl, R50 and R51 together with the intervening atoms form a phenyl, preferably optionally substituted as disclosed herein. In some embodiments, for a heterocyclyl, R50 and R51 together with the intervening atoms form a 5-6 membered heteroaryl containing up to 2 heteroatoms, prefera bly optionally substituted as disclosed herein. In some embodiments, the heteroaryl is substituted with 1-3 halo. In some embodiments, the heteroaryl is substituted with 1-3 Ci-C6 alkyl groups. In some embodiments, R50 and R51 together with the intervening atoms form a 5-6 membered cycloalkyl group. In some embodiments, the cycloalkyl is substituted with 1-3 halo. In some embodiments, the cycloalkyl is substituted with 1-3 Ci-C6 alkyl groups.
[0115] In some embodiments, for a cycloalkyl, R50 and R51 together with the intervening atoms form a phenyl. In some embodiments, the phenyl is substituted with 1-3 halo. In some
embodiments, the phenyl is substituted with 1-3 Ci-C6 alkyl groups. In some embodiments, for a cycloalkyl, R50 and R51 together with the intervening atoms form a 5-6 me heterocyle membered heteroaryl containing up to 2 heteroatoms. In some embodiments, the heteroaryl is substituted with 1-3 halo. In some embodiments, the heteroaryl is substituted with 1-3 Ci-C6 alkyl groups. In some embodiments, for a cycloalkyl, R50 and R51 together with the intervening atoms form a 5-6 membered heterocyle containing up to 2 heteroatoms. In some embodiments, the heterocyle is substituted with 1-3 halo. In some embodiments, the heterocyle is substituted with 1-3 C C6 alkyl groups.
[0116] In some embodiments, ring C is a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. Preferably, ring C is a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatom, wherein the heterocycle is optionally substituted. Preferably, the heterocycle is optionally substituted with 1, 2 or 3 substituents selected from COR26, C02R26, and - S02R26 and optionally substituted Ci-C6 alkyl, such as methyl. [0117] In some embodiments, is optionally su bstituted Ci-C6 alkyl. In some em bodiments, R is optionally su bstituted C6-Ci0 aryl. In some em bodiments, R26 is optionally su bstituted 5-6 membered heteroaryl. In some em bodiments, R26 is optionally su bstituted C3-C6 cycloalkyl. In some
embodiments, R26 is N(R25)2, such as NH2.
[0118] In some embodiments, each R25 is hydrogen. In some embodiments, each R25 is Ci-C6 alkyl optionally su bstituted with 1-5 halo, prefera bly fluoro groups. In some embod iments, two R25 groups together with the nitrogen atom they are bonded to forms a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some embodiments, two R25 groups together with the nitrogen atom they are bonded to forms a a 4-7 mem bered heterocycle containing 2, or more preferably, a single, ring heteroatoms; wherein the heterocycle is optionally su bstituted, prefera bly, with 1-3, more prefera bly a single, group selected from optionally su bstituted Ci-Cg alkyl, prefera bly C C6 alkyl, such as methyl.
[0119] In some embodiments, ring C is C6-Ci0 aryl. In some embodiments, ring C is 5-10 membered heteroaryl containing u p to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. In some embodiments, the aryl or heteroaryl is optionally su bstituted with 1-3, prefera bly, 2, more prefera bly a single su bstituent.
[0120] In some embodiments, ring C is C3-C8 cycloalkyl optionally su bstituted with 1, 2 or 3, preferably, 2, and more prefera bly a single su bstituent.
[0121] In some embodiments, when C is aryl or heteroaryl, ^ is a dou ble bond. In some embodiments, when C is a heterocyl or cycloalkyl,
Figure imgf000025_0001
is a single bond. In some em bodiments, when C is a heterocyle or cycloalkyl,
Figure imgf000025_0002
is a dou ble bond.
[0122] In some embodiments, R is hydrogen or Ci-C6 alkyl optionally su bstituted with halo, preferably fluoro, r is 1, 2, or 3, preferably, 2, more prefera bly, 1, and the remaining varia bles are defined a bove.
[0123] In some embodiments, the compound of formula I is of formula l-B where any of the varia bles can be defined as described a bove for formula I:
Figure imgf000026_0001
wherein ring C is a 5-6 membered heteroaryl, optionally su bstituted with 1-3, preferably, 2, more preferably, 1, substituent as defined in claim 1, and the remaining variables are defined above.
[0124] In some embodiments the compound of formula I is of formula l-C:
Figure imgf000026_0002
l-C
[0125] In some embodiments the compound of formula I is of form
Figure imgf000026_0003
l-D
[0126] In some embodiments the compound of formula I is of form
Figure imgf000027_0001
l-E
[0127] In some embodiments the compound of formula I is of form
Figure imgf000027_0002
[0128] In formulas l-C, l-D, l-E or l-F, any of the variables can be defined as described above for formula I; and independently each p is 1, 2, or 3; independently each X2 is O, S, SO, S02, CH 22, optionally substituted N-(C C6 alkyl), NH, -N- CO-R26, -N-CO2-R26, or -NS02R26; independently each R21 is hydrogen or optionally substituted Ci-C6 alkyl; independently each R22 is hydrogen or optionally substituted Ci-C6 alkyl; independently each q is 1, 2, 3, or 4, preferably, 3, more preferably 1 or 2;
2 of A, B, C are independently CHR22 preferably -CH2-, and 1 of A, B, and C is O, S, SO, S02, optionally substituted N-(C C6 alkyl), NH, -N-CO-R26, -N-C02-R26, or -NS02R26; where the remaining variables are defined above.
[0129] In some embodiments the compound of formula I is of formula l-G:
Figure imgf000028_0001
wherein the other variables are defined above.
In some embodiments the compound of formula I is of formula l-H:
Figure imgf000028_0002
, and
Figure imgf000029_0001
wherein R is H, -CO-R , -C02-R , or -S02R , or optionally substituted C C6 alkyl, such as methyl, and the remaining variables are defined above. In some embodiments, R23 is H. In some embodiments, R23 is CO-R26. In some embodiments, R23 is -C02-R26. In some embodiments, R23 is- S02R26. In some embodiments, R23 is optionally substituted Ci-C6 alkyl, such as methyl.
[0132] In some embodiments the compound of formula I is of formula l-l:
Figure imgf000029_0002
wherein v is 1, 2, 3 or 4;
R27 is optionally substituted C C6 alkyl, preferably substituted with 1-5 halo, more preferably fluoro; p is 1, 2, or 3, and the remaining variables are defined above. [0133] In some embodiments the compound of formula I is of formula l-J:
Figure imgf000030_0001
I -J wherein the remaining variables are defined above. [0134] In some embodiments the compound of formula I is of formula l-K:
Figure imgf000030_0002
wherein the remaining variables are defined above. [0135] In some embodiments the compound of formula I is of formula l-L:
Figure imgf000030_0003
wherein ring C is a 6-membered aryl or a 6 member heteroaryl containing a single nitrogen atom; 35 is methyl substituted with a 5 membered heteroaryl containing 2 nitrogen atoms, -0-(6 membered heteroaryl containing a single nitrogen atom), or -0-(6 membered heterocyclyl containing a single nitrogen atom); is hydrogen, or R and R together with the intervening carbon atoms form a 5 mem bered heteroaryl containing 1-2 nitrogen atoms, which heteroaryl ring is su bstituted with 1-2, C C6 alkyl, prefera bly methyl groups.
[0136] In some embodiments, RA is CR10. In some embodiments, RA is CH. In some embodiments, RA is N.
[0137] In some embodiments, RB is N. In some em bodiments, RB is CR10. In some em bodiments, RB is CH.
[0138] In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SO or S02. In some embodiments, X1 is N R15.
[0139] In some embodiments, R15 is hydrogen. In some em bodiments, R15 is an amino protecting group.
[0140] In some embodiments, L1 is -CH2- or -CO-, prefera bly -CH2-.
[0141] In some embodiments, R1 is optionally su bstituted C6-Ci0 aryl or optionally su bstituted 5-10 mem bered heteroaryl.
[0142] In some embodiments, L3 is -CH2-. In some embodiments, R3 is optionally su bstituted C6-Ci0 aryl or optionally su bstituted 5-10 membered heteroaryl.
[0143] In some embodiments, ring C is:
Figure imgf000031_0001
wherein R is hydrogen or Ci-C6 alkyl, optionally su bstituted with halo, preferably fluoro, or N(R25)2; C C6 alkoxy optionally su bstituted with halo, prefera bly fluoro, or N(R25)2; r is 1, 2, or 3, prefera bly, 2, more prefera bly, 1.
[0144] In some embodiments, ring C is a 5-6 membered heteroaryl, optionally su bstituted with 1-3, preferably, 2, more preferably, 1, su bstituent, yet more preferably, ring C is a 6 mem bered heteroaryl, containing a single nitrogen atom.
[0145] In some embodiments, ring C is of formula : l l-C or 11 - D
Figure imgf000032_0001
ll-C ll-D wherein independently each p is 1, 2, or 3; independently each X2 is O, S, SO, S02, CH 22, N-( optionally substituted C C6 alkyl), NH, -N- CO-R26, -N-CO2-R26, or -NS02R26; independently each R21 is hydrogen or optionally substituted Ci-C6 alkyl; independently each R22 is hydrogen or optionally substituted Ci-C6 alkyl; and independently each q is 1,2, 3, or 4, preferably, 3, more preferably 1 or 2.
[0146] In some embodiments, ring C is of formula ll-E or ll-F:
Figure imgf000032_0002
ll-E ll-F wherein the other variables are defined above.
[0147] In some embodiments, ring C is selected from:
Figure imgf000032_0003
wherein R is, H, -CO-R , -C02-R , -S02R , or optionally substituted C C6 alkyl, and R b is defined above.
[0148] In some embodiments, ring C is:
Figure imgf000033_0001
wherein v is 1, 2, 3 or 4; 27 is optionally substituted Ci-C6 alkyl, preferably substituted with 1-5 halo, more preferably fluoro; and p is 1, 2, or 3. wherein p is 1, 2, or 3, and the remaining variables are defined above.
[0149] In some embodiments, the compound of formula I is selected from the table below.
Figure imgf000033_0002
Figure imgf000034_0001
Synthesis of Compounds
Synthetic Schemes and Experimental Procedures Scheme 1. General s nthetic route to compounds I
Figure imgf000034_0002
Alcohol INT-1 INT-2 I
General synthetic route (Scheme 1) for preparing novel plasma kallikrein inhibitors (I). [0150]
[0084] Plasma kallikrein inhibitors (I) can be synthesized by a number of approaches such as the synthetic route described in Scheme 1. As used herein N-P can refer to a protected nitrogen atom,which protecting groups are well known in the art and to the skilled artisan. The free NH tricyclic chloride INT-1 is first reacted with reagent 1 with a leaving group such as an alkyl halide (alkylation reaction) or an alcohol (Mitsunobu reaction) to give the N-substituted tricyclic chloride INT-2. Other alkylating reagents such as alkyl mesylate or tosylate can also be used to substitute alkyl halide; a sulfonyl chloride can also be used to react with INT-1 to form a sulfonamide INT-2. Regioisomers may be generated if at least one of RA or RB is a nitrogen atom, separation of the N- regioisomers can be achieved by preparative HPLC or flash silica gel chromatography. Alternatively, the N-regioisomer mixture can be directly applied to the next reaction and separation done after the final reaction. The plasma kallikrein inhibitors are prepared via the nucleophilic aromatic substitution of INT-2 chloride with the appropriate nucleophile (R^L^X1!-!). The reaction is typically carried out in the presence of a base such as Hunig's base and/or Lewis acid or a catalyst (e.g., a palladium catalyst).
Figure imgf000035_0001
INT-2
[0085] One way to make the tricyclic chloride intermediate INT-1 (and or INT-2) is oxidation of the nitrogen containing tricyclic scaffold (Scheme 2, step 1) with appreciate oxidation reagent such as acid peroxide (e.g., mCPBA); the reaction gives a N-oxide product, which can be transformed to the ortho hydroxyl compound (step 2) or the ortho chloride analog depending on the reaction conditions. For example, treating the N-oxide with or phosphorus trichloride or phosphorus oxychloride under heating gives the tricyclic chloride INT-2 product directly via mechanism shown in scheme 3 (Meiseheimer reaction).
INT-2
Scheme 3. General synthetic route to INT-2
R3" λΑΓ Cl — 7 R3!- 1;cAc,—■ R3 H CI — - R /3"V-
U INT-2
[0086] General synthetic route (Scheme 4) for preparing novel plasma kallikrein inhibitors (I) with tricyclic heteroaromatic ring system. The tricyclic core scaffold can be constructed by synthetic sequence shown in scheme 4. First, ethyl 3-amino-lH-pyrazole-4-carboxylate (A=N) or ethyl 3- amino-lH-pyrrole-4-carboxylate (A=CH) is converted to the corresponding 3-bromo analog via Sandmeyer reaction involving diazotization with a nitrite reagent such as t-BuONO and subsequent displacement with copper (II) bromide. The NH analog (2a) is converted to N-substituted analog (2b) via similar conditions described in scheme 1 (INT-1 to INT-2). Suzuki coupling of the bromide with a 2-amino (or 2-nitro) aryl/heteroaryl boronic acid derivative (step 2) and subsequent cyclization produces the tricyclic hydroxyl analog 3. Reacting the hydroxyl analog with phosphorus oxychloride furnishes the key chloride INT-2, which is transformed to the kallikrein inhibitor (I) via similar conditions described in Schemel. As used herein NR refers to an N-L2-R2 moety or a protected nitrogen atom N-P. Scheme 4. General synthetic route to heteroaromatic tricyclic compounds I
Figure imgf000036_0001
[0087] General synthetic route (Scheme 5) for preparing novel plasma kallikrein inhibitors with unsaturated c-ring (I). Tricyclic plasma kallikrein inhibitors (I) with a cycloalkyl C-ring can be synthesized according to the general synthetic route described in Scheme 5. Suzuki coupling of a cyclic boronate analog with 3-bromopyrazole or 3-bromopyrrole (step 1) produces intermediate 3. The double bond of 3 is converted to ketone functionality in compound 5 via hydroboration and oxidation (steps 2&3). Treatment of the ketone 5 with an appropriate amino reagent (such as NH3 in MeOH, ammonium chloride or ammonium acetate) gives the cyclized tricyclic intermediate 6. Alternatively, mesylation or tosylation of the hydroxyl intermediate 4 followed by reaction with ammonia (NH3, or NH4OH, or NH4CI etc.) (step 5) gives compound 6 with partially unsaturated B-ring (dotted line). Compound 6 can also be obtained from compound 3 via amino intermediate 4a by conditions shown in scheme 5. Final conversion of compound 6 to chloride INT-2 and plasma kallikrein inhibitors (I) can be achieved by methods similar to these described in scheme 1 for heteroaromatic tricyclic analogs.
Figure imgf000036_0002
[0088] General synthetic route (Scheme 6) for preparing novel plasma kallikrein inhibitors with cyclo(hetero)alkyl c-ring (I). An alternative approach to tricyclic plasma kallikrein inhibitors (I) with a cycloalkyi C-ring is shown in Scheme 6. The 2-carboxylate boronic acid derivative 4, obtained by the sequence shown (1 to 4), is coupled with 3-bromopyrazole or 3-bromopyrrole 5 under Suzuki conditions to produce biscarboxylate 6. Selective conversion of one of the two carboxylic esters to acid (eg, from '=t-Bu or Me to R'=H) followed by Curtius rearrangement via acyl azide 7, gives key amine intermediate 8, which may cyclize directly under the reaction conditions or with the aid of heating and/or acid. The hydroxyl intermediate 9 can be transformed to kallikrein inhibitors (I) via the chloride INT-2 by methods similar to those described in scheme 1 for heteroaromatic tricyclic analogs.
Scheme 6. General synthetic route to heteroaromatic compounds I with cyclo(hetero)alkyl C-
Figure imgf000037_0001
[0089] General synthetic route (Scheme 7) for preparing novel plasma kallikrein inhibitors with bridged C-ring (I). Analogous to the methods for the preparation of compounds I with cycloalkyi C- rings (Schemes 5&6), the kallikrein inhibitors I with a bridged c-ring can be synthesized according to scheme 7 by using bridged boronic acid starting materials 2.
Scheme 7. General synthetic route to heteroaromatic compounds I with a bridged C-ring
Figure imgf000037_0002
[0090] Preparation of INT-2 by general method A - alkylation reaction. In a typical alkylation reaction, a mixture of the NH bicyclic derivative (INT-1) (0.1-2 mmol, leq.), alkyl chloride or bromide (la) (1 to 1.5 eq), and a base such as Cs2C03 (2-5 eq.) (catalytic amount of Nal or Bu4NI may also be added) in DMF or acetonitrile (1 to 10 mL) was stirred at T or up to 120 °C for 0.5-24 h under nitrogen atmosphere. In workup A, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then subjected to preparative HPLC or flash silica gel chromatography purification. In workup B (for products that did not precipitate), dilute HCI or aqueous NH4CI was added at 0 °C to adjust the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride.The organic layer was separated, dried, and the solvent removed under vacuum to afford crude product which was purified by automated silica gel column chromatography using appropriate solvent mixtures (e.g., ethyl acetate/hexanes).
[0091] Preparation of INT-2 by general method B - Mitsunobu reaction: To a solution of NH bicyclic derivative (INT-1) (0.1-2 mmol, leq.), (0.1-2 mmol) in THF (1-lOmL) and alcohol (lb) (0.8 to 1.2eq) was added PPh3 (l-1.5eq) in anhydrous THF (1-lOmL), followed by the addition of DIAD or DEAD (1.1 eq) in THF or toluene. The reaction is typically carried out at 0 °C (or RT) and reagents added dropwise. After addition, the reaction is continued at 0 °C (or RT) for up to 48 hours. The mixture was concentrated and the residue was purified by preparative HPLC or flash silica gel
chromatography.
[0092] Preparation of compound I by general method C - SNAr reaction: In a typical procedure, a mixture of N-substituted bicyclic chloride (INT-2) (0.1-2 mmol, leq.) and a nucleophile such as an amine (2a) (1.2 to 5 eq) in a polar solvent (0.5 to 5mL) such as n-BuOH, ethylene glycol dimethyl ether, l-ethoxy-2-(2-ethoxyethoxy)ethane or DMF was placed in a microwave vial. A Lewis acid (such as ZnCI2) and a base (such as Hunig's base, DIPEA) may also be added to the reaction mixture to facilitate the reaction. The reaction mixture was then heated by either conventional methods or in a microwave reactor at elevated temperatures between 100 and 250 °C for up to 24 hrs. In workup A, the reaction mixture was concentrated on a rotavap to remove all volatiles, and the resulting residue was purified by preparative HPLC or flash silica gel chromatography. In workup B, water was added to the reaction mixture, the precipitated product was collected, washed with water, and then, if necessary, subjected to preparative HPLC or flash silica gel chromatography purification. In workup C (for products that did not precipitate), dilute HCI or aqueous NH4CI was added at 0 °C to adjusted the pH to ~7, the reaction mixture was partitioned between ethyl acetate or dichloromethane and aqueous sodium chloride and the organic layer separated, dried, and solvent removed under vacuum to afford crude product. This was purified by automated silica gel column chromatography using appropriate solvent mixtures (e.g., ethyl acetate/hexanes).
Pharmaceutical Compositions
[0093] In further aspects of the invention, provided is a pharmaceutical composition comprising a compound of Formula (I) as provided herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
[0094] The compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or
physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like.
[0095] Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
[0096] The concentration of the excipient is one that can readily be determined to be effective by those skilled in the art, and can vary depending on the particular excipient used. The total concentration of the excipients in the solution can be from about 0.001% to about 90% or from about 0.001% to about 10%.
[0097] The concentration of compounds provided herein and/or utilized herein can be from about 1 to about 99% by weight in the pharmaceutical compositions provided herein. In certain embodiments, the concentration of compounds provided herein and/or utilized herein in the pharmaceutical composition is about 5% by weight, or alternatively, about 10%, or about 20%, or about 1%, or about 2%, or about 3%, or about 4%, or about 6%, or about 7%, or about 8%, or about 9%, or about 11%, or about 12%, or about 14%, or a bout 16%, or about 18%, or about 22%, or about 25%, or about 26%, or about 28%, or about 30%, or about 32%, or about 34%, or about 36%, or about 38%, or about 40%, or about 42%, or about 44%, or about 46%, or about 48%, or about 50%, or about 52%, or about 54%, or about 56%, or about 58%, or about 60%, or about 64%, or about 68%, or about 72%, or about 76%, or about 80% by weight. [0098] Compounds and pharmaceutical compositions of this invention maybe used alone or in combination with other compounds. When administered with another agent, the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time. However, co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention. In some embodiments, a compound of this invention can be used as an adjunct to conventional drug therapy of the conditions described herein.
[0099] Pharmaceutical compositions can be formulated for different routes of administration, including oral delivery and other routes such as intravenous, intraarterial, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous, transdermal, intracranial, and subcutaneous routes. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
Methods of Use
[0100] In another aspect, this invention provides a method for inhibiting plasma kallikrein activity in a subject, the method comprising administering to the subject an effective amount of the compound of Formula I, or a subformula thereof, or a pharmaceutical composition of any thereof.
[0101] Plasma kallikrein is contemplated to have implications in disorders such as (HAE) , retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, CM E following vascular occlusion (e.g. central retina vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion), retinal edema, complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet aged-related macular degeneration (AM D), ischemic reperfusion injuries, e.g. in all kind of contexts associated with tissue and/or organ transplantation, surgically-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma- associated edema, spinal cord injury, pain, ischemia, focal brain ischemia, neurological and cognitive deficits, deep vein thrombosis, stroke, myocardial infarction, acquired angioedema drug- related (ACE-inhibitors), edema, high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation induced edema, lymph edema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral stroke or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, cerebral trauma associate with injury or surgery, brain aneurysm, arterio-venous malformation, reduction of blood losses during surgical procedures (e.g.cardiothoracic surgery, such as cardiopulmonary bypass or coronary artery bypass grafting), blood coagulation disorders such as thrombosis, itch, disorders with an inflammation component (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, essential hypertension, increased blood pressure associated with dia betes or hyperlipidemia, renal insufficiency, chronic kidney disease, heart failure, microalbuminuria, albuminuria, proteinuria, disorders associated with increased vascular permeability (e.g. increased retinal vascular permeability, increased leg, feet, ankle vascular permeability), cerebral hemorrhage, microalbuminuria, albuminuria and proteinuria, , deep vein thrombosis, coagulation from post fibrinolytic treatments, angina, angioedema, sepsis, arthritis (e.g. rheumatoid arthritis,
osteoarthritis, infection arthritis), lupus, gout, psoriasis, blood loss during cardiopulmonary bypass, inflammatory bowel, diabetes, diabetic complications, infectious diseases, astrocyte- activation related diseases (e.g. Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, stroke, epilepsy andtrauma (e.g. brain trauma).
[0102] Plasma kallikrein inhibitors are also contemplated to be useful in the treatment of a wide range of disorders, in particular retinopathy or edema-associated diseases, such as hereditary angioedema, macular edema and brain edema. Plasma kallikrein inhibitors are also contemplated to be useful in the treatment of retinopathy, e.g. retinopathy associated with diabetes and/or hypertension; hereditary angioedema; edema formation in diseases, e.g. edema formation related to ischemic reperfusion injuries; macular edema, e.g. macular edema associated with diabetes and/or hypertension; .in the prevention and treatment of thrombosis; in the treatment of intracerebral hemorrhage induced by hyperglycemia in diabetic patients.
[0103] In some embodiments of the method for treatment, upon administration to the patient, a therapeutically effective amount of the compound of Formula I, or a subformula thereof, reduces protease activity, such as kallikrein activity, for up to 12, 24, 26 or 48 hours after administration.
[0104] An effective amount of the compound of Formula I is the amount of the compound of Formula I required to produce a therapeutic effect in vitro or in vivo. In some embodiments the effective amount in vitro is about from 0.1 nM to about 1 mM. In some embodiments the effective amount in vitro is from a bout 0.1 nM to about 0.5 nM or from about 0.5 nM to about 1.0 nM or from about 1.0 nM to about 5.0 nM or from a bout 5.0 nM to about 10 nM or from about 10 nM to about 50 nM or from about 50 nM to about 100 nM or from about 100 nM to about 500 nM or from about 500 nM to about 1 mM. In some embodiments, the effective amount for an effect in vivo is about 0.1 mg to about 100 mg, or preferably, from about 1 mg to about 50 mg, or more preferably, from about 1 mg to about 25 mg per kg/day. In some other embodiments, the effective amount in vivo is from about 10 mg/kg/day to about 100 mg/kg/day, about 20 mg/kg/day to about 90 mg/kg/day, about 30 mg/kg/day to about 80 mg/kg/day, about 40 mg/kg/day to about 70 mg/kg/day, or about 50 mg/kg/day to about 60 mg/kg/day. In still some other embodiments, the effective amount in vivo is from about 100 mg/kg/day to about 1000 mg/kg/day.
[0105] Routes of administration refer to the method for administering a compound of Formula I or a composition thereof to a mammal. Administration can be achieved by a variety of methods. These include but are not limited to subcutaneous, intravenous, transdermal, su blingual, or intraperitoneal injection or oral administration.
[0106] In certain aspects, the methods described herein relate to administering the compound of Formula I or compositions thereof in vitro. In other aspects the administration is in vivo. In yet other aspects, the in vivo administration is to a mammal. Mammals include but are not limited to humans and common laboratory research animals such as, for example, mice, rats, dogs, pigs, cats, and rabbits.
Examples
[0107] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.
Example 1: Preparation of Intermediates
[0108] Amine-1: Synthesis of 6-(aminomethyl)isoquinolin-l-amine:
Figure imgf000043_0001
Figure imgf000043_0002
[0109] Step 1. Into a 500-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of l,4-dibromo-2-methyl benzene (15 g, 60.02 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL). CuCN (20.4 g, 227.77 mmol, 3.80 equiv) was added to the reaction. The resulting solution was heated to reflux for 6 h, and then diluted with 200 mL of ammonia. The solids were filtered. The filtrate was extracted with 2x200 mL of ethyl acetate. The combined organic layers were washed with 2x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (50/1-30/1) as eluent to provide 3.8 g (45%) of 2-methylbenzene-l,4- dicarbonitrile as a light yellow solid.
[0110] Step 2. Into a 250-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-methylbenzene-l,4-dicarbonitrile (4 g, 28.14 mmol, 1.00 equiv), [(tert-butoxy)(dimethylamino)methyl]dimethylamine (9.8 g, 56.23 mmol, 2.00 equiv) in N,N-dimethylformamide (50 mL). The resulting solution was stirred overnight at 75 °C, and then concentrated under vacuum. The resulting mixture was washed with 50 mL of hexane. The solids were collected by filtration. This provided 5.3 g (95%) of 2-[(E)-2- (dimethylamino)ethenyl]benzene-l,4-dicarbonitrile as a yellow solid.
[0111] Step 3. Into a 250-mL round-bottom flask, was placed a mixture of 2-[(E)-2- (dimethylamino)ethenyl]benzene-l,4-dicarbonitrile (5.4 g, 27.38 mmol, 1.00 equiv), DMPU (15 mL), and (2,4-dimethoxyphenyl)methanamine (7.58 mL). The resulting solution was stirred for 3 h at 140 °C, and then cooled with an ice bath. The resulting solution was diluted with 200 mL of hexane/EA (2/1). The precipitates were collected by filtration. The solid was dried in an oven under reduced pressure. This provided 7.55 g (86%) of 2-[(2,4-dimethoxyphenyl)methyl]-l-imino-l,2,3,4- tetrahydroisoquinoline-6-carbonitrile as a yellow solid. [0112] Step 4. Into a 250-m L round-bottom flask, was placed a solution of 2-[(2,5- dimethoxyphenyl)methyl]-l-imino-l,2-d ihydroisoquinoline-6-carbonitrile (7.55 g, 23.64 mmol, 1.00 equiv) and anisole (3.9 m L, 1.50 equiv) in trifluoroacetic acid (100 mL). The resulting solution was stirred for 2 days at 70 °C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sodium bicarbonate (sat. aq.), and then the mixture was extracted with 3x200 mL of ethyl acetate. The com bined organic layers were dried over anhydrous sodiu m sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichlorometha ne/methanol (50/1-30/1) as eluent to yield 2.5 g (63%) of l-aminoisoquinoline-6- carbonitrile as a yellow solid.
[0113] Step 5. 6-(aminomethyl)isoquinolin-l-amine. Into a 500-mL round-bottom flask, was placed 6-isocyanoisoquinolin-l-amine (7.9 g, 46.70 mmol, 1.00 equiv), methanol (100 mL), ammonia (100 mL), and Raney-Ni (10 g). To the a bove, hydrogen (1 atm) was introduced. The resulting mixture was stirred for 5 h at room temperature. The solids were filtered. The resulting mixture was
concentrated under vacuum. The crude product was re-crystallized from methanohether in the ratio of 1:20. The solids were collected by filtration. This resulted in 6.5 g (80%) of 6- (aminomethyl)isoquinolin-l-amine as a yellow solid. 1H NM R (300M Hz, CD30D, ppm): 8.091-8.063(d, J=8.4Hz, 1H), 7.732-7.712(d, J=6.0Hz, 1H), 7.663(s, 1H), 7.560-7.494(m, 1H), 3.965(s,lH); MS (ES, m/z): 174.2 [M+l]+
Amine-2:
[0114] Synthesis of (5-chloro-lH-indazol-3-yl)metha namine
Figure imgf000044_0001
[0115] Step 1. Into a 500-m L round-bottom flask, was placed 4-chloroaniline (20 g, 156.77 mmol, 1.00 equiv) in toluene (172 mL). This was followed by the addition of BCI3 in d ichloromethane (1M, 172.4 mL, 1.10 equiv) dropwise with stirring. To this was added CICH2CN (12 m L, 1.20 equiv), AICI3 (23 g, 1.10 equiv). The resulting solution was stirred for 24 h at 120 °C in an oil bath. The reaction was then quenched by the addition of 240 mL of 2M hydrogen chloride. The resulting mixture was extracted with 3x500 m L of dichloromethane a nd the organic layers com bined and dried over anhydrous sodium sulfate. The solids were filtered. The filtrate was concentrated under vacuum. The crude product was purified by re-crystallization from ethanol/n-hexane. This resulted in 10.8 g (34%) of l-(2-amino-5-chlorophenyl)-2-chloroethan-l-one as a yellow solid.
[0116] Step 2. Into a 500-m L round-bottom flask, was placed l-(2-amino-5-chlorophenyl)-2- chloroethan-l-one (9.8 g, 48.03 mmol, 1.00 equiv) and hydrogen chloride in H20 (37%, 146.3 m L). This was followed by the addition of a solution of Na N02 (3.651 g, 52.91 mmol, 1.10 equiv) in water (22.5 m L) d ropwise with stirring at -10 °C. The mixture was stirred for 2 h. To this was added SnCI2 2H20 (26 g, 2.40 equiv). The resulting solution was stirred for 1 h at -10 ° C in an ice/salt bath. The reaction was then quenched by the addition of 200 m L of water/ice. The solids were collected by filtration. This resulted in 10.8 g (95%) of 5-chloro-3-(chloromethyl)-lH-indazole hydrochloride as a brown solid.
[0117] Step 3. Into a 250-m L round-bottom flask, was placed 5-chloro-3-(chloromethyl)-lH- indazole hydrochloride (10.8 g, 45.47 mmol, 1.00 equ iv), N, N-dimethylformamide (91 m L), water (9.4 mL), and NaN3 (3.8 g, 58.45 mmol, 1.30 equiv). The resulting solution was stirred for 1 h at 90 °C. The resulting mixture was concentrated under vacuum. The residue was diluted with 500 m L of water/ice. The resulting solution was extracted with 3x500 mL of dichloromethane and the organic layers combined and concentrated. This resulted in 9.3 g of 3-(azidomethyl)-5-chloro-lH-indazole as a crude solid.
[0118] Step 4. (5-chloro-lH-indazol-3-yl)methanamine. Into a 250-m L rou nd-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed 3-(azidomethyl)-5- chloro-lH-indazole (9.3 g, 44.79 mmol, 1.00 equiv), methanol (147.8 mL), and Pt02 (790 mg, 0.08 equiv). To the a bove, hydrogen (1 atm) was introduced. The resulting mixture was stirred for 1 day at room temperature. The solids were filtered. The filtrate was concentrated under vacuum. The residue was diluted with 300 m L of 1M HCI (aq.). The resulting mixture was washed with 2x300 mL of MTBE. The pH value of the solution was adjusted to 10 with sodium hyd roxide (2 M). The resulting solution was extracted with 6x500 m L of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 5.1 g (63%) of (5-chloro-lH-indazol-3-yl)metha namine as a yellow solid. XH N M (400M Hz, CD3OD, ppm): 7.90 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.14 (s, 2H); MS (ES, m/z): 182.0[M+H]+
Amine-3 :
Synthesis of 5-(aminomethyl)-4,6-dimethylpyridin-2-amine
Figure imgf000046_0001
Amine 3b Amine 3a
[0119] Step 1. Into a 500-mL three neck round-bottom flask, was placed PPA (300 g). This was followed by the addition of (2E)-3-aminobut-2-enenitrile (30 g, 365.39 mmol, 1.00 equiv) at 100 °C. The resulting solution was stirred for 3 h at 165 °C. The reaction mixture was cooled to 90 °C. The reaction was then quenched by the addition of 500 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10%). The resulting solution was extracted with 3x1500 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12.4 g (23%) of 6-amino-2,4-dimethylpyridine-3- carbonitrile as a yellow solid.
[0120] Step 2. Into a 500-mL round-bottom flask, was placed 6-amino-2,4-dimethylpyridine-3- carbonitrile (12.4 g, 84.25 mmol, 1.00 equiv), 4-dimethylaminopyridine (1.03 g, 8.43 mmol, 0.10 equiv), and tetrahydrofuran (100 mL). This was followed by the addition of a solution of Boc20 (55.0 g, 252.00 mmol, 3.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 200 mL of H2Oextracted with 4x100 mL of ethyl acetate and the organic layers combined. The combined organics were washed with 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent. This resulted in 13.2 g (45%) of tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-cyano-4,6- dimethylpyridin-2-yl)carbamate as a light yellow solid.
[0121] Step 3. Into a 250-mL round-bottom flask, was placed tert-butyl N-[(tert-butoxy)carbonyl]- N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate (7.1 g, 20.44 mmol, 1.00 equiv), methanol (70 mL), and dichloromethane (20 mL). This was followed by the addition of H202 (2.69 mL, 1.50 equiv) dropwise with stirring. To this was added a solution of sodium hydroxide (1.228 g, 30.70 mmol, 1.50 equiv) in water (10 mL) dropwise with stirring. The resulting solution was stirred for 2 h at 0 °C in a water/ice bath. The reaction was then quenched by the addition of 100 mL of 10% Na2C03. The resulting mixture was extracted with 2x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent. This resulted in 3.8 g (75%) of tert-butyl N-(5-cyano-4,6-dimethylpyridin-2-yl)carbamate as a white solid.
[0122] Step 4. tert-butyl (5-(aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate. Into a 100-m L round-bottom flask, was placed tert-butyl N-(5-cyano-4,6-d imethylpyridin-2-yl)carbamate (3.8 g, 15.37 mmol, 1.00 equiv), N H3/MeOH (10 m L), methanol (20 mL), and a ney-Ni (3.8 g). To the a bove, hydrogen (1 atm) was introduced . The resulting mixture was stirred overnight at room temperature. The solids were filtered. The resulting mixture was concentrated under vacuum. This resulted in 3.1975 g (83%) of tert-butyl N-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]carbamate as a white solid. XH NM R (300M Hz, DMSO, ppm): δ: 9.38 (s, 1H), 7.43 (s, 1H), 3.65 (s, 1H), 2.42 (s, 3H), 2.32 (s, 3 H), 1.59 (s, 2H), 1.44 (s, 9H); MS (ES, m/z): [M+H+] :252
Halide-1 and alcohol-1:
Figure imgf000047_0001
Halide la Halide lb
[0123] Synthesis of l-(4-(chloromethyl)benzyl)-lH-pyrazole and l-(4-(bromomethyl)benzyl)-lH- pyrazole
[0124] Step 1. Into a 500-m L 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed lH-pyrazole (6.2 g, 91.07 mmol, 1.00 equiv) in N, N- dimethylformamide (100 mL). This was followed by the addition of Na H (60%) (5.5 g, 137.50 mmol, 1.51 equiv) in several batches at 0 °C. The mixture was stirred for 1 h at 0 °C. To this was added a solution of methyl 4-(bromomethyl)benzoate (21 g, 91.67 mmol, 1.01 equiv) in N, N- dimethylformamide (100 mL) dropwise with stirring at 0 °C. The reaction was stirred for 5 h at room temperature, and then quenched by the addition of 100 mL of water/ice. The resulting mixture was extracted with 2x200 mL of ethyl acetate and the organic layers combined. The combined organics were washed with 3x200 mL of brine and concentrated under vacuum. This resu lted in 13 g (66%) of methyl 4-(lH-pyrazol-l-ylmethyl)benzoate as yellow oil. [0125] Step 2. (4-((lH-pyrazol-l-yl)methyl)phenyl)methanol. Into a 250-mL 3-necked round- bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 4-(lH-pyrazol-l-ylmethyl)benzoate (8 g, 37.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL). This was followed by the addition of LiAIH4 (1.69 g, 44.53 mmol, 1.20 equiv) in several batches at 0 °C. The resulting solution was stirred for 30 min at 0 °C and for an additional 3 h at room temperature. The reaction was then quenched by the addition of 1.7 mL of water, 1.7 mL of 15% NaOH, and 5.1 mL of water. The solids were filtered. The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40-1:4) as eluent. This resulted in 3.9 g (56%) of [4-(lH-pyrazol-l-ylmethyl)phenyl]methanol as a yellow oil.
[0126] Step 3a. l-(4-(chloromethyl)benzyl)-lH-pyrazole. Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed [4-(lH-pyrazol-l- ylmethyl)phenyl]methanol (328 mg, 1.74 mmol, 1.00 equiv) in dichloromethane (1.2 mL). This was followed by the addition of thionyl chloride (0.13 mL, 1.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 0.5 h at room temperature and thenconcentrated under vacuum. This resulted in 360 mg (100%) of l-[[4-(chloromethyl)phenyl]methyl]-lH-pyrazole as a brown oil.
[0127] Step 3b. l-(4-(bromomethyl)benzyl)-lH-pyrazole. Into a 500-mL round-bottom flask, was placed [4-(lH-pyrazol-l-ylmethyl)phenyl]methanol (4.5 g, 23.91 mmol, 1.00 equiv) in
dichloromethane (150 mL). This was followed by the addition of PBr3 (13 g, 48.03 mmol, 2.01 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at room temperature. The pH value of the solution was adjusted to 8 with sodium bicarbonate (sat. aq.). The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30%) as eluent. This resulted in 5 g (83%) of l-[[4-(bromomethyl)phenyl]methyl]-lH-pyrazole as a white solid.
Example 2: Preparation of compounds provided herein
Compound 1
Figure imgf000049_0001
Preparation of 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-aminoisoquinolin-6-yl)methyl)-2H- pyrazolo[4,3-c]quinolin-4-amine (GBT2020)
[0128] Step 1. To a suspension of ethyl 3-bromo-lH-pyrazole-4-carboxylate (219.00 mg; 1.00 mmol; 1.00 eq.) and l-{[4-(bromomethyl)phenyl]methyl}-lH-pyrazole (263.64 mg; 1.05 mmol; 1.05 eq.) in AcCN (3 mL) was added potassium carbonate (275.95 mg). The mixture was stirred at room temperature for 1 h, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to give crude product, which was purified by column to give ethyl l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-bromo-lH-pyrazole-4-carboxylate (120 mg).
[0129] Step 2. To a solution of l-(4-((lH-pyrazol-l-yl)methyl)benzyl)-3-bromo-lH-pyrazole-4- carboxylate (120.00 mg; 0.31 mmol; 1.00 eq.) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (74.30 mg; 0.34 mmol; 1.10 eq.) in Toluene (2 mL), iPrOH (0.5 mL), and water (0.5 mL) was added disodium carbonate (65.35 mg; 0.62 mmol; 2.00 eq.). The mixture was degassed for 5 min. After heating at 100 °C for 15 h, the mixture was cooled and concentrated, diluted with EtOH (amount?) and heated at 100 °C for 24 h. The mixturewas cooled and concentrated to give a residue, which when treated with water provided precipitates. These were collected by filtration to give 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one as crude product (84 mg).
[0130] Step 3. A suspension of 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-2,5-dihydro-4H-pyrazolo[4,3- c]quinolin-4-one (84.00 mg; 0.24 mmol; 1.00 eq.) in POCI3 (1 mL) was heated at 100 °C for 2 h. The reaction mixturewas then cooled and concentrated. The residue was diluted with ice water and sat. NaHC03 and the aqueous layer was extracted with DCM. The organic layer was washed with brine, dried and concentrated to give a residue, which was lyophilized to give 2-(4-((lH-pyrazol-l- yl)methyl)benzyl)-4-chloro-2H-pyrazolo[4,3-c]quinolone (77 mg) as a greenish powder.
[0131] Step 4. 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-aminoisoquinolin-6-yl)methyl)-2H- pyrazolo[4,3-c]quinolin-4-amine (GBT2020). To a suspension of 2-(4-((lH-pyrazol-l- yl)methyl)benzyl)-4-chloro-2H-pyrazolo[4,3-c]quinolone (70.00 mg; 0.19 mmol; 1.00 eq.) in nBuOH (2 mL) was added 6-(aminomethyl)isoquinolin-l-amine (97.30 mg; 0.56 mmol; 3.00 eq.). The mixture was heated at 190 °C for 25 min, then it was diluted with water and ACN. The mixture was purified by prep HPLC to give 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-aminoisoquinolin-6-yl)methyl)-2H- pyrazolo[4,3-c]quinolin-4-amine (28 mg). XH NM (400 MHz, DMSO- /6) δ 8.52 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.78 (dd, J = 2.3, 0.7 Hz, 1H), 7.72 (d, J = 5.8 Hz, 1H), 7.63 (s, 1H), 7.52 - 7.43 (m, 2H), 7.42 (dd, J = 1.8, 0.7 Hz, 1H), 7.37 (ddd, J = 8.3, 7.0, 1.6 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.17 (m, 2H), 7.14 (ddd, J = 7.8, 7.0, 1.3 Hz, 1H), 6.82 (dd, J = 5.9, 0.8 Hz, 1H), 6.71 (s, 2H), 6.23 (dd, J = 2.3, 1.8 Hz, 1H), 5.63 (s, 2H), 5.30 (s, 2H), 4.88 (d, J = 5.1 Hz, 2H). MS (M+H)+ found for
Figure imgf000050_0001
Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-benzyl-2H-pyrazolo[4,3-c]quinolin-4-amine.
[0132] Compound 2 was synthesized in a manner similar to GBT2020 using benzyl bromide to replace l-{[4-(bromomethyl)phenyl]methyl}-lH-pyrazole. XH NMR (400 M Hz, DMSO- /6) δ 8.55 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.06 (dt, J = 3.3, 1.7 Hz, 1H), 8.04 (dd, J = 1.6, 0.6 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.56 - 7.43 (m, 2H), 7.43 - 7.27 (m, 6H), 7.15 (ddd, J = 8.0, 7.1, 1.3 Hz, 1H), 6.93 - 6.82 (m, 3H), 5.67 (s, 2H), 4.89 (d, J = 3.0 Hz, 2H). MS (M+H)+ found for C27H22N6: 431.1.
Compound 3
Figure imgf000051_0001
-aminoisoquinolin-6-yl)methyl)-2-((1 -methyl-1 H-indazol-6-yl)
methyl)-2/-/-pyrazolo[4,3-c]quinolin-4-amine
Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((l-methyl-lH-indazol-6-yl) methyl)-2H-pyrazolo[4,3-c]quinolin-4-amine.
[0133] Compound 3 was synthesized in a manner similar to GBT2020. XH N M (400 M Hz, DMSO- /6) δ 8.47 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.07 - 8.02 (m, 2H), 7.94 (t, J = 5.7 Hz, 1H), 7.78 (dd, J = 1.6, 0.8 Hz, 1H), 7.71 (d, J = 5.8 Hz, 1H), 7.65 (dt, J = 8.7, 0.9 Hz, 1H), 7.61 (s, 1H), 7.51 - 7.45 (m, 2H), 7.43 (dd, J = 8.7, 1.6 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.15 (ddd, J = 7.7, 7.0, 1.3 Hz, 1H), 6.81 (dd, J = 6.1, 0.8 Hz, 1H), 6.68 (s, 2H), 5.74 (s, 2H), 4.87 (d, J = 5.4 Hz, 2H), 4.01 (s, 3 H). MS (M+H)+ found for C29H24N8:
485.2.
Figure imgf000051_0002
2-(4-((1 H-pyrazol-1 -yl)methyl)benzyl)-A/-((1 -aminoisoquinolin-6-yl)
methyl)-2/-/-pyrazolo[4,3-c][1 ,6]naphthyridin-4-amine
Compound 4
Preparation of 2-(4-((lH-pyrazol-l-yl)methyl)benzyl)-N-((l-aminoisoquinolin-6-yl) methyl)-2H-pyrazolo [4,3-c] [l,6]naphthyridin-4-a mine.
[0134Compound 4 was synthesized in a manner similar to GBT2020. 1H NM R (400 M Hz, DMSO- /6) δ 9.21 - 9.16 (m, 1H), 8.60 (s, 1H), 8.53 (dd, J = 8.1, 5.8 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.14 (dd, J = 22.1, 7.4 Hz, 1H), 7.78 (ddd, J = 2.3, 1.6, 0.7 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.50 - 7.44 (m, 1H), 7.44 - 7.34 (m, 2H), 7.34 - 7.26 (m, 2H), 7.27 - 7.17 (m, 2H), 6.85 - 6.79 (m, 1H), 6.68 (s, 1H), 6.26 - 6.19 (m, 1H), 5.65 (d, J = 6.9 Hz, 2H), 5.33 - 5.28 (m, 2H), 4.91 (d, J = 5.7 Hz, 2H). MS (M+H)+ found for C30H25N9: 512.2.
Example 3: ln-vitro Plasma Kallikrein Inhibition
Materials
[0135] The chromogenic substrate D-Pro-Phe-Arg-pNa, 2HCI (BIOPHEN CS-31(02) from Hyphen BioMed, Neuville-Sur-oise, France) was dissolved in 5mL deionized water and stored at 4°C. Concentration was determined in the spectrophotometer at 342 nm using an extinction coefficient of 8270. All other chemicals were of analytical grade.
Human plasma kallikrein was purchased from Enzyme Research Labs (South Bend, IN, USA, batch HPKa 2830). A stock solution of 7 μΜ in 50% glycerol was stored at -20°C.
Enzyme reactions were conducted in "assay buffer" comprised of 20mM HEPES at pH 7.4, 150 mM NaCI, 0.1% PEG-8000 and 0.01% Triton X-100.
Both enzyme and substrate were diluted in assay buffer.
[0136] The compound solutions as well as the enzyme and the substrate solutions were transferred to 96-well plates (Clear, UV-Star, Flat-bottom, Half-Area plates; cat. No. 675801 Greiner Bio-one, purchased from VWR International, Arlington Heights, IL, USA) using a Rainin LTS 96- channel pipettor (Rainin, Columbus, OH, USA). Plate measurements were conducted using a SPECTROStar Nano reader (BMG Labtech, San Francisco, CA, USA). The SPECTROStar Nano is a spectrophotometer and absorbance was measured at 405nm. We used discrete wavelength, precise, kinetic reads of 15 cycles with a 60 sec cycle time.
Determination of IC^n values
[0137] For the determination of IC50 values, the assays were performed at room temperature in 96-well plates with a total assay volume of 85 μί per well. The test compound was dissolved in 100% DMSO. The compounds were serially diluted in DMSO in a 7 point dose response. For the assays, 66.5μί of protease solution (protease in assay buffer) was added per well followed by the addition of 8.5μί of compound in 100% DMSO. The final assay concentration of the human plasma kallikrein was 250 pM. After 30 min incubation at room temperature on an orbital shaker, the reactions were started by the addition of ΙΟμί substrate solution (in assay buffer, final assay concentration was 600 uM). After the addition of the substrate solution the final DMSO concentration was 10%. The plate went back on the shaker for 5 sec, was spun at 2000 rpm for 5 sec and read on the spectrophotometer. The effect of the compound on the enzymatic activity was obtained from the linear part of the progress curves and determined after 15 minutes. The IC50 value was calculated from the plot of rate vs. inhibitor concentration by a 4 parameter logistic equation: y = A + ((B-A)/(l=((C/x)*D))) where y is the rate at the inhibitor concentration, x. A is the minimum y value at the highest inhibitor concentration and B is the y value in the absence of inhibitor, C is the IC50 value and D is the slope factor. The curve fitting was conducted with the non-linear regression routine of the analysis software Xlfit (IDBS, version 5.3.1).
[0138] All abbreviations used herein have their ordinary scientific meaning as known to the skilled artisan.
[0139] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.
[0140] Throughout the description of this invention, reference is made to various patent applications and publications, each of which are herein incorporated by reference in their entirety.

Claims

What is claimed is:
1. A compound of formula I:
Figure imgf000054_0001
or a tautomer thereof, a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, wherein each of A and RB independently is N or CR10;
R10 is hydrogen, halo, or an optionally substituted Ci-C6 alkyl;
X1 is O, S, SO, S02, NR15,
R15 is hydrogen or an amino protective group each of L1 and L3 independently is -(L )m(CO)n(L12)0-;
L11 and L12 each independently are optionally substituted C C3 alkylene or C C3 heteroalkylene provided that -X1 .1 does not contain an -0-CO-, -S-CO-, -CO-S-, -S-CO- and such other esterase hydrolyzable moieties in the chain joining R1 to the rest of the compound; each of m, n, and o is 0 or 1; each of R1 and R3 is independently C6-Ci0 aryl, 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, a 4-15 membered heterocyclyl containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, or a C3-C8 cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted; ring C is a 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; preferably, a 4-7 membered heterocycle containing 2, or more preferably, a single, ring heteroatom; wherein the heterocycle is optionally substituted; 26 is optionally substituted Ci-C6 alkyl, optionally su bstituted C6-Ci0 aryl, optionally substituted 5-6 membered heteroaryl, optionally su bstituted C3-C6 cycloalkyl, or N(R25)2; each R25 is independently hydrogen or C C6 alkyl optionally substituted with 1-5 halo, or the two R25 groups together with the nitrogen atom they are bonded to form a: 4-15 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; preferably, a 4-7 membered heterocycle containing 1-2 ring heteroatoms; wherein the heterocycle is optionally substituted; or ring C is C6-C10 aryl or 5-10 membered heteroaryl containing up to 3 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the aryl or heteroaryl is optionally substituted with 1-3 substituents; or ring C is C3-C8 cycloalkyl optionally substituted with 1-3 substituents;
Figure imgf000055_0001
is a double or a single bond, provided that when C is aryl or heteroaryl it is a double bond, and when C is a heterocyle or cycloalkyl it can be a double bond or a single bond.
2. The compound of claim 1 of formula l-A:
Figure imgf000055_0002
wherein R is hydrogen or Ci-C6 alkyl optionally substituted with halo, r is 1, 2, or 3, and the remaining variables are defined as in claim 1.
3. The compound of claim 1 of formula l-B:
Figure imgf000056_0001
wherein ring C is a 5-6 membered heteroaryl, optionally su bstituted with 1-3 substituents as defined in claim 1, and the remaining variables are defined as in claim 1.
4. The compound of claim 1, of formula l-C, l-D, l-E or l-F:
Figure imgf000056_0002
l-E wherein independently each p is 1, 2, or 3; independently each X2 is O, S, SO, S02, CH 22, optionally substituted N-(C C6 alkyl), NH, -N- CO-R26, -N-CO2-R26, or -NS02R26; independently each R21 is hydrogen or optionally substituted Ci-C6 alkyl; independently each R22 is hydrogen or optionally substituted Ci-C6 alkyl; independently each q is 1, 2, 3, or 4;
2 of A, B, C are independently CHR22 preferably -CH2-, and 1 of A, B, and C is O, S, SO, S02, optionally substituted N-(C C6 alkyl), NH, -N-CO-R26, -N-C02-R26, or -NS02R26; and the remaining variables are defined as above or as in claim 1.
5. The compound of claim 1 of formula l-G or l-H:
Figure imgf000057_0001
Figure imgf000058_0001
wherein R is H, -CO-R , -C02-R , or -S02R , or optionally substituted C C6 alkyl, and the remaining variables are defined as in claim 1.
7. The compound of claim 1 of formula l-l:
Figure imgf000058_0002
wherein v is 1, 2, 3 or 4;
R27 is optionally substituted Ci-C6 alkyl; p is 1, 2, or 3, and the remaining variables are defined as in claim 1. 8. A compound of claim 4, of formula l-J or l-K:
Figure imgf000058_0003
l-J l-K wherein the remaining variables are defined as in claim 4.
9. A compound of claim 1, of formula l-L:
Figure imgf000059_0001
l-L wherein ring C is a 6-membered aryl or a 6 member heteroaryl containing a single nitrogen atom; 35 is methyl substituted with a 5 membered heteroaryl containing 2 nitrogen atoms, -0-(6 membered heteroaryl containing a single nitrogen atom), or -0-(6 membered heterocyclyl containing a single nitrogen atom);
R36 is hydrogen, or R35 and R36 together with the intervening carbon atoms form a 5 membered heteroaryl containing 1-2 nitrogen atoms, which heteroaryl ring is substituted with 1-2, C C6 alkyl.
10. The compound of claim 1, wherein RA is CR10.
11. The compound of claim 1, wherein RA is CH.
12. The compound of claim 1, wherein RA is N.
13. The compound of claim 1, wherein RB is N.
14. The compound of claim 1, wherein RB is CR10.
15. The compound of claim 1, wherein RB is CH.
16. The compound of claim 1, wherein X1 is O.
17. The compound of claim 1, wherein X1 is S.
18. The compound of claim 1, wherein X1 is SO or S02.
19. The compound of claim 1, wherein X1 is NR15.
20. The compound of claim 1, wherein R15 is hydrogen.
21. The compound of claim 1, wherein R is an amino protecting group.
22. The compound of claim 1, wherein L1 is -CH2- or -CO-.
23. The compound of claim 1, wherein R1 is optionally substituted C6-Ci0 aryl or optionally substituted 5-10 membered heteroaryl.
24. The compound of claim 1, wherein L3 is -CH2-.
25. The compound of claim 1, wherein R3 is optionally substituted C6-Ci0 aryl or optionally substituted 5-10 membered heteroaryl.
26. The compound of claim 1, wherein ring C is:
Figure imgf000060_0001
wherein R is hydrogen or Ci-Cg alkyl, optionally substituted with halo, or N(R )2; Ci-Cg alkoxy optionally substituted with halo, or N(R25)2; r is 1, 2, or 3.
27. The compound of claim 1, wherein ring C is a 5-6 membered heteroaryl, optionally substituted with 1-3 substituents.
28. The compound of claim 1 wherein ring C is of formula: ll-C or ll-D
Figure imgf000060_0002
Il-C Il-D wherein independently each p is 1, 2, or 3; independently each X2 is O, S, SO, S02, CHR22, N-( optionally substituted C C6 alkyl), NH, -N- CO-R26, -N-C02-R26, or -NS02R26; independently each R21 is hydrogen or optionally substituted Ci-C6 alkyl; independently each R22 is hydrogen or optionally substituted Ci-C6 alkyl; and independently each q is 1,2, 3, or 4.
29. The compound of claim 28 of formula ll-E or ll-F:
Figure imgf000061_0001
ll-E I wherein the other variables are defined as in claim 26. The compound of claim 1, wherein ring C is selected from
Figure imgf000061_0002
wherein R is, H, -CO-R , -C02-R , -S02R , or optionally substituted C C6 alkyl, and R is defined as in claim 1.
31. The compound of claim 1, wherein ring C is:
Figure imgf000061_0003
wherein v is 1, 2, 3 or 4;
R27 is optionally substituted Ci-C6 alkyl; and p is 1, 2, or 3. wherein p is 1, 2, or 3, and the remaining variables are defined as in claim 1. 32. The compound of claim 1 of formula:
Figure imgf000062_0001
NH2
2-(4-((1 H-pyrazol-1 -yl)methyl)benzyl)-/\/-((1 -aminoisoquinolin-6-yl)
methy[)-2/-/-pyrazolo[4,3-c][1 ,6]naphthyridin-4-amine
33. A pharmaceutically acceptable composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
34. A method of inhibiting plasma kallikrein activity in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable composition of claim 33.
35. A method of treating a disorder or a disease in a subject mediated by plasma kallikrein, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable composition of claim 33.
36. A method of treating hereditary angiodema, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or the pharmaceutically acceptable composition of claim 33.
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