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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions

• compositions comprising an effective amount of such compounds, and methods for treating or preventing liver fibrotic disorders or a condition treatable or preventable by inhibition of a JNK pathway, comprising administering an effective amount of such diaminocarboxamide and diaminocarbonitrile pyrimidine compounds to a subject in need thereof.
• JNK is a ubiquitously expressed serine/threonine kinase belonging, together with ERK (extracellular-regulated kinase) and p38, to the family of mitogen-activated protein kinases (MAPKs).
• MAPKs mitogen-activated protein kinases
• JNK also phosphorylates non-nuclear proteins, for example, IRS-1, and Bcl-2 family members.
• the mitogen activated protein (MAP) kinases participate in the transduction of signals to the nucleus of the cell in response to extracellular stimuli.
• MAP kinases from the ER p38 and JNK iso forms include but are not limited to, mitogen- activated protein kinase 1 (ERK2), mitogen-activated protein kinase 8 (JNK1), mitogen- activated protein kinase 9 (MAPK9 or JNK2), mitogen-activated protein kinase 10 (MAPK10 or JNK3) and mitogen-activated protein kinase 14 (MAPK14 or p38alpha).
• MAP kinases are a family of proline-directed serine/threonine kinases that mediate signal transduction from extracellular receptors or heat shock, osmotic stress, reactive oxidant species (ROS) or UV radiation. [See Sridhar et al., Pharmaceutical Research, 17: 11 1345- 1353 (2000)]. MAP kinases are activated via the phosphorylation of theonine and tyrosine by upstream dual-specificity protein kinases, including MK and MEK kinases. Cell proliferation and differentiation have been shown to be under the regulatory control of multiple MAP kinase cascades. [See Sridhar et al., Pharmaceutical Research, 17: 11 1345- 1353 (2000)].
• MAP kinase pathway plays critical roles in a number of disease states. For example, defects in activities of MAP kinases have been shown to lead to aberrant cell proliferation and carcinogenesis. [See Hu et al., Cell Growth Differ.
• MAP kinase activity has also been implicated in insulin resistance associated with type-2 diabetes [See Virkamaki et al., J. Clin. Invest. 103:931-943 (1999)] and obesity. Changes in insulin resistance may have a direct impact on the metabolism of glucose and lipid in the liver contributing to the development of steatosis that may progress to liver fibrosis [Vallerie et al. Science Trans lational Medicine 2(60): 1-7 (2010)].
• FFA saturated or unsaturated free fatty acids
• JNK2-/- mice are partially protected from steatosis and apoptosis by saturated FFA (e.g. stearic acid) but not by unsaturated FFA [Malhi et al. J.Biol. Chem. 281 : 12093-12101 (2006)]. JNK1-/- mice were not protected from FFA induced injury. The role of XNKl and XNK2 has been studied in CDAA-fed mice that progressed from steatosis to steatohepatitis to
• JNKl-/- macrophages do not express IL-1, IL-6, TNF and NO in response to LPS [Sanchez-Tillo et al, J Biol Chem. 282(17): 12566-73 ("2007)], and Kupffer cells derived from JNKl -/- mice or from wild-type mice and treated with JNK inhibitor SP600125 display reduced TNF, IL-6, and IL-1 expression in response to LPS [Kodama et al, Gastroenterology 137: 1467-1477 (2009)].
• a compound of formula (I) or formula (IB) or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer or prodrug thereof (each being referred to herein as an "Diaminopyrimidine Compound") is useful for treating or preventing liver fibrotic disorders, or diabetes and/or metabolic syndrome leading to liver fibrotic disorders, as described herein.
• a Diaminopyrimidine Compound is useful for treating or preventing a condition treatable or preventable by inhibition of a JNK pathway, as described herein.
• Diaminopyrimidine Compounds as described in the instant disclosure such as, for example, in Tables 1, 2 and 3.
• compositions comprising an effective amount of a Diaminopyrimidine Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
• the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.
• liver fibrotic disorders such as non-alcoholic steatohepatitis, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, and liver fibrosis coincident with chronic or repeated alcohol ingestion, with infection, with liver transplant, or with drug induced liver injury, comprising administering to a subject in need thereof an effective amount of a Diaminopyrimidine Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle.
• provided herein are methods for treating or preventing diabetes or metabolic syndrome leading to liver fibrotic disorders, such as non-alcoholic steatohepatitis, steatosis, hepatitis, or cirrhosis, comprising administering to a subject in need thereof an effective amount of a Diaminopyrimidine Compound. Also provided herein are methods for treating or
• ATI-2514175vl preventing a condition treatable or preventable by inhibition of a JNK pathway, comprising administering to a subject in need thereof an effective amount of a
• a kinase for example JNK1, JNK2 or both
• methods for inhibiting a kinase comprising contacting said cell with an effective amount of a Diaminopyrimidine Compound as described herein.
• alkyl group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms.
• alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl,
• alkyl group can be substituted or unsubstituted.
• the alkyl groups described herein may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;
• ATI- 2 514175vl sulfonamide ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;
• a "cycloalkyl” group is a saturated, partially saturated, or unsaturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with from 1 to 3 alkyl groups.
• the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.
• Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
• unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others.
• a cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
• aryl group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryls include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase "aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
• a "heteroaryl” group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms.
• heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen.
• the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl,
• ATI- 2 514175vl isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl
• indolyl-2-onyl or isoindolin-l-onyl e.g., indolyl-2-onyl or isoindolin-l-onyl
• azaindolyl pyrrolopyridyl or lH-pyrrolo[2,3- b]pyridyl
• indazolyl benzimidazolyl (e.g., lH-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl)
• pyrazolopyridyl triazolopyridyl
• benzotriazolyl e.g., lH-benzo[d][l,2,3]triazolyl
• benzoxazolyl e.g., benzo[d]oxazolyl
• benzothiazolyl benzothiadiazolyl,
• heterocyclyl is an aromatic (also referred to as heteroaryl) or non- aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
• heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.
• Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring).
• a heterocycloalkyl group can be substituted or unsubstituted.
• Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl) groups.
• heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1-and 2-aminotetraline, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzimidazolyl (e.g., lH-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl.
• the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
• heterocyclyl group examples include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazol
• dithianyl pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-l-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or lH-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g. lH-benzo[d][l,2,3]triazolyl),
• non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group.
• non- aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl
• substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.
• a "cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl
• cycloalkylalkyl groups include but are not limited to methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl,
• An "aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
• heterocyclylalkyl is a radical of the formula: -alkyl- heterocyclyl, wherein alkyl and heterocyclyl are defined above. Substituted
• heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group.
• Representative heterocylylalkyl groups include but are not limited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
• a "halogen” is fluorine, chlorine, bromine or iodine.
• a "hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
• alkoxy is -O-(alkyl), wherein alkyl is defined above.
• alkoxyalkyl is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
• amino group is a radical of the formula: -NH 2 .
• alkylamino is a radical of the formula: -NH-alkyl or -N(alkyl) 2 , wherein each alkyl is independently as defined above.
• a "carboxy” group is a radical of the formula: -C(0)OH.
• aminocarbonyl is a radical of the formula: -C(0)N(R ) 2 ,
• acylamino is a radical of the formula: -NHC(0)( R ) or
• a "sulfonylamino" group is a radical of the formula: -NHS0 2 (R ) or
• a "urea” group is a radical of the formula: -N(alkyl)C(0)N(R ) 2 ,
• substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxy
• pyrrolidyl e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl
• monocyclic or fused or non- fused polycyclic aryl or heteroaryl e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl,
• benzimidazolyl benzothiophenyl, or benzofuranyl
• aryloxy aralkyloxy
• heterocyclyloxy aralkyloxy
• heterocyclyl alkoxy aralkyloxy
• Diaminopyrimidine Compound refers to compounds of formula (I) and formula (IB) as well as to further embodiments provided herein.
• a “Diaminopyrimidine Compound” is a compound set forth in Tables 1, 2 and 3.
• the term “Diaminopyrimidine Compound” includes pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers, and prodrugs of the compounds provided herein.
• pharmaceutically acceptable salt(s) refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an
• Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine,
• non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic,
• Non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids.
• Examples of specific salts thus include hydrochloride and mesylate salts.
• Others are well-known in the art, see for example, Remington 's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).
• prodrug means a
• Diaminopyrimidine Compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a Diaminopyrimidine Compound or a compound of formula (I).
• prodrugs include, but are not limited to, derivatives and metabolites of a Diaminopyrimidine Compound that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
• biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
• prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
• the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
• Prodrugs can typically be prepared using well-known methods, such as those described by Burger 's Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed., 2001, Wiley)
• stereomerically pure means one stereoisomer of a Diaminopyrimidine Compound that is substantially free of other stereoisomers of that compound.
• a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
• a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
• stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20%> by weight of other stereoisomers of the compound, greater than about 90%> by weight of one stereoisomer of the compound and less than about 10%> by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
• the Diaminopyrimidine Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
• mixtures comprising equal or unequal amounts of the enantiomers of a particular Diaminopyrimidine Compound may be used in methods and compositions disclosed herein.
• These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.
• Diaminopyrimidine Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
• the Diaminopyrimidine Compounds are isolated as either the E or Z isomer. In other embodiments, the Diaminopyrimidine Compounds are a mixture of the E and Z isomers.
• Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
• concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
• pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
• Diaminopyrimidine Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
• an “isotopologue” is an isotopically enriched compound.
• the term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic
• isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
• isotopic composition refers to the amount of each isotope present for a given atom.
• Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Diaminopyrimidine Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments
• isotopologues of the Diaminopyrimidine Compounds for example, the isotopologues are deuterium, carbon-13, or nitrogen- 15 enriched Diaminopyrimidine Compounds.
• JNK means a protein or an isoform thereof expressed by a JNKl , JNK2, or JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard, B. and Davis, R.J. The EMBO J. 15:2760-2770 (1996)).
• Treating means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
• the disorder is a liver fibrotic disorder, such as non-alcoholic steatohepatitis, steatosis (i.e.
• liver fatty liver
• cirrhosis primary sclerosing cholangitis
• primary biliary cirrhosis primary biliary cirrhosis
• hepatitis hepatocellular carcinoma
• infection e.g. viral infection such as HCV
• liver transplant or with drug induced liver injury
• treating means an alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with diabetes or metabolic syndrome leading to liver fibrotic disorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), hepatitis or cirrhosis, or a slowing, or halting of further progression or worsening of those symptoms.
• the symptom is jaundice.
• "treating" means and alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with a condition, treatable or preventable by inhibition of a INK pathway.
• Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
• the disorder is a liver fibrotic disorder, or diabetes or metabolic syndrome leading to liver fibrotic disorders, as described herein, or symptoms thereof.
• the disorder is a condition, treatable or preventable by inhibition of a JNK pathway.
• Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.
• subject includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.
• a subject is a human having or at risk for having liver fibrotic disorders or diabetes or metabolic syndrome leading to liver fibrotic disorders, or a condition, treatable or preventable by inhibition of a TNK pathway, or a symptom thereof.
• Pv 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that Pv 1 is not 1-aminocyclohexyl; and
• R 2 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.
• the compound of formula (I) is not:
• R 1 is not
• R 1 is a branched
• Ci_8 alkyl for example, R 1 is isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl,
• R 1 is isopropyl, sec-butyl, isobutyl, tert-butyl, 2,3-dimethylbutyl, isopentyl, 2-methylpentyl, neopentyl, tert-pentyl, or 3-methylpentyl.
• R 1 is a substituted or unsubstituted cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[l . l . l]pentyl, or bicyclo[2.2.2]octyl.
• the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,
• the cycloalkyl is substituted with one or more halogen, -(Ci_ 4 alkyl), -NR 2 , -(C 0 _ 3 alkyl)OR, -NRC(0)R', -C(0)R', -C(0)NR 2 , -C(0)OR', or -NRS(0) 2 R', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• the cycloalkyl is substituted with one or more methyl, ethyl, t-butyl, -F, -OH, -OCH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -CH 2 OH, -CH 2 OCH 3 , -C(CH 3 ) 2 OH, -NH 2 , -NH(CH 3 ), -NHC(0)CH 3 ,
• the cycloalkyl is substituted with one or more halogen, -CF 3 , -(Ci_ 4 alkyl), -(Ci_ 6 cycloalkyl), -NR 2 , -(Co-3 alkyl)OR, -(C 0 _ 3 alkyl)OR", -NRC(0)R', -C(0)R', -C(0)NR 2 , -C(0)OR', or -NRS(0) 2 R', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R" is independently a Ci_ 6 cycloalkyl, wherein the cycloalkyl is optionally fluorinated.
• the cycloalkyl is substituted with one or more methyl, ethyl, t-butyl, cyclopropyl, -CF 3 , -F, -OH, -OCH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(cyclopropyl), -CH 2 OH, -CH 2 OCH 3 , -C(CH 3 ) 2 OH, -NH 2 , -NH(CH 3 ), -NHC(0)CH 3 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , or -NHS0 2 CH 3 .
• R 1 is a substituted or unsubstituted non-aromatic heterocyclyl, for example, pyrrolidinyl, tetrahydropyranyl, l,4-dioxaspiro[4.5]decanyl, or piperidyl.
• the non-aromatic heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydropyranyl,
• R 1 is a substituted or unsubstituted alkylcycloalkyl, for example, (Ci_ 3 alkyl)cyclopropyl, (Ci_ 3 alkyl)cyclobutyl,
• R 1 is -(CH 2 )cyclopropyl, -(CH 2 )cyclobutyl, -(CH 2 )cyclopentyl, -(CH 2 )cyclohexyl,
• R 1 is -(CH 2 )cyclopropyl, -CH(CH 3 )cyclopropyl, -CH(CH 3 )cyclobutyl,-CH(CH 3 )cyclohexyl, or -C(CH 3 ) 2 cyclopropyl.
• R 1 is a substituted or unsubstituted alkylheterocyclyl, for example,
• R 1 is selected from branched Ci_g alkyl
• R 3' is halogen, -CF 3 , -(Ci_ 4 alkyl), -(Ci_ 6 cycloalkyl), -NR 2 , -(C 0 _ 3 alkyl)OR, -(Co-3 alkyl)OR", -NRC(0)R', -C(0)R ⁇ -C(0)NR 2 , -C(0)OR', or -NRS(0) 2 R';
• R 4' is -C(0)R', or -C(0)OR'
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R" is independently a Ci_ 6 cycloalkyl wherein the cycloalkyl is optionally fluorinated;
• n 0-2.
• R 3 is methyl, ethyl, t-butyl, cyclopropyl, -CF 3 ,
• R 2 is a substituted or unsubstituted Ci_ 8 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, tert-pentyl, isopentyl, or 2-methylpentyