WO2022011274A1 - Inhibiteurs de cdk5 de type 1,6-naphtyridine substituée - Google Patents

Inhibiteurs de cdk5 de type 1,6-naphtyridine substituée Download PDF

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WO2022011274A1
WO2022011274A1 PCT/US2021/041106 US2021041106W WO2022011274A1 WO 2022011274 A1 WO2022011274 A1 WO 2022011274A1 US 2021041106 W US2021041106 W US 2021041106W WO 2022011274 A1 WO2022011274 A1 WO 2022011274A1
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phenyl
fluoro
alkyl
alkylene
equiv
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PCT/US2021/041106
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English (en)
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Goran MALOJCIC
Matthew H. Daniels
Brett D. WILLIAMS
Maolin Yu
Mark W. Ledeboer
Jean-Christophe P. HARMANGE
Jenna Lijie WANG
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Goldfinch Bio, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Cyclin-dependent kinases belong to a family of proline-directed serine/threonine kinases that play important roles in controlling cell cycle progression and transcriptional control.
  • Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine kinase, is unique due to its indispensable role in neuronal development and function.
  • CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts.
  • CDK5 can interact with certain cyclins, amongst other proteins, which modulate CDK5 activity levels. Recent findings report molecular interactions that regulate CDK5 activity and CDK5 associated pathways implicated in various diseases. Also covered herein is the growing body of evidence for CDK5 in contributing to the onset and progression of tumorigenesis.
  • CDK5 plays a diverse physiological role in neural cells, including neuronal migration (Xie et ah, 2003) and axon guidance (Connell-Crowley et ah, 2000) during early neural development as well as synapse formation and synaptic plasticity (Cheung et ah, 2006; Lai and Ip, 2009).
  • CDK5 has also been found to play important roles outside the central nervous system such as pain signaling that involves the sensory pathways (Pareek et ah, 2006), and in modulating glucose-stimulated insulin levels in pancreatic beta cells, (Wei et ah, 2005).
  • CDK5 deregulation triggers neuronal apoptosis (Cheung and Ip, 2004), suggesting that aberrant regulation of CDK5 activity is responsible for the progression of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • Aberrant CDK5 activity is also linked to cancer development, progression and metastasis such as prostate and thyroid carcinoma (Strock et ah, 2006; Lin et ah, 2007).
  • CDK5 is one of the key kinases that regulate the formation of senile plaques (Monaco, 2004) and neurofibrillary tangles (Cruz et ah, 2003).
  • PD Parkinson’s disease
  • Muntane et ah a PD mouse model induced by l-methyl-4- phenyl-l,2,3,6-tetrahydropyridine (MPTP)
  • MPTP l-methyl-4- phenyl-l,2,3,6-tetrahydropyridine
  • elevated expression and activity of CDK5 have been reported to be correlated with dopaminergic neurons cell death (Smith et ah, 2003; Qu et ah, 2007).
  • inhibition of CDK5 results in an increase in dopamine release, which may help ameliorate PD progression (Chergui et ah, 2004).
  • CDK5 has also been implicated in a plethora of other neurodegenerative diseases and neurological disorders such as Huntington's disease (Anne et ah, 2007), Amyotrophic Lateral Sclerosis (ALS; Bajaj et ah, 1998) and ischemic injury (Wang et ah, 2003).
  • CDK5 activity has also been linked to the pathogenesis of diabetes mellitus (type-2 diabetes).
  • p35 the activator of CDK5
  • pancreatic beta cells Aberrant CDK5 activity has also been linked to the pathogenesis of diabetes mellitus (type-2 diabetes).
  • p35 the activator of CDK5
  • a sustained increase in p35 protein and CDK5 activity is reported in murine pancreatic beta cells upon high glucose exposure (Ubeda et ah, 2006).
  • inhibition of CDK5 activity by chemical inhibitors increases insulin secretion in cultured beta cells and in a mouse model of diabetes in a glucose-dependent manner (Ubeda et ah, 2006).
  • CDK5 inhibitors could be potential therapeutic agents for the treatment of type-2 diabetes (Kitani et ah, 2007).
  • CDK5 has also been emerging as a major potential target for analgesic drugs.
  • CDK5/p35 has been indirectly linked to nociceptive pathways.
  • CDK5 regulates the activation of mitogen activated protein kinase (MAPK) in nociceptive neurons potentially modifying the hyperalgesia that results in increased MAPK activity.
  • MAPK mitogen activated protein kinase
  • CDK5 has also been implicated in other pain pathways such as calcium calmodulin kinase II, delta FosB, the NMDA receptor and the P/Q type voltage-dependent calcium channel.
  • studies suggest that CDK5 inhibitors may be of benefit in the management of acute pain.
  • CDK5/p35 is shown to be involved in the processing of pain while its inhibition reduces the responsiveness of normal pain pathways (Pareek et al., 2006; Pareek and Kulkami, 2006).
  • CDK5 also regulates mitogen-activated protein kinasel/2 (MEKl/2)/lM activity through a negative feedback loop during a peripheral inflammatory response (Pareek and Kulkami, 2006).
  • MEKl/2 mitogen-activated protein kinasel/2
  • MKl/2 mitogen-activated protein kinasel/2
  • TRPV1 transient receptor potential vanilloid 1
  • CDK5 was identified as playing a critical role in controlling ciliary length and tubular epithelial differentiation. Pharmacological or genetic reduction of CDK5 lead to effective and sustained arrest of PKD. CDK5 might act on primary cilia, at least in part, by modulating microtubule dynamics. It was suggested that new therapeutic approaches aimed at restoration of cellular differentiation are likely to yield effective treatments for cystic kidney diseases (Husson et al. 2016). Further, CDK5 was shown to be detrimental and promotes tubulointerstitial fibrosis (TIF) via the extracellular signal-regulated kinase 1/2 (ERKl/2)/peroxisome proliferator-activated receptor gamma (PPRAy) pathway in DN.
  • TNF tubulointerstitial fibrosis
  • ERKl/2 extracellular signal-regulated kinase 1/2
  • PPRAy peroxisome proliferator-activated receptor gamma
  • CDK5 increases tubulointerstitial fibrosis by activating the ERKl/2/PPARy pathway and EMT in DN.
  • CDK5 might have therapeutic potential in diabetic nephropathy. (Bai et al. 2016).
  • the invention features compounds that are inhibitors of CDK5.
  • the compound of the invention is a compound having structural formula
  • ring B is monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl;
  • R 5 is hydrogen; C1-C4 alkyl optionally substituted with one or more of -CN, -OH,
  • R 5 is taken together with a ring carbon atom in ring A to form a heterocyclyl ring that is spirofused, fused or bridged to ring A; each R 6 is independently hydrogen or -C1-C4 alkyl; m is 0,1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and “ — ” represents a single bond or a double bond.
  • the invention relates to pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.
  • the invention relates to methods of treating a disease or condition characterized by aberrant CDK5 overactivity, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound or composition disclosed herein.
  • the disease or condition is a disease or condition of the kidney.
  • the disease is polycystic kidney disease.
  • the disease or condition is a ciliopathy.
  • the methods are effective for a variety of subjects including mammals, e.g., humans and other animals, such as laboratory animals, e.g., mice, rats, rabbits, or monkeys, or domesticated and farm animals, e.g., cats, dogs, goats, sheep, pigs, cows, or horses.
  • the subject is a human.
  • the invention provides several advantages.
  • the prophylactic and therapeutic methods described herein are effective in treating kidney disease and ci!iopathies, and have minimal, if any, side effects. Further, methods described herein are effective to identify compounds that treat or reduce risk of developing a kidney disease, such as polycystic kidney disease, or a ciliopathy.
  • Figure 1 shows NMR and MS data for exemplar ⁇ ' compounds 100-414 of the invention.
  • Figure 2 shows NMR and MS data for additional exemplar ⁇ ' compounds 415-823 of the invention.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkyl group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, a halogen (e.g., fluoro), a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
  • a halogen
  • the substituents on substituted alkyls are selected from Ci-6 alkyl, C3- 6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl -substituted alkyls, -CF 3 , -CN, and the like.
  • alkylene by itself or as part of another substituent refers to a saturated straight-chain or branched divalent group having the stated number of carbon atoms and derived from the removal of two hydrogen atoms from the corresponding alkane.
  • straight chained and branched alkylene groups include -CH2- (methylene), - CH2-CH2- (ethylene), -CH2-CH2-CH2- (propylene), -C(CH 3 ) 2 -, -CH 2 -CH(CH 3 )-, -CH2-CH2- CH2-CH2-, -CH2-CH2-CH2-CH2- (pentylene), -CH2-CH(CH 3 )-CH 2 -, and -CH 2 -C(CH 3 )2- CH2-.
  • Cx- y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Cx- y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups.
  • Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C2- y alkenyl and C2- y alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group wherein each R A independently represent a hydrogen or hydrocarbyl group, or two R A are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R A independently represents a hydrogen or a hydrocarbyl group, or two R A are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 6- or 10- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carboxylate is art-recognized and refers to a group wherein each R A independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or both R A taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • a “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -0C02-R A , wherein R A represents a hydrocarbyl group.
  • esters refers to a group -C(0)0R A wherein R A represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl or “heterocycloalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety
  • the substituents on substituted alkyls are selected from Ci- 6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the term “sulfate” is art-recognized and refers to the group -OSCbH, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein each R A independently represents hydrogen or hydrocarbyl, such as alkyl, or both R A taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(0)-R A , wherein R A represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SChH, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group -S(0)2-R A , wherein R A represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR A or -SC(0)R A wherein R A represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein each R A independently represents hydrogen or a hydrocarbyl, such as alkyl, or any occurrence of R A taken together with another and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et ah, Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethyl silyl (“IMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • a therapeutic that “prevents” or “reduces the risk of developing” a disease, disorder, or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disease, disorder, or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treating includes prophylactic and/or therapeutic treatments.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the phrases “conjoint administration” and “administered conjointly” refer to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds).
  • the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention.
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids
  • some or all of the compounds of the invention in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • small molecules refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons.
  • small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da).
  • the small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).
  • a “small molecule” refers to an organic, inorganic, or organometailic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.
  • an “effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every' other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.
  • One embodiment of the invention provides methods of treating a disease or a condition characterized by aberrant CDK5 overactivity, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.
  • the compound is a small molecule inhibitor of CDK5.
  • the compound has structural formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: ring A is a monocyclic or bicyclic cycloalkyl or a monocyclic or bicyclic saturated heterocyclyl; ring B is monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl;
  • R 5 is hydrogen; C1-C4 alkyl optionally substituted with one or more of -CN, -OH,
  • R 5 is taken together with a ring carbon atom in ring A to form a heterocyclyl ring that is spirofused, fused or bridged to ring A; each R 6 is independently hydrogen or -C1-C4 alkyl; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and “ — ” represents a single bond or a double bond.
  • each R 3 is independently halo; -CN; -OH; - N(R 6 ) 2 ; -C1-C4 alkyl; -O-C1-C4 alkyl; -O-C1-C4 alkylene-C(0)-N(R 6 ) 2 ; -C(0)-0-Ci-C 4 alkyl; -C(0)-N(R 6 )2; -S(0)2-N(R 6 )2; -S(0)2-CI-C4 alkyl; an optionally substituted aryl; an optionally substituted heteroaryl; or an optionally substituted heterocyclyl, wherein any alkyl portion of R 3 is optionally substituted with one or more of halo, -CN, or -N(R 6 )2, or -OH.
  • ring B is piperidin-4-yl, oxetan-3-yl, azeti din-3 -yl, 2-oxaspiro[3.5]nonan-7-yl, indazolyl, or l,3-dihydro-2H-benzo[d]imidazolyl; b.
  • one R 3 is -CH2CF3, -CH(OH)CHF 2 , -CH(CH 3 )CF3, -OCH(CH 3 )2, - CH(CH3)CH 2 OH, -0CH(CH3)CH 2 0H, -S(0) 2 CH(CH3)2, -0CH 2 CH(CH3) 2 , - OCH 2 CH(CH3)2, -CPs, -OCF3, -CHF2, or -OCHF2; c.
  • one R 3 is an aryl, heteroaryl, or heterocyclyl, wherein the one R 3 is substituted with up to three substituents independently selected from -C(0)-Ci-C4 alkyl, -C1-C4 alkylene-COOH, -S(0) 2 -Ci-C 4 alkyl, -C(0)-N(R 6 )-Ci-C 4 hydroxyalkyl, -C1-C4 alkylene-C(0)-N(R 6 )2, -C(0)N(R 6 )-saturated heterocyclyl, -C(0)-saturated heterocyclyl, -C(0)-C 3 -C7 cycloalkyl, and -O-C1-C4 hydroxyalkyl, wherein at least one substituent is -C(0)-Ci-C4 alkyl, -C1-C4 alkylene-COOH, -S(0)2-Ci-C4 alkyl, - C(0)-N(R 6 )-
  • one R 3 is oxetan-3-yl, azetidin-l-yl, l,4-oxazepan-4-yl, pyridazin-4-yl, 1,2- dihydropyrazin-2-yl, l,6-dihydropyrimdin-5-yl, l,6-dihydropyridazin-4-yl, piped din- 3-yl, piperidin-4-yl, pyrimidin-2-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, hexahydropyrimidin- 1-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2,6-
  • R 2 is -C(0)NH 2 , -CH2CN, -CH2CHF2, -CH2COOH, -CH2CH2F, CH 2 C(0)NHCH 3 , CH 2 C(0)N(CH 3 ) 2 , -CH 2 CH(OH)CH 3 ,
  • R 1 is -C(0H)(CHF2)-, -C(NH2)(CF 3 )-, oxiran-2,2-diyl, or l,3-dioxolan-2,2- diyl; and/or g.
  • R 1 is fused to ring A to form 2-oxo-octahydro-2H-imidazo[4,5-c]pyridin-l-yl, l-oxa-6-azaspiro[2.5]octan-2-yl, octahydro-lH-pyrrolo[3,2-c]pyridin-l-yl, 2-oxo- hexahydrooxazolo[5,4-c]pyridin-l-yl, or 2,2-dioxo-octahydro-[l,2,5]thiadiazolo[3,4- c]pyridin-l-yl.
  • the compound has structural formula (II):
  • ring A is a monocyclic or bicyclic cycloalkyl or a monocyclic or bicyclic saturated heterocyclyl
  • ring B is monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl
  • each R 3 is independently halo; -CN; -OH; -N(R 6 ) 2 ; -C1-C4 alkyl; -O-C1-C4 alkyl; -O- C1-C4 alkylene-C(0)-N(R 6 ) 2 ; -C(0)-0-Ci-C 4 alkyl; -C(0)-N(R 6 ) 2 ; -S(0) 2 -N(R 6 ) 2 ; -S(0) 2 -Ci- C4 alkyl; C 2 -C4 alkyny
  • R 5 is hydrogen; C1-C4 alkyl optionally substituted with one or more of -CN, -OH,
  • R 5 is taken together with a ring carbon atom in ring A to form a heterocyclyl ring that is spirofused, fused or bridged to ring A; each R 6 is independently hydrogen or -C1-C4 alkyl;
  • R 7 is -0-(C3-C7 optionally substituted cycloalkyl), or -O-optionally substituted saturated heterocyclyl; r is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, 5, or 6; and
  • — represents a single bond or a double bond.
  • the compound has structural formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein: ring A is a monocyclic or bicyclic cycloalkyl or a monocyclic or bicyclic saturated heterocyclyl; ring B is monocyclic or bicyclic aryl, a monocyclic or bicyclic heteroaryl, or a monocyclic or bicyclic heterocyclyl;
  • R 5 is hydrogen; C1-C4 alkyl optionally substituted with one or more of -CN, -OH, -COOH, C(0)-0-Ci-C 4 alkyl, or pyrazolyl; -S(0) 2 -Ci-C 4 alkyl; -C(0)C(0)0H; -COOH; or -C(0)-0-Ci-C 4 alkyl; or R 5 is taken together with a ring carbon atom in ring A to form a heterocyclyl ring that is spirofused, fused or bridged to ring A; each R 6 is independently hydrogen or -C1-C4 alkyl; m is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, or 5; and “ — ” represents a single bond or a double bond.
  • ring B is phenyl, -C(0)-phenyl, l,3,4-thiadiazol-2-yl, imidazo[l,2-b]pyridazin-3-yl, isoxazol-3-yl, l,3-dihydroisobenzofuran-5-yl, 2H-chromen-6-yl, l,2,3,4-tetrahydroisoquinolin-6-yl, 1, 2,3,4- tetrahydroisoquinolin-7-yl, isoindolin-5-yl, l,2-dihydropyridin-3-yl, l,2-dihydropyridin-5-yl, pyridinyl or pyrimidinyl.
  • ring B is piperidin-4-yl, oxetan-3-yl, azeti din-3 -yl, 2-oxaspiro[3.5]nonan-7-yl, indazolyl, or 1,3- dihydro-2H-benzo[d]imidazolyl.
  • At least one R 3 is
  • At least one R 3 is 1,2,4-triazol-l-yl, 1,2,4-triazol-l-ylmethyl, 1,2,3,4-tetrazol-l-yl, l,2,3,4-tetrazol-5-yl, l,2,4-oxadiazol-3-yl, l,2-dihydropyridin-6-yl, 1,2-dihydropyri din-3 -yl, l,2-dihydropyridin-5- yl, 1,2-dihydropyridin-l-yl, 4,5-dihydro-l,2,4-oxadiazol-3-yl, isothiazolidin-2-yl, pyrazolyl, pyrazin-2-yl, pyri din-2 -yl, pyridin-3-yl, pyridin-4-yl, pyrimindin-4-yl, pyrrolidin-
  • R 3 is 1,2,4-triazol-l-yl, 1,2,4-triazol-l-ylmethyl, 1,2,3,4-tetrazol-l-yl, l,2,3,4-tetrazol-5- yl, l,2,4-oxadiazol-3-yl, l,2-dihydropyridin-6-yl, 1,2-dihydropyri din-3 -yl, 1,2- dihydropyridin-5-yl, 1 ,2-dihydropyridin- 1 -yl, 4, 5-dihydro- 1 ,2,4-oxadiazol-3 -yl, isothiazolidin-2-yl, pyrazolyl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimindin-4-yl, pyrrolidin
  • At least one R 3 is oxetan-3-yl, azetidin-l-yl, l,4-oxazepan-4-yl, pyridazin-4-yl, l,2-dihydropyrazin-2-yl, 1,6- dihydropyrimdin-5-yl, l,6-dihydropyridazin-4-yl, piperi din-3 -yl, piperidin-4-yl, pyrimidin-2- yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxa-6- azaspiro[3.3]heptan-6-yl, hexahydropyrimidin-l-yl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-yl, 8-
  • -C1-C4 haloalkyl -COOH, -C(0)-N(R 6 ) 2 , -(C0-C4 alkylene)-C(0)-0-Ci-C 4 alkyl, -O-C1-C4 alkyl, -C(0)-Ci-C 4 alkyl, -C1-C4 alkylene-COOH, -S(0) 2 -Ci-C 4 alkyl, -C(0)-N(R 6 )-CI-C 4 hydroxy alkyl, -Ci-C 4 alkylene-C(0)-N(R 6 ) 2 ,
  • R 7 is optionally substituted cyclopropyloxy, optionally substituted cyclobutyloxy, optionally substituted tetrahydrofuran- 3-yloxy, or optionally substituted piperidin-4-yloxy.
  • a compound of Formula I or III in certain embodiments of a compound of Formula I or III, or a salt thereof, the l,3-dihydroisobenzofuran-5-yl, l-fluoro-2-methylisoindolin-6-yl, 1-oxo-l, 2,3,4- tetrahydroisoquinolin-6-yl, 1 -oxo- 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl, 2-(l -hydroxy- 1 - methylethan-l-yl)pyridin-5-yl, 2-(morpholin-4-yl)phenyl, 2-fluoro-4-(l,2,4-oxadiazol-3- yl)phenyl, 2-fluoro-4-( 1 ,2,4-triazol- 1 -ylmethyl)phenyl, 2-fluoro-4-(l -ethyl-2-oxo- 1 ,2 dihydropyridin-3-y
  • ring A is piperidinyl, piperidinylidene, piperazinyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclopentyl, cyclobutyl, azabicyclo[3.3.1]nonanyl, or azabicyclo[2.2.1]heptanyl.
  • each R 2 or R 2a is independently -F, -OH, -CH 3 , -CH2CH3, -CH2CF3, -CH2CH2OH, - CH 2 CH(OH)CH 2 OH, -CH(CH 3 )2, -CH(CH 3 )-COOH, -COOH, -NH2, -NH(CH 3 ), -N(CH 3 )2- CH2C(0)NH2, or oxetan-3-ylmethyl.
  • each R 2 or R 2a is independently -F, -OH, -CH3, -CH2CH3, -CH2CF3, -CH2CH2OH, - CH 2 CH(OH)CH 2 OH, -CH(CH 3 )2, -CH(CH 3 )-COOH, -COOH, -NH2, -NH(CH 3 ), -N(CH 3 )2- CH 2 C(0)NH 2 , -C(0)NH 2 ,
  • At least one R 2 or R 2a is -C(0)NH 2 , -CH2CHF2, -CH2COOH, -CH2CH2F, CH 2 C(0)NHCH3, CH 2 C(0)N(CH3)2, -CH 2 CH(OH)CH3, -CH(CH3)CH 2 0H, -CH2CH2OCH3, azeti din-3 -yl, azeti din-3 -ylmethyl, or oxazol-2-ylmethyl.
  • At least one R 2a is -CH2CN.
  • the portion of the compound represented by is: l-(2,2-difluoroethan-l- yl)piperidin-4-yl, 1 -(2-hydroxypropan- 1 -yl)piperidin-4-yl, 1 -(2 -m ethoxy ethan- 1 -yl)piperidin- 4-yl, l-(3-hydroxypropan-2-yl)piperidin-4-yl, l-(N,N-dimethylcarbamylmethyl)piperidin-4- yl, l-(N-methylcarbamylmethyl)piperidin-4-yl, l-(oxazol-5-ylmethyl)piperidin-4-yl, 1- carbamylpiperidin-4-yl, l-oxetan-3-ylpiperidin-4-yl, or cyclohexyl.
  • R 1 is -N(CH 3 )-, -NH-, -N(CH 2 CH 2 OH)-, -N(CH 2 COOH)-, -N(CH 2 CH 2 COOH)-, -N(S(0) 2 CH 3 )-, -N(C(0)C(0)0H)-, -C(O)-, -S-, -S(O)-, -S(0) 2 -, -C(CH 3 )(OH)-, -C(CH 3 )(F)-, -C(CH 2 CH 3 )(OH)-, -C(CF 3 )(OH)-, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -CH(OH)-,
  • -CH , -CH 2 -, -CH(NH 2 )-, -CH(NHCH 3 )-, -NH-S(0) 2 -, -N(CH 2 CN)-, -S(0) 2 -NH-, -N(CH 2 COOCH 3 )-, -CH 2 -S(0) 2 -, -N(CH(CH 3 )COOH)-, pyrazol-4-ylmethylaminylene, cyclopropan-l,l-diyl, and oxetan-2,2-diyl.
  • R 1 is -C(OH)(CHF 2 )-, -C(NH 2 )(CF 3 )-, oxiran-2,2-diyl, or l,3-dioxolan-2,2-diyl; or R 1 is fused to ring A to form 2-oxo-octahydro-2H-imidazo[4,5-c]pyridin-l-yl, l-oxa-6-azaspiro[2.5]octan- 2-yl, octahydro- lH-pyrrolo[3 ,2-c]pyridin- 1 -yl, 2-oxo-hexahydrooxazolo[5,4-c]pyridin- 1 -yl, or 2,2-dioxo-octahydro-[l,2,5]thiadiazolo[3,4-c]pyridin-l-yl-y
  • the compound has structural formula (la):
  • ring B’ is phenyl, pyridin-3-yl, or l,3-dihydroisobenzofuran-5-yl;
  • R 11 is -S-, -S(0) 2 -, -CF 2 -, -C(F)(CH 3 )-, -C(OH)(CH 3 )-, -CH(CH 3 )-, or -C(O)-;
  • R 12a is hydrogen, -CH3, -CH2CH2OH, or oxetan-3-ylmethyl;
  • R 12b is hydrogen or -CH3; each R 13 , if present, is independently fluoro; C1-C4 alkyl optionally substituted with one or more of -CN and -OH; C2-C4 alkynyl optionally substituted with one or more -OH; -C(0)N(R 6 ) 2 ; -C(0)0-CI-C 4 alkyl; -N(R 6 ) 2 ; -S(0) 2 N(R 6 ) 2 ; -SO2-C1-C4 alkyl; phenyl optionally substituted one or more of fluoro, -CN, -C(0)N(R 6 ), -COOH, -O-C1-C4 alkyl, and C1-C4 hydroxyalkyl; pyridinyl optionally substituted with one or more O-C1-C4 alkyl; pyrazolyl optionally substituted with one or more of -COOH, C1-C4 hydroxyalkyl, -C
  • p is 2, and one R 13 is fluoro.
  • ring B’ is phenyl
  • each R 13 is independently, fluoro, -CH3, -CH2CH3, -CH2CN, - CH(CH 3 )2, -CoC-C(CH3) 2 OH, -C(OH)(CH 3 )CH3, -C(CH 3 )3, -C(0)NH 2 , -C(0)0CH 2 CH3, -N(CH3)2, -S(0) 2 NH 2 , -SO2CH3, l,l-dioxothiazolidin-2-yl, l,l-dioxothiomorpholin-4-yl, 2-cyanophenyl, 2-methoxypyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyrimidin-4-yl, 2-oxo- l,2-dihydropyridin-6-yl, 2-oxo-l,2-dihydropyri din-3 -yl, 2-
  • the compound has structural formula (lb):
  • R 22 is hydrogen, -CH3, -CH 2 CH3, -CH 2 CH 2 OH, or azetidin-3-ylmethyl; each R 23 is independently fluoro; C1-C4 alkyl; C 2 -C4 alkynyl optionally substituted with hydroxy; -N(R 6 ) 2 ; -O-C1-C4 alkylene-C(0)-N(R 6 ) 2 ; phenyl optionally substituted with one or more of halo, -CN, C1-C4 alkyl, -O-C1-C4 alkyl, -C(0)N(R 6 ) 2 , and -C(0)-Ci-C4 alkyl; pyridinyl optionally substituted with -O-C1-C4 alkyl; pyrazolyl optionally substituted with one or more of -CN, -C1-C4 alkyl, -C1-C4 hydroxyalkyl, -C(0)N(R
  • q is 2; and one R 23 is -CFb or fluoro.
  • each R 23 is independently fluoro, -CFb, -CFhCFb, -CH(CH3) 2 , -CoC-C((CH 3 ) 2 )OH, -N(CH 3 ) 2 , -0CH 2 CH 2 C(0)NH 2 , l,2,3,4-tetrazol-5-yl, 2- methoxypyri din-3 -yl, 2-methoxypyridin-4-yl, 2-methoxypyridin-5-yl, 2-methoxypyridin-6-yl, 3-(N,N-dimethylcarbamyl)pyrazol-l-yl, 3-carbamylphenyl, 3-carbamylpyrazol-l-yl, 3- carboxypyrazol-l-yl, 3-cyanophenyl, 3-cyanopyrazol-l-yl, 3 -ethoxy carbonylphenyl, 3- fluoropheny
  • the compound has structural formula (IV): pharmaceutically acceptable salt thereof, wherein:
  • X is C(CN) or N
  • R 22 is -CH3, -CH2CHF2, -CH2CH2OH, -CH 2 CH(CH3)OH, -CH(CH3)CH 2 0H;
  • R 23 is morpholin-4-yl, or -CF3, wherein the morpholinyl is optionally substituted with -CH3, or wherein two non-adjacent carbon atoms in the morpholinyl are optionally taken together to form a saturated ring bridged to the morpholinyl.
  • R 23 is -CF3, morpholin-4-yl, 3-methylmorpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2-oxa-5- azabicyclo[2.2.1]heptan-5-yl, or 2-oxa-5-azabicyclo[2.2.2]octan-5-yl.
  • the compound is selected from any one of the compounds 100-315 in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is selected from any one of the compounds 316-315 in Table 2, or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention may be racemic. In certain embodiments, the compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
  • the compounds of the invention have more than one stereocenter. Accordingly, the compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. In certain embodiments, the compounds of the invention have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configurations at the remaining stereogenic centers.
  • the enantiomeric excess of the stereocenter is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 92% ee, 94% ee, 95% ee, 96% ee, 98% ee or greater ee.
  • hashed or bolded non-wedge bonds indicate relative, but not absolute, stereochemical configuration (e.g., do not distinguish between enantiomers of a given diastereomer).
  • hashed or bolded wedge bonds indicate absolute stereochemical configuration.
  • the invention relates to pharmaceutical composition
  • a therapeutic preparation or pharmaceutical composition of the compound of the invention may be enriched to provide predominantly one enantiomer of a compound.
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • a therapeutic preparation or pharmaceutical composition may be enriched to provide predominantly one diastereomer of the compound of the invention.
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • compositions and methods of the present invention may be utilized to treat a subject in need thereof.
  • the subject is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of the disclosed compounds.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, bitartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic, and sulfosalicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of compounds disclosed herein are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non- pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds disclosed herein for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds disclosed herein.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop).
  • routes of administration including, for example, orally (for example, drenches as in aqueous or
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
  • a preferred route of administration is local administration (e.g ., topical administration, such as eye drops, or administration via an implant).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, intraocular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to about 99.5% (more preferably, about 0.5 to about 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher el al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In certain embodiments, the active compound will be administered once daily.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body ( e.g ., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds).
  • the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.
  • conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention or the one or more additional therapeutic agent(s).
  • the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1 -(2-hydroxy ethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
  • the compounds and compositions described here may be used to treat a disease or condition characterized by aberrant CDK5 overactivity, such as a disease or condition of the kidney or a ciliopathy.
  • Administration of CDK5 inhibitors will show benefits in therapeutic indications associated with upregulation of CDK5 (i.e., increased levels of CDK5 protein in diseased tissue compared to healthy tissue).
  • the disease or condition is a disease or condition of the kidney.
  • the kidney disease or condition is a cystic kidney disease, renal fibrosis, diabetic nephropathy, a parenchymal renal disease, or decreased renal function.
  • the kidney disease or condition is chronic kidney disease, polycystic kidney disease, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or nephronophthisis-medullary cystic kidney disease.
  • the disease is polycystic kidney disease.
  • the disease or condition is a ciliopathy.
  • the ciliopathy is a neurodegenerative disease, a liver disease, inflammation, a cancer, or a tumor.
  • the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease.
  • the liver disease is polycystic liver disease.
  • Kidney diseases and conditions include, but are not limited to, kidney failure (also known as end stage kidney disease or ESRD), kidney stones, polycystic kidney disease, cystic kidney disease, renal fibrosis, diabetic nephropathy, a parenchymal renal disease, decreased renal function, chronic kidney disease, polycystic kidney disease, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, and nephronophthisis-medullary cystic kidney disease.
  • Major causes of kidney diseases in the United States include diabetes, high blood pressure, and glomerulonephritis, a disease that damages the kidneys’ filtering units, the giomeaili.
  • Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions. With the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation of disease may be from birth, or much later into adult life. Cystic disease may involve one or both kidneys and may or may not occur in the presence of other anomalies. A higher incidence of cystic kidney disease is found in the male population and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and cause related pain and/or hemorrhage.
  • Autosomal Recessive Polycystic Kidney Disease APKD
  • ADPKD Autosomal dominant polycystic kidney disease
  • Fibrotic disorders are commonplace, take many forms and can be life-threatening. No better example of this exists than the progressive fibrosis that accompanies all chronic renal disease. Renal fibrosis is a direct consequence of the kidney's limited capacity to regenerate after injury. Renal scarring results in a progressive loss of renal function, ultimately leading to end-stage renal failure and a. requirement for dialysis or kidney transplantation. [Hewitson: Fibrosis in the kidney: is a problem shared a problem halved? Fibrogenesis & Tissue Repair 2012 5(Suppl 1): S 14].
  • the renal parenchyma is the functional part of the kidney that includes the renal cortex (the outermost part of the kidney) and the renal medulla.
  • the renal cortex contains the approximately 1 million nephrons (these have glomeruli which are the primary filterer of blood passing through the kidney, and renal tubules which modify the fluid to produce the appropriate amount/content of urine).
  • the renal medulla consists primarily of tubules/ducts which are the beginning of the collecting system that allows the urine to flow' onwards to being excreted. Renal parenchyma disease describes medical conditions winch damage these parts of the kidney. These diseases may be congenital, hereditary or acquired.
  • Causes vary and include genetic conditions like polycystic kidneys, hereditary conditions passed on from parents, bacterial and viral infections, kidney stones, high blood pressure, diabetes, autoimmune diseases like lupus nephritis or nephritis associated with purpura, medications and others.
  • Common signs include swelling of hands/feet/eyes (edema), high blood pressure, anemia, bone changes, blood in the urine, abdominal swelling.
  • Common symptoms include loss of appetite, itching, nausea and vomiting, fatigue, joint pain, frequent night urination and dizziness [https://www.nicklauschildrens.org/conditions/renal-parenchyma-diseases]
  • Chronic kidney disease also called chronic kidney failure, describes the gradual loss of kidney function.
  • Chronic kidney disease When chronic kidney disease reaches an advanced stage, dangerous levels of fluid, electrolytes and wastes can build up in the body. Chronic kidney disease may not become apparent until kidney function is significantly impaired.
  • Treatment for chronic kidney disease focuses on slowing the progression of the kidney damage, usually by controlling the underlying cause.
  • Chronic kidney disease can progress to end-stage kidney- failure, which is fatal without artificial fdtering (dialysis) or a kidney transplant.
  • Chronic kidney disease occurs when a disease or condition impairs kidney function, causing kidney damage to worsen over several months or years.
  • kidney disease diseases and conditions that cause chronic kidney disease include, but are not limited to, diabetes, high blood pressure, glomerulonephritis, interstitial nephritis, polycystic kidney disease, prolonged obstruction of the urinary tract (e.g., from conditions such as enlarged prostate, kidney stones, and some cancers), vesicoureteral reflux, and recurrent kidney infection, also called pyelonephritis. [htps://www.mayoclinic.org/diseases-conditions/chronic-kidney-disease/symptoms- causes/sy c-20354521]
  • MCKD Medullary cystic kidney disease
  • NPH nephronophthisis
  • Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy. Its incidence has been estimated to be 09 eases per million people in the United States, and 1 in 50,000 births in Canada. Infantile, juvenile, and adolescent forms of nephronophthisis have been identified.
  • nephronophthisis typically present with polyuria (production of a large volume of urine), polydipsia (excessive liquid intake), and after several months to years, end-stage kidney disease, a condition necessitating either dialysis or a kidney transplant in order to survive.
  • Some individuals that suffer from nephronophthisis also have so-called "extra-renal symptoms” which can include tapetoretinal degeneration, liver problems, ocular motor apraxia, and cone-shaped epiphysis (Saldino- Mainzer syndrome).
  • extra-renal symptoms can include tapetoretinal degeneration, liver problems, ocular motor apraxia, and cone-shaped epiphysis (Saldino- Mainzer syndrome).
  • Mechanism of nephronophthisis indicates that all proteins mutated in cystic kidney diseases express themselves in primary cilia.
  • NPHP gene mutations cause defects in signaling resulting in flaws of planar cell polarity.
  • MCKD Medullary cystic kidney disease
  • ADTKD autosomal dominant tubulointerstitial kidney disease
  • medullary' cystic kidney disease mucin- 1 kidney disease 1 (MKD1) and mucin-2 kidney disease/uromodulin kidney disease (MKD2).
  • MKD1 mucin- 1 kidney disease 1
  • MKD2 mucin-2 kidney disease/uromodulin kidney disease
  • a third form of the d sease occurs due to mutations in the gene encoding renin (ADTKD-REN), and has formerly been known as familial juvenile hyperuricemic nephropathy type 2 In terms of the signs/symptoms of medullary cystic kidney di sease, the disease is not easy to diagnose and is uncommon.
  • Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well. PKD is one of the most common hereditary' diseases in the United States, affecting more than 600,000 people. It is the cause of nearly 10% of all end-stage renal disease.
  • PKD is caused by abnormal genes which produce a specific abnormal protein; this protein has an adverse effect on tubule development.
  • PKD is a general term for twO types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney- disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).
  • ADPKD autosomal dominant polycystic kidney- disease
  • ARPKD autosomal recessive polycystic kidney disease
  • the abnormal gene exists in all cells in the body; as a result, cysts may occur in the liver, seminal vesicles, and pancreas. This genetic defect can also cause aortic root aneurysms, and aneurysms in the circle of Willis cerebral arteries, which if they rupture, can cause a subarachnoid hemorrhage.
  • Diagnosis may be suspected from one, some, or all of the following: new' onset flank pain or red urine; a positive family history; palpation of enlarged kidneys on physical exam; an incidental finding on abdominal sonogram; or an incidental finding of abnormal kidney function on routine lab work (BUN, serum creatinine, or eGFR).
  • Polycystic kidney disease can be ascertained via a CT scan of abdomen, as well as, an MRI and ultrasound of the same area. A physical exam/test can reveal enlarged liver, heart murmurs and elevated blood pressure.
  • Complications include hypertension due to the activation of the renin-angiotensin- aldosterone system (RAAS), frequent cyst infections, urinary bleeding, and declining renal function.
  • RAAS renin-angiotensin- aldosterone system
  • Hypertension is treated with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).
  • ACEIs angiotensin converting enzyme inhibitors
  • ARBs angiotensin receptor blockers
  • Infections are treated with antibiotics.
  • Declining renal function is treated with renal replacement therapy (RRT): dialysis and/or transplantation. Management from the time of the suspected or definitive diagnosis is by a board-certified nephrologist. There is no FDA-approved treatment. However, it has been shown that mild to moderate dietary restrictions slow' the progression of autosomal dominant polycystic kidney disease (ADPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • kidney failure typically stage 4 or 5 of chronic kidney disease
  • a ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary' function.
  • Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem.
  • the similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual cause, it is clustering of a set of characteristic features which define whether a syndrome is a ciliopathy.
  • Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue. PLD is commonly seen in association with autosomal-dominant polycystic kidney disease, with a prevalence of 1 in 400 to 1000, and accounts for 8-10% of all cases of end stage renal disease. The much rarer autosomal- dominant polycystic liver disease will progress without any kidney involvement.
  • Polycystic liver disease comes in two forms as autosomal dominant polycystic kidney disease (with kidney cysts) and autosomal dominant polycystic liver disease (liver cysts only).
  • Most patients with PLD are asymptomatic with simple cysts found following routine investigations. After confirming the presence of cysts in the liver, laboratory tests may be ordered to check for liver function including bilirubin, alkaline phosphatase, alanine aminotransferase, and prothrombin time.
  • Patients with PLD often have an enlarged liver which will compress adjacent organs, leading to nausea, respirator ⁇ ' issues, and limited physical ability.
  • AD Alzheimer's disease
  • a chronic neurodegenerative disease that usually starts slowly and gradually worsens over lime. It is the cause of 60-70% of cases of dementia.
  • the most common early symptom is difficulty in remembering recent events.
  • symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioural issues.
  • the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.
  • the cause of Alzheimer's disease is poorly understood. About 70% of the risk is believed to be inherited from a person's parents with many genes usually involved.
  • risk factors include a history of head injuries, depression, and hypertension.
  • the disease process is associated with plaques and neurofibrillary tangles in the brain.
  • a probable diagnosis is based on the history' of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal ageing.
  • Parkinson's disease is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. As the disease worsens, non-motor symptoms become more common. The symptoms usually emerge slowly. Early in the disease, the most obvious symptoms are shaking, rigidity, slowness of movement, and difficulty with walking. Thinking and behavioral proble s may also occur. Dementia becomes common in the advanced stages of the disease. Depression and anxiety are also common, occurring in more than a third of people with PD. Other symptoms include sensory, sleep, and emotional problems. The main motor symptoms are collectively called “parkinsonism", or a "parkinsonian syndrome". The cause of Parkinson's disease is believed to involve both genetic and environmental factors. Those with a family member affected are more likely to get the disease themselves.
  • MS Multiple Sclerosis
  • MS is a major cause of neurological disability in young adults. Pareek et ah, J. Exp. Med. (2010), doi: 10.1084/jem.20100876.
  • the immune system attacks the protective sheath, or myelin, that covers nerve fibers, thereby interfering with communication between the brain and the rest of the body; when the protective myelin is damaged and the nerve fiber is exposed, messages traveling along that nerve fiber may be slowed or blocked https://www.mayoclinic.org/diseases-conditions/multiple- sclerosis/symptoms-causes/syc-20350269 (last accessed July 1, 2021).
  • MS is the most common chronic demyelinating d sorder of the central nervous system.
  • MS patients experience a relapsing-remitting disease course, with periods of new symptoms or relapses over days or weeks that usually improve partially or completely; the relapses are followed by periods of remission which can last months or years.
  • At least 50% of relapsing-remitting MS patients develop a steady- progression of symptoms within 10-20 years of disease onset; this progression is known as secondary -progressive MS, and the rate of disease progression varies greatly among these patients.
  • the worsening of symptoms usually includes problems with mobility and gait.
  • MS patients experience a gradual onset and steady progression of signs and symptoms with no relapses, and this disease course is known as primary-progressive MS.
  • a combination of genetics and environmental factors may he responsible for the development of MS, with risk factors including age, sex, family history, certain infections, race, climate, certain other autoimmune diseases, and smoking.
  • MS patients may also develop other issues, such as muscle stiffness or spasms, paralysis (especially in the legs), mental changes (such as forgetfulness or mood swings), depression, and epilepsy. Id.
  • Huntington’s disease is an autosomal dominant neurodegenerative disease predominantly caused by the production of mutant antiapoptotic buntingtin (niHTT) protein that contains abnormally long polyglutamine repeats. Allnutt et ak, ACS Chemical Neuroscience (2020) 11:1218-1230. Excessive cleavage of mHTT results in the accumulation of toxic fragments that cause degeneration in striatal neurons and the motor cortex. Id. Huntington’s is a rare, genetic disease and usually results in movement, cognitive, and psychiatric disorders https://www.mayoclinic.org/diseases-conditions/huntingtons- disease/symptoms-causes/syc-20356117 (last accessed July 1, 2021).
  • Movement disorders can both include involuntary movements and affect voluntary movements, and include involuntary jerking movements, muscle rigidity, slow or abnormal eye movements, impaired gait, and difficulty with speech or swallowing.
  • Cognitive impairments include difficulty organizing, prioritizing, or focusing, lack of flexibility, lack of impulse control, lack of awareness of one’s own behaviors and abilities, slowness in processing thoughts, and difficulty in learning new information.
  • Psychiatric disorders include depression, obsessive-compulsive disorder, mania, and bipolar disorder.
  • Symptoms often first appear when people are in their 30s or 40s, and medications are available to help manage the symptoms. Id.
  • Cdk5-p35 activity is neuroprotective in Huntington’s. Allnutt at 1224. Cdk5-p35 has been shown to mitigate mHTT aggregation by phosphorylation of mHTT at Ser434, significantly reducing polyglutamine cleavage, accumulation, and subsequent toxicity. Id. Inhibition of Cdk5 has also been found to be correlated with increased fragment aggregation and cell death in cells with another polyglutamine protein disease, spinocerebellar ataxia type3 positive cells. Id. Moreover,
  • Cdk5 has been shown to phosphorylate mHTT at Seri 181 and Seri 201 in response to DNA damage in vitro and in vivo , preventing polyglutamine-induced p53-mediated toxicity and cell death in striatal neurons. Id.
  • Proteinuria is a pathological condition wherein protein is present in the urine.
  • Albuminuria is a type of proteinuria. Microalbuminuria occurs when the kidney leaks small amounts of albumin into the urine. In a properly functioning body, albumin is not normally present in urine because it is retained in the bloodstream by the kidneys. Microalbuminuria is diagnosed either from a 24-hour urine collection (20 to 200 pg/min) or, more commonly, from elevated concentrations (30 to 300 mg/L) on at least two occasions. Microalbuminuria can be a forerunner of diabetic nephropathy. An albumin level above these values is called macroalbuminuria. Subjects with certain conditions, e.g., diabetic nephropathy, can progress from microalbuminuria to macroalbuminuria and reach a nephrotic range (>3.5 g/24 hours) as kidney disease reaches advanced stages.
  • Proteinuria can be associated with a number of conditions, including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, lupus nephritis, membranoproliferative glomerulonephritis, progressive (crescentic) glomerulonephritis, and membranous glomerulonephriti s.
  • FGS Focal Segmental Glomerulosclerosis
  • FSGS Focal Segmental Glomerulosclerosis
  • glomeruli glomeruli
  • FSGS is one of the many causes of a disease known as Nephrotic Syndrome, which occurs when protein in the blood leaks into the urine (proteinuria).
  • Primary FSGS when no underlying cause is found, usually presents as nephrotic syndrome.
  • Secondary FSGS when an underlying cause is identified, usually presents with kidney failure and proteinuria FSGS can be genetic, there are currently several known genetic causes of the hereditary forms of FSGS.
  • IgA nephropathy also known as IgA nephritis, IgAN, Berger's disease, and synpharyngitic glomerulonephritis
  • IgA nephropathy is a form of glomerulonephritis (inflammation of the glomeruli of the kidney).
  • IgA nephropathy is the most common glomerulonephritis throughout the world.
  • Primary IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus.
  • I ISP Henoch-Schonlein purpura
  • HSP Henoch-Schonlein purpura presents with a characteristic purpuric skin rash, arthritis, and abdominal pain and occurs more commonly in young adults (16-35 yrs old). HSP is associated with a more benign prognosis than IgA nephropathy. In IgA nephropathy there is a slow progression to chronic renal failure in 25- 30% of cases during a period of 20 years.
  • Diabetic nephropathy also known as Kimmelstiel-Wilson syndrome and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is due to longstanding diabetes meilitus and is a prime cause for dialysis. The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus. At this stage, the kidney may start allowing more serum albumin than normal in the urine. As diabetic nephropathy progresses, increasing numbers of glomeruli are destroyed by nodular glomerulosclerosis and the amount of albumin excreted in the urine increases.
  • Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematosus. Lupus nephritis occurs when antibodies and complement build up in the kidneys, causing inflammation. It often causes proteinuria and may progress rapidly to renal failure. Nitrogen waste products build up in the bloodstream. Systemic lupus erythematosus causes various disorders of the internal structures of the kidney, including interstitial nephritis. Lupus nephritis affects approximately 3 out of 10,000 people.
  • Membranoproliferative glomerulonephritis is a type of glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane thickening, activating complement and damaging the glomeruli.
  • Type I is caused by immune complexes depositing in the kidney and is believed to be associated with the classical complement pathway.
  • Type II is similar to Type I, however, it is believed to be associated with the alternative complement pathway.
  • Type III is vety rare and it is characterized by a mixture of subepitheiial deposits and the typical pathological findings of Type I disease.
  • MPGN cardiovascular disease
  • immune complex-mediated MPGN complement activation occurs via the classic pathway and is typically manifested by a normal or mildly decreased serum C3 concentration and a low serum C4 concentration.
  • complement-mediated MPGN there are usually low serum C3 and normal C4 levels due to activation of the alternate pathway.
  • complement-mediated MPGN is not excluded by a normal serum C3 concentration, and it is not unusual to find a normal C3 concentration in adults with dense deposit disease (DDD) or C3 glomerulonephritis (C3GN).
  • DDD dense deposit disease
  • C3GN C3 glomerulonephritis
  • C3 glomerulonephritis show's a glomerulonephritis on light microscopy (LM), bright C3 staining and the absence of C lq, C4 and immunoglobulins (Ig) on immunofluorescence microscopy (IF), and mesangial and/or subendotheiial electron dense deposits on electron microscopy (EM). Occasional intramembranous and suhepithelial deposits are also frequently present.
  • the term ‘C3 glomerulopathy” is often used to include C3GN and Dense Deposit Disease (DDD), both of which result from dysregulation of the alternative pathway (AP) of complement. C3GN and DDD may be difficult to distinguish from each other on LM and IF studies.
  • C3GN mesangial and/or subendotheiial, intramembranous and subepithelial deposits in C3GN, while dense osmiophilic deposits are present along the glomerular basement membranes (GBM) and in the mesangium in DDD.
  • GBM glomerular basement membranes
  • DDD glomerular basement membranes
  • PG Progressive (crescentic) glomerulonephritis
  • PG Progressive (crescentic) glomerulonephritis
  • an underlying disease such as Goodpasture's syndrome, systemic lupus erythematosus, or Wegener granulomatosis; the remaining cases are idiopathic.
  • PG involves severe injury to the kidney's glomeruli, with many of the glomeruli containing characteristic crescent-shaped scars.
  • Patients with PG have hematuria, proteinuria, and occasionally, hypertension and edema.
  • the clinical picture is consistent with nephritic syndrome, although the degree of proteinuria may occasionally exceed 3 g/24 hours, a range associated with nephrotic syndrome. Untreated disease may progress to decreased urinary volume (oliguria), which is associated with poor kidney function.
  • MGN Membranous glomerulonephritis
  • Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect sight, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.
  • Hypertensive kidney disease (Hypertensive nephrosclerosis (HN or HNS) or hypertensive nephropathy (HN)) is a medical condition referring to damage to the kidney due to chronic high blood pressure.
  • HN can be divided into two types: benign and malignant. Benign nephrosclerosis is common in individuals over the age of 60 while malignant nephrosclerosis is uncommon and affects 1-5% of individuals with high blood pressure, that have diastolic blood pressure passing 130 mm Hg. Signs and symptoms of chronic kidney- disease, including loss of appetite, nausea, vomiting, itching, sleepiness or confusion, weight loss, and an unpleasant taste in the mouth, may develop.
  • kidney tissue This includes the small blood vessels, glomeruli, kidney tubules and interstitial tissues.
  • the tissue hardens and thickens which is known as nephrosclerosis.
  • the narrowing of the blood vessels means less blood is going to the tissue and so less oxygen is reaching the tissue resulting in tissue death (ischemia).
  • Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure. Causes include a number of kidney- diseases such as focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. It may also occur as a complication of diabetes or lupus. The underlying mechanism typically involves damage to the glomeruli of the kidney. Diagnosis is typically- based on urine testing and sometimes a kidney biopsy. It differs from nephritic syndrome in that there are no red blood cells in the urine.
  • Nephrotic syndrome is characterized by large amounts of proteinuria (>3.5 g per 1.73 m2 body surface area per day, or > 40 mg per square meter body surface area per hour in children), hypoalbuminemia ( ⁇ 2,5 g/dl), hyperlipidemia, and edema that begins in the face. Lipiduria (lipids in urine) can also occur, but is not essential for the diagnosis of nephrotic syndrome. Hyponatremia also occur with a low fractional sodium excretion. Genetic forms of nephrotic syndrome are typically resistant to steroid and other immunosuppressive treatment. Goals of therapy are to control urinary protein loss and swelling, provide good nutrition to allow the child to grow, and prevent complications. Early and aggressive treatment are used to control the disorder.
  • Minimal change disease (also known as MCD, minimal change glomerulopathy, and nil disease, among others) is a disease affecting the kidneys which causes a nephrotic syndrome.
  • the clinical signs of minimal change disease are proteinuria (abnormal excretion of proteins, mainly albumin, into the urine), edema (swelling of soft tissues as a consequence of water retention), weight gain, and hypoalbuminem a (low serum albumin). These signs are referred to collectively as nephrotic syndrome.
  • the first clinical sign of minimal change disease is usually edema with an associated increase in weight.
  • the swelling may be mild but patients can present with edema in the lower half of the body, periorbital edema, swelling in the scrotal/labial area and anasarca in more severe cases. In older adults, patients may also present with acute kidney injury (20-25% of affected adults) and high blood pressure. Due to the disease process, patients with minimal change disease are also at risk of blood clots and infections.
  • Membranous nephropathy refers to the deposition of immune complexes on the glomerular basement membrane (GBM) with GBM thickening.
  • the cause is usually unknown (idiopathic), although secondary causes include drugs, infections, autoimmune disorders, and cancer. Manifestations include insidious onset of edema and heavy proteinuria with benign urinary sediment, normal renal function, and normal or elevated blood pressure.
  • Membranous nephropathy is diagnosed by renal biopsy. Spontaneous remission is common. Treatment of patients at high risk of progression is usually with corticosteroids and cyclophosphamide or chlorambucil
  • Acute proliferative glomerulonephritis is a disorder of the glomeruli (glomerulonephritis), or small blood vessels in the kidneys. It is a common complication of bacterial infections, typically skin infection by Streptococcus bacteria types 12, 4 and 1 (impetigo) but also after streptococcal pharyngitis, for which it is also known as postinfectious or poststreptococcal glomerulonephritis. It can be a risk factor for future albuminuria. In adults, the signs and symptoms of infection may still be present at the time when the kidney problems develop, and the terms infection-related glomerulonephritis or bacterial infection-related glomerulonephritis are also used.
  • Acute glomerulonephritis resulted in 19,000 deaths in 2013 down from 24,000 deaths in 1990 worldwide.
  • Acute proliferative glomerulonephritis (post-streptococcal glomerulonephritis) is caused by an infection with streptococcus bacteria, usually three weeks after infection, usually of the pharynx or the skin, given the time required to raise antibodies and complement proteins.
  • streptococcus bacteria usually three weeks after infection, usually of the pharynx or the skin, given the time required to raise antibodies and complement proteins.
  • the infection causes blood vessels in the kidneys to develop inflammation, this hampers the renal organs ability to filter urine. [citation needed]
  • Acute proliferative glomerulonephritis most commonly occurs in children.
  • Thin basement membrane disease also known as benign familial hematuria and thin basement membrane nephropathy or TBMN
  • TBMN thin basement membrane nephropathy
  • IgA nephropathy the most common cause of hematuria without other symptoms.
  • the only abnormal finding in this disease is a thinning of the basement membrane of the glomeruli in the kidneys. Its importance lies in the fact that it has a benign prognosis, with patients maintaining a normal kidney function throughout their lives.
  • Most patients with thin basement membrane disease are incidentally discovered to have microscopic hematuria on urinalysis. The blood pressure, kidney function, and the urinary protein excretion are usually normal.
  • glomerulonephritis is a form of glomerulonephritis associated primarily with the mesangium. There is some evidence that interleukin- 10 may inhibit it in an animal model. [2] It is classified as type II lupus nephritis by the World Health Organization (WHO). Mesangial cells in the renal glomerulus use endocytosis to take up and degrade circulating immunoglobulin. This normal process stimulates mesangial cell proliferation and matrix deposition. Therefore, during times of elevated circulating immunoglobulin (i.e. lupus and IgA nephropathy) one would expect to see an increased number of mesangial cells and matrix in the glomerulus. This is characteristic of nephritic syndromes. P. Amyloidosis (primary)
  • Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds up in tissue.
  • Symptoms depend on the type and are often variable. [2] They may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen. [2] There are about 30 different types of amyloidosis, each due to a specific protein misfolding.[5] Some are genetic w'hile others are acquired. [3] They are grouped into localized and systemic forms.
  • At. The four most common types of systemic disease are light chain (At.), inflammation (AA), dialysis (Ab2M), and hereditary and old age (ATTR).
  • Primary amyloidosis refers to amyloidosis in which no associated clinical condition is identified.
  • Clq nephropathy is a rare glomerular disease with characteristic mesangial Clq deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion.
  • Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases.
  • the presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. (Devasahayam, et a!., “Clq Nephropathy: The Unique Underrecognized Pathological Entity,” Analytical Cellular Pathology, vol. 2015, Article ID 490413, 5 pages, 2015. https://doi.Org/10.i 155/2015/490413.)
  • Anti -glomerular basement membrane (GBM) disease also known as Goodpasture's disease, is a rare condition that causes inflammation of the small blood vessels in the kidneys and lungs.
  • the aiitiglomerular basement membrane (GBM) antibodies primarily attack the kidneys and lungs, although, generalized symptoms like malaise, weight loss, fatigue, fever, and chilis are also common, as are joint aches and pains. 60 to 80% of those with the condition experience both lung and kidney involvement; 20-40% have kidney involvement alone, and less than 10% have lung involvement alone.
  • Lung symptoms usually antedate kidney symptoms and usually include: coughing up blood, chest pain (in less than 50% of cases overall), cough, and shortness of breath.
  • Kidney symptoms usually include blood in the urine, protein in the urine, unexplained swelling of limbs or face, high amounts of urea in the blood, and high blood pressure.
  • GPS causes the abnormal production of anti-GBM antibodies, by the plasma cells of the blood.
  • the anti-GBM antibodies attack the alveoli and glomeruli basement membranes. These antibodies bind their reactive epitopes to the basement membranes and activate the complement cascade, leading to the death of tagged cells. T cells are also implicated. It is generally considered a type II hypersensitivity reaction.
  • Protein levels in urine can be measured using methods known in the art. Until recently, an accurate protein measurement required a 24-hour urine collection. In a 24-hour collection, the patient urinates into a container, which is kept refrigerated between trips to the bathroom. The patient is instructed to begin collecting urine after the first trip to the bathroom in the morning. Every drop of urine for the rest of the day is to be collected in the container. The next morning, the patient adds the first urination after waking and the collection is complete.
  • a single urine sample can provide the needed information.
  • the amount of albumin in the urine sample is compared with the amount of creatinine, a waste product of normal muscle breakdown.
  • the measurement is called a urine albumin-to-creatinine ratio (UACR).
  • UCR urine albumin-to-creatinine ratio
  • a urine sample containing more than 30 milligrams of albumin for each gram of creatinine (30 rng/g) is a warning that there may be a problem. If the laboratory test exceeds 30 mg/g, another UACR test should be performed 1 to 2 weeks later. If the second test also shows high levels of protein, the person has persistent proteinuria, a sign of declining kidney function, and should have additional tests to evaluate kidney function.
  • Tests that measure the amount of creatinine in the blood will also show whether a subject's kidneys are removing wastes efficiently. Too much creatinine in the blood is a sign that a person has kidney damage. A physician can use the creatinine measurement to estimate how efficiently the kidneys are filtering the blood. This calculation is called the estimated glomerular filtration rate, or eGFR. Chronic kidney disease is present when the eGFR is less than 60 milliliters per minute (mL/min).
  • Cyclin-dependent kinases are the family of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved.
  • CDK5 has emerged as an essential kinase in sensory pathways.
  • CDK5 is required for proper development of the brain and, to be activated, CDK5 must associate with CDK5R1 or CDK5R2.
  • Cdk5 is involved in the processes of neuronal maturation and migration, phosphorylating the key intracellular adaptor of the reelin signaling chain. Dysregulation of this enzyme has been implicated in several neurodegen erative diseases including Alzheimer's. It is also involved in invasive cancers, apparently by reducing the activity of the actin regulatory protein caldesmon.
  • CDK5 a regulator of differentiation, proliferation, and morphology in podocytes, which are highly specialized and terminally differentiated glomerular cells that play a vital role in renal physiology, including the prevention of proteinuria (Griffin et al ., Am J Pathol. (2004)
  • CDK5 has also been demonstrated to play a role in other non-neuronal tissues (Dhavan R and Tsai LH, Nat Rev Mol Cell Biol. (2001) 2:749-759).
  • the invention provides methods for treating, or the reducing risk of developing, a disease or condition characterized by aberrant CDK5 overactivity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention (e.g., a compound having structural formula (I)) or a pharmaceutical composition comprising said compound.
  • a compound of the invention e.g., a compound having structural formula (I)
  • a pharmaceutical composition comprising said compound.
  • the disease is or condition is a disease or condition of the kidney. In some aspects of these embodiments, the disease is polycystic kidney disease. In other aspects of these embodiments, the disease is diabetic nephropathy, glomerulonephritis, Heymann nephritis.
  • the disease or condition to be treated by a compound or composition of this invention is a neurological or neurodegenerative disease.
  • the disease or condition Alzheimer’s disease, schizophrenia, epilepsy, Parkinson’s disease, ALS, multiple sclerosis, or Huntington’s disease.
  • the disease or condition to be treated by a compound or composition of this invention is one that affects the blood vessels or the heart (e.g., a disease or condition caused by blood clots or restricted blood flow).
  • the disease or condition is atherosclerosis.
  • the disease or condition is, ischemic stroke.
  • the disease or condition is ischemia reperfusion injury.
  • the disease or condition to be treated by a compound or composition of this invention is pain.
  • the condition is neuropathic pain.
  • the condition is bone pain due to bone cancer.
  • the disease or condition to be treated by a compound or composition of this invention is cancer.
  • the cancer is adenocarcinoma, B-cell lymphoma, other B-cell malignancies, breast cancer, Burkitt’s lymphoma, colorectal cancer, corticosurrenaloma, Ewing’s sarcoma, glioma, hepatocellular carcinoma, nasopharyngeal carcinoma, non-small cell lung cancer, osteosarcoma, parotid cylindroma, prostate cancer, thymic carcinoma, or uterine carcinoma.
  • the disease or condition to be treated by a compound or composition of this invention is a viral disease.
  • the viral disease is HIV infection, HIV encephalitis, other HIV-related neurotoxicities, herpes simplex virus infection, or herpetic keratitis.
  • the disease or condition to be treated by a compound or composition of this invention is multiple sclerosis.
  • the disease or condition to be treated by a compound or composition of this invention is a disease of the eye.
  • the disease is glaucoma or retinal degeneration.
  • the disease or condition to be treated by a compound or composition of this invention is diabetes mellitus.
  • the disease or condition to be treated by a compound or composition of this invention is systemic lupus.
  • the disease or condition to be treated by a compound or composition of this invention is salivary gland dysfunction. In some aspects of these embodiments, the disease is radiation-induce salivary gland dysfunction.
  • the disease or condition to be treated by a compound or composition of this invention is graft versus host disease.
  • a subject is selected on the basis that they have, or are at risk of developing, a disease or condition characterized by aberrant CDK5 overactivity, such as a disease or condition of the kidney, such as polycystic kidney disease.
  • Subjects that have, or are at risk of developing, a disease or condition of the kidney include those with diabetes, hypertension, or certain family backgrounds.
  • diabetes is the leading cause of end-stage renal disease (ESKD).
  • EKD end-stage renal disease
  • albumin in the urine is one of the first signs of deteriorating kidney function. As kidney function declines, the amount of albumin in the urine increases.
  • Another risk factor for developing kidney diseases is hypertension. Proteinuria in a person with high blood pressure is an indicator of declining kidney function. If the hypertension is not controlled, the person can progress to full kidney failure. African Americans are more likely than Caucasians to have high blood pressure and to develop kidney problems from it, even when their blood pressure is only mildly elevated. Other groups at risk for proteinuria are American Indians, Hispanics/Latinos, Pacific Islander Americans, older adults, and overweight subjects.
  • a subject is selected on the basis that they have, or are at risk of developing a disease or condition of the kidney.
  • a subject that has, or is at risk of developing, a disease or condition of the kidney is one having one or more symptoms of the condition.
  • Symptoms of proteinuria are known to those of skill in the art and include, without limitation, large amounts of protein in the urine, which may cause it to look foamy in the toilet. Loss of large amounts of protein may result in edema, where swelling in the hands, feet, abdomen, or face may occur. These are signs of large protein loss and indicate that kidney disease has progressed. Laboratory testing is the only way to find out whether protein is in a subject's urine before extensive kidney damage occurs.
  • the methods are effective for a variety of subjects including mammals, e.g., humans and other animals, such as laboratory animals, e.g , mice, rats, rabbits, or monkeys, or domesticated and farm animals, e.g., cats, dogs, goats, sheep, pigs, cows, or horses.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • Prep-HPLC Reversed ⁇ phase HPLC purifications
  • the resulting mixture was stirred for 75 °C under argon atmosphere for 24 hours.
  • the reaction was quenched by the addition of brine (600 mL)
  • the aqueous layer was extracted with EtOAc (3 x 600 mL).
  • the collect organic layer was washed with brine (3 x 500 mL).
  • the resulting mixture was stirred for 2 hours at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue product was purified by reverse phase flash with the following conditions (column, C18,330g; mobile phase: A:Water/0.05% NH4HCO3, Mobile Phase B:ACN; Flow rate:80 mL/m in; Gradient: 25%B to 60%B in 25 min; Detector, 220nm, Monitor, 254 nm, the desired product were collected at 33%B)) to afford 2-fluoro-5-(morpholin-4-yl)aniline (190 mg, 18 %) as a light brown solid.
  • the residue product was purified by reverse phase flash with the following conditions (Column: Spherical Cl 8, 20-40 um, 80 g; Mobile Phase A: Water (plus 0.05% formic acid); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient of B: 5%, 6 min; 5% ⁇ 25%, 15 min; 25% ⁇ 45%,15 min;45% ⁇ 95%,15 min, Detector: 220 nm.
  • the fractions containing the desired product were collected at 30% B and concentrated under reduced pressure to afford 3-(4-amino-3- fluorophenyl)-4H-l,2,4-oxadiazol-5-one (730 mg, 24) as a light brown solid.
  • the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 um, 330; Mobile Phase A: Water (10MMOL/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 70 ml/min; Gradient: 0%- 0% B, 8 min, 10%-40% B gradient in 30 min; 98%-98% B, 8 min, Detector: 220 nm.
  • the fractions containing the desired product were collected at 30% B and concentrated under reduced pressure to afford the crude.
  • 3-ethenyl-2-fluoroaniline To a stirred mixture of 3-bromo-2-fluoroaniline (3000.0 mg, 15.788 mmol, 1 equiv) and ethenylboronic acid (1702.1 mg, 23.682 mmol, 1.50 equiv) in DMF (35 mL) and H2O (5 mL) were added K2CO3 (3273.0 mg, 23.682 mmol, 1.50 equiv) and Pd(PPh3)4 (912.2 mg, 0.789 mmol, 0.05 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS.
  • 3-ethyl-2-fluoroaniline A mixture of 3-ethenyl-2-fluoroaniline (1500 mg, 10.94 mmol) and Pd/C (30.0 mg, 0.282 mmol, 0.03 equiv) in MeOH was stirred for 6 h at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc and ether (3x5 30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with ether (4 x 50 mL). The combined organic layers were washed with EtOAc (3x5 30 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to afford 3-ethyl-2-fluoroaniline (1050 mg) as a brown oil.
  • 2-ethenyl-5-fluoropyridin-4-amine A mixture of 2-chloro-5-fluoropyridin-4-amine (500.0 mg, 3.412 mmol, 1 equiv), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (788.2 mg, 5.118 mmol, 1.50 equiv), Pd(PPh3)2Cl2 (359.2 mg, 0.512 mmol, 0.15 equiv) and CsF (777.4 mg, 5.118 mmol, 1.50 equiv) dissolved in H2O (2 mL) in dioxane (20 mL) was stirred for overnight at 90 °C under nitrogen atmosphere.
  • Desired product could be detected by LCMS.
  • the mixture was allowed to cool down to room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (2:1) to afford 2-ethenyl-5- fluoropyridin-4-amine (213 mg, 45%) as a yellow oil.
  • 2-ethyl-5-fluoropyridin-4-amine A mixture of 2-ethenyl-5-fluoropyridin-4-amine (200.0 mg, 1.448 mmol, 1 equiv) and Pd/C (70.0 mg, 0.658 mmol, 0.45 equiv) in MeOH (8 mL) was stirred for overnight at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 x 8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (0:1) to afford 2-ethyl-5-fluoropyridin-4-amine (77.5 mg, 38%) as a colorless oil.
  • Desired product could be detected by LCMS.
  • the resulting mixture was filtered, the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether/EtOAc 1:1) to afford 5-fluoro-l-methylindazol-6-amine (80 mg, 86%) as a yellow solid.
  • FIX 4-amino-2-ethyl-5-fluorobenzonitrile tert-butyl N-(4-bromo-5-ethyl-2-fluorophenyl)carbamate.
  • 4- bromo-5-ethyl-2-fluoroaniline (163.8 mg, 0.751 mmol, 1 equiv) in 1,4-dioxane (1.50 mL, 7.51 mmol
  • di-tert-butyl dicarbonate (1639.3 mg, 7.511 mmol, 10 equiv
  • tert-butyl N-(4-cyano-5-ethyl-2-fluorophenyl)carbamate To a stirred solution of tert-butyl N-(4-bromo-5-ethyl-2-fluorophenyl)carbamate (200.0 mg, 0.629 mmol, 1 equiv) and Zn(CN)2 (147.6 mg, 1.257 mmol, 2 equiv) in DMF (2 mL) were added Pd(PPh3)4 (145.3 mg, 0.126 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere.
  • the resulting mixture was stirred for 2 h at 120 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous MgS04. After filtration, the filtrate was concentrated under reduced pressure. The resulting oil was dried in an oven under reduced pressure and used as-is.
  • tert-butyl N-(2-tert-butyl-5- fluoropyridin-4-yl)carbamate 260 mg, 17%) as a yellow oil.
  • 2-tert-butyl-5-fluoropyridin-4-amine A mixture of tert-butyl N-(2-tert-butyl-5- fluoropyridin-4-yl)carbamate (260.0 mg, 0.969 mmol, 1 equiv) and TFA (0.40 mL) in DCM was stirred at room temperature for 16 hours. The reaction was monitored by TLC.
  • the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 um, 120; Mobile Phase A: Water(10MMOL/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 70 ml/min; Gradient: 0%-0% B, 8 min, 0%-20% B gradient in 20 min; 98%-98% B, 8 min, Detector: 220 nm.
  • the fractions containing the desired product were collected at 5% B and concentrated under reduced pressure to afford the crude. The crude product was used in the next step directly without further purification.
  • tert-butyl N-(5-fluoro-2-formylpyridin-4- yl)carbamate 142 mg, 34%) as a white solid.
  • tert-butyl N-[2-(difluoromethyl)-5-fluoropyridin-4-yl] carbamate tert-butyl N-(5-fluoro- 2-formylpyridin-4-yl)carbamate (130.0 mg, 0.541 mmol, 1 equiv) in DAST (2 mL) was stirred for 2 h at 0 °C under nitrogen atmosphere.
  • the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 um, 120 g; Mobile Phase A: Water (plus 5 mM NH4HCO3); Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 5% - 5% B, 10 min, 25% B - 45% B gradient in 20 min; Detector: 220 nm.
  • the fractions containing the desired product were collected at 37% B and concentrated under reduced pressure to afford l-(4-amino-3-fluorophenyl)-3-methyl-l,3-diazinan-2-one (15 mg, 16%) as a yellow solid.
  • Desired product could be detected by LCMS.
  • To the mixture was added water (100 mL) at room temperature.
  • the mixture was extracted with EtOAc (1 x 200 mL).
  • the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by Prep-TLC (petroleum ether/EtOAc 2:1) to afford 5-fluoro-N2-isopropyl-N2-methylpyridine-2, 4-diamine (20 mg, 13%) as a yellow crude oil.
  • 5-bromo-l-ethyl-4-fluoropyridin-2-one A mixture of 5-bromo-4-fluoro-lH-pyridin-2-one (1.00 g, 5.21 mmol, 1 equiv), ethyl iodide (0.97 g, 6.22 mmol, 1.20 equiv) and K2CO3 (2.16 g, 15.6 mmol, 3 equiv) in DMSO (8 mL) was stirred for 2 h at 100 °C under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure.
  • GD 4-amino-5-fluoro-2-methoxybenzonitrile l-bromo-5-fluoro-2-methoxy-4-nitrobenzene.
  • 2-bromo-4-fluoro-5- nitrophenol 500.0 mg, 2.119 mmol, 1 equiv
  • K2CO3 585.6 mg, 4.237 mmol, 2 equiv
  • ACN 5 mL
  • methyl iodide 451.1 mg, 3.178 mmol, 1.50 equiv
  • tert-butyl N-(tert-butoxycarbonyl)-N-(2-chloro-3,5-difluoropyridin-4- yl)carbamate (90 mg, 81%) as a white solid.
  • tert-butyl N-(tert-butoxycarbonyl)-N-(2-chloro-3,5-difluoropyridin-4- yl)carbamate 90.0 mg, 0.247 mmol, 1 equiv
  • morpholine 25.8 mg, 0.296 mmol, 1.2 equiv
  • CS2CO3 241.2 mg, 0.740 mmol, 3 equiv
  • XPhos Pd G3 (41.8 mg, 0.049 mmol, 0.2 equiv) in dioxane (3 mL) at room temperature.
  • the resulting mixture was stirred for 1 hour at 100 °C under nitrogen atmosphere.
  • tert-butyl N-[2-fluoro-5-(isopropylsulfanyl)phenyl]carbamate 400 mg, 70%
  • tert-butyl N-[2-fluoro-5-(propane-2-sulfonyl)phenyl] carbamate tert-butyl N-[2-fluoro-5-(propane-2-sulfonyl)phenyl] carbamate.
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 um, 120 g; Mobile Phase A: Water (plus 5 mM NH4HCO3); Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 5% - 5% B, 10 min, 20% B - 40% B gradient in 20 min; Detector: 220 nm.
  • the fractions containing the desired product were collected at 33% B and concentrated under reduced pressure to afford 3-(4-amino-2-ethyl-5-fluorophenyl)-l-methylpyridin-2-one (65 mg, 58%) as an orange solid.
  • tert-butyl 4-[4-[(tert-butoxycarbonyl)amino]-5-fluoropyridin-2-yl]-4-fluoropiperidine-l- carboxylate To a stirred solution of tert-butyl 4-[4-[(tert-butoxycarbonyl)amino]-5- fluoropyridin-2-yl]-4-hydroxypiperidine-l-carboxylate (300.0 mg, 0.729 mmol, 1 equiv) in DCM (5 mL) was added DAST (2 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C. The reaction was monitored by LCMS.
  • 5-bromo-2-cyanopyridin-l-ium-l-olate To a mixture of 5-bromopyridine-2-carbonitrile (2500.0 mg, 13.661 mmol, 1 equiv) and urea peroxide (2698.6 mg, 28.687 mmol, 2.10 equiv) in DCM (50 mL) were added trifluoroacetic anhydride (5737.5 mg, 27.321 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS.
  • 5-bromo-6-oxo-lH-pyridine-2-carbonitrile To a solution of 5-bromo-2-cyanopyridin-l- ium-l-olate (1000.0 mg, 5.025 mmol, 1 equiv) in DMF (20 mL) was added trifluoroacetic anhydride (4221.0 mg, 20.100 mmol, 4 equiv) dropwise at 0 °C. The resulting mixture was stirred for 32 hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure.
  • the resulting mixture was stirred for 48 h at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash with the following conditions (Column:C18,120 g; Mobile Phase A:Water/0.05% NFLNCCh, Mobile Phase B:ACN; Flow rate:80 mL/min; Gradient: 25%B to 55%B in 30 min; Detector, 254nm and 220 nm, the desired product were collected at 45%B). Concentrated under reduced pressure to afford 5-bromo-l-methyl-6-oxopyridine-2- carbonitrile (200 mg, 78%) as a brown solid.
  • 2-ethenyl-3-fluoropyridin-4-amine A mixture of 2-chloro-3-fluoropyridin-4-amine (1000.0 mg, 6.824 mmol, 1 equiv), 2-ethenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1261.2 mg, 8.188 mmol, 1.20 equiv), Pd(PPh3)4 (1577.0 mg, 1.365 mmol, 0.20 equiv) and CS2CO3 (4446.5 mg, 13.647 mmol, 2 equiv) in dioxane (8 mL) was stirred for 16 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.
  • 6-chloro-2-ethyl-3-fluoropyridin-4-amine 6-chloro-2-ethyl-3-fluoropyridin-4-amine.
  • a mixture of 2-(6-chloro-2-ethyl-3- fluoropyridin-4-yl)isoindole-l,3-dione (170.0 mg, 0.558 mmol, 1 equiv) and hydrazine hydrate (85%) (279.3 mg, 5.579 mmol, 10 equiv) in EtOH (10 mL) was stirred for 1 hour at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure.
  • tert-butyl N-(tert-butoxycarbonyl)-N-(5-chloro-4- cyano-2-fluorophenyl)carbamate 500 mg, 46%) as a white solid.
  • tert-butyl N-[2-fluoro-4-(5-hydroxypyrimidin-2-yl)phenyl]carbamate 150 mg, 17%) as a light yellow solid.
  • tert-butyl N-[4-(5-ethoxypyrimidin-2-yl)-2-fluorophenyl] carbamate tert-butyl N-[4-(5-ethoxypyrimidin-2-yl)-2-fluorophenyl] carbamate.
  • tert-butyl N-[4- (2-ethoxypyridin-4-yl)-2-fluorophenyl]carbamate 750 mg, 95%) as a light yellow oil.
  • 4-(2-ethoxypyridin-4-yl)-2-fluoroaniline A mixture of tert-butyl N-[4-(2-ethoxypyridin-4- yl)-2-fluorophenyl]carbamate (750.0 mg, 2.256 mmol, 1 equiv) and TFA (1 mL) in DCM (10 mL) was stirred for 5 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere.
  • Boc tert-butyl N-(6-fluoro-l-methylindazol-5-yl)carbamate To a stirred mixture of 5-bromo- 6-fluoro-l-methylindazole (30.0 mg, 0.131 mmol, 1 equiv) and tert-butyl carbamate (23.0 mg, 0.196 mmol, 1.50 equiv) in dioxane (2 mL) were added XPhos Pd G3 (22.2 mg, 0.026 mmol, 0.20 equiv) and CS2CO3 (85.4 mg, 0.262 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere.
  • the residue/crude product was purified by reverse phase flash with the following conditions (column, C18,120g; mobile phase,: A:Water/0.05% NH4HCO3, Mobile Phase B:ACN; Flow rate:50 mL/min; Gradient: 10%B to 30%B in 20 min; Detector, 220nm, Monitor, 254 nm, the desired product were collected at 20%B) to afford l-(2-methoxypyridin-4-yl)piperidin-4- amine (100 mg, 74%) as a yellow oil.
  • tert-butyl N-[2-(2,2-difluoro-l-hydroxyethyl)-5-fluoropyridin-4-yl]carbamate A mixture of tert-butyl N-[2-(2,2-difluoroacetyl)-5-fluoropyridin-4-yl]carbamate (176.0 mg, 0.606 mmol, 1 equiv) and NaBFL (68.8 mg, 1.819 mmol, 3 equiv) in MeOH (5 mL) was stirred for 2 h at room temperature under air atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL).
  • 5-bromo-4-fluoro-2-(oxan-4-yloxy)pyridine To a stirred solution of 5-bromo-4-fluoro-lH- pyridin-2-one (100.0 mg, 0.521 mmol, 1 equiv), 5-bromo-4-fluoro-lH-pyridin-2-one (100.0 mg, 0.521 mmol, 1 equiv) and PPh3 (273.2 mg, 1.042 mmol, 2 equiv) in THF (8 mL) were added and DIEA (210.8 mg, 1.042 mmol, 2 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
  • Tert-butyl 4-[(2-methoxy-2-oxoethyl)amino]piperidine-l-carboxylate To a stirred mixture of tert-butyl 4-aminopiperidine-l-carboxylate (10 g, 49.930 mmol, 1 equiv) and methyl 2-bromoacetate (6.11 g, 39.941 mmol, 0.80 equiv) was added DIEA (19.36 g, 149.795 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 hours at 100 °C under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature.
  • Tert-butyl 4-[(7-chloro-l,6-naphthyridin-2-yl) (2-methoxy-2-oxoethyl)amino]piperidine- 1-carboxylate To a stirred mixture of 2,7-dichloro-l,6-naphthyridine (1.12 g, 5.627 mmol, 0.90 equiv) and tert-butyl 4-[(2-methoxy-2-oxoethyl)amino]piperidine-l-carboxylate (1.70 g, 6.242 mmol, 1 equiv) was added DIEA (2.42 g, 18.724 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere.
  • Methyl 2-[(7-chloro-l,6-naphthyridin-2-yl) (piperidin-4-yl)amino] acetate To a stirred solution of tert-butyl 4-[(7-chloro-l,6-naphthyridin-2-yl) (2-methoxy-2- oxoethyl)amino]piperidine-l-carboxylate (800 mg) in MeOH (20 mL) was added HCl(gas)in 1,4-dioxane (20 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.
  • Methyl 2-[(7-chloro-l,6-naphthyridin-2-yl) (l-methylpiperidin-4-yl)amino]acetate To a stirred mixture of methyl 2-[(7-chloro-l,6-naphthyri din-2 -yl) (piperidin-4-yl)amino]acetate (Step 3 from synthesis of Compound 101, 120 mg, 0.358 mmol, 1 equiv) and HCHO (16.14 mg, 0.538 mmol, 1.50 equiv) in THF (15 mL) were added TEA (72.54 mg, 0.717 mmol, 2 equiv) and NaBH(OAc)3 (113.95 mg, 0.538 mmol, 1.50 equiv) in portions at 0 °C under nitrogen atmosphere.
  • TEA 72.54 mg, 0.717 mmol, 2 equiv
  • NaBH(OAc)3
  • the resulting mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the reaction mixture was purified by reverse phase flash with the following conditions (ColummCl 8,330 g; Mobile Phase A:Water/0.05% NH4HCO3, Mobile Phase B:ACN; Flow rate:80 mL/min; Gradient: 40%B to 70%B in 20 min; Detector, 254nm, Monitor, 220 nm, the desired product were collected at 62%B) to afford tert-butyl 4-[(7-chloro-l,6-naphthyridin-2-yl)amino]piperidine-l- carboxylate (3 g, 82%) as a yellow solid.
  • the crude product was purified by reverse phase flash with the following conditions (Column:C18,330 g; Mobile Phase A:Water/0.05% NH4HCO3, Mobile Phase B:ACN; Flow rate: 80 mL/min; Gradient: 40%B to 70%B in 20 min; Detector, 254nm, Monitor, 220 nm, the desired product were collected at 65%B) to afford tert-butyl 4- [[7-([2-fluoro-4-[3-(hydroxymethyl)pyrazol-l-yl]phenyl]amino)-l,6-naphthyridin-2- yl]amino]piperidine-l-carboxylate (215 mg, 97%) as a white solid.
  • the resulting mixture was stirred for 2 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ACN (10 mL). The mixture was basified to pH 8 with saturated NaHCCb (aq.). The resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 um, 330 g; Mobile Phase A: Water (plus 5 mM NH4CO3); Mobile Phase B: ACN; Flow rate: 85mL/min; Gradient: 5% - 5% B, 10 min, 30% B - 75% B gradient in 20 min; Detector: 254 nm.
  • the fractions containing the desired product were collected at 38% B and concentrated under reduced pressure to afford desired product (35 mg mixture).
  • Compound 545 was synthesized following the methods and protocols as described for the synthesis of Compounds 103 and 105, starting with the appropriate materials.
  • the crude product was purified by reverse phase flash with the following conditions (ColummC 18,330 g; Mobile Phase A:Water/0.05%TFA, Mobile Phase B:ACN; Flow rate:80 mL/min; Gradient: 40%B to 70%B in 20 min; Detector, 220nm, Monitor, 254 nm, the desired product were collected at 70%B) to afford tert-butyl 4-[N-(7-chloro-l,6-naphthyridin-2- yl)methanesulfonamido]piperidine-l -carboxylate (200 mg, 66%) as a yellow oil.
  • Tert-butyl 4-[N-(7-chloro-l,6-naphthyridin-2-yl)-2-methoxy-2-oxoacetamido]piperidine- 1-carboxylate To a stirred mixture of tert-butyl 4-[(7-chloro-l,6-naphthyridin-2- yl)amino]piperidine-l-carboxylate (from step 1 of synthesis of Compound 102, 50 mg, 0.138 mmol, 1 equiv) and TEA (27.89 mg, 0.276 mmol, 2 equiv) in DCM (10 mL) was added methyl oxalochloridate (25.32 mg, 0.207 mmol, 1.50 equiv) dropwise at 0 °C.
  • the resulting mixture was stirred for 16 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for 5 hours at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure.
  • 1-tert-butyl 3-methyl 4-amino-5,6-dihydro-2H-pyridine-l,3-dicarboxylate To a stirred solution of 1-tert-butyl 3-methyl 4-oxopiperidine-l,3-dicarboxylate (4 g, 15.547 mmol, 1 equiv) in MeOH (100 mL) was added MLOAc (3.60 g, 46.641 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 16 hours at room temperature. The reaction was monitored by TLC. The resulting mixture was extracted with DCM (3 x 200 mL).
  • 1-tert-butyl 3-methyl 4-[(7-chloro-l,6-naphthyridin-2-yl)amino]piperidine-l,3- dicarboxylate To a stirred mixture of 1-tert-butyl 3-methyl 4-aminopiperi dine- 1,3- dicarboxylate (500 mg, 1.936 mmol, 1 equiv) and 2,7-dichloro-l,6-naphthyridine (192.62 mg, 0.968 mmol, 0.5 equiv) in THF (5 mL) was added DIEA (250.16 mg, 1.936 mmol, 1 equiv) at room temperature.
  • the resulting mixture was stirred for 16 hours at 110 °C.
  • the reaction was monitored by LCMS.
  • the mixture was allowed to cool down to room temperature.
  • the crude product was purified by reverse phase flash with the following conditions (ColummC 18,330 g; Mobile Phase A:Water/0.05% TFA, Mobile Phase B:ACN; Flow rate: 80 mL/min; Gradient: 20%B to 50%B in 20 min; Detector, 254nm and 220 nm, the desired product were collected at 50%B) to afford 1-tert-butyl 3-methyl 4-[(7-chloro-l,6- naphthyri din-2 -yl)amino]piperi dine- 1, 3 -dicarboxylate (500 mg, 61%) as a white solid.
  • the reaction mixture was purged with nitrogen for 3 times and stirred under nitrogen atmosphere at 100 °C for 2 hours.
  • the resulting mixture was cooled down to ambient temperature and filtered.
  • the filter cake was washed with ethyl acetate (3 x 10.0 mL).
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse phase flash chromatography. The fractions containing the desired product were collected and concentrated under reduced pressure to afford the title compound (0.27 g, 38%) as a yellow solid.

Abstract

L'invention concerne des composés ayant la formule structurale I, et des sels et des compositions pharmaceutiques associés. L'invention concerne également des méthodes thérapeutiques, par exemple pour traiter des maladies et des états pathologiques tels que la néphropathie, l'insuffisance rénale, les calculs rénaux ou la polykystose rénale, à l'aide des composés de formule (I), et des sels et des compositions pharmaceutiques associés.
PCT/US2021/041106 2020-07-10 2021-07-09 Inhibiteurs de cdk5 de type 1,6-naphtyridine substituée WO2022011274A1 (fr)

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WO2023231966A1 (fr) * 2022-05-30 2023-12-07 赛诺哈勃药业（成都）有限公司 Utilisation d'un dérivé de tétrahydronaphtyridine pour préparer un produit permettant d'améliorer l'hyperpigmentation

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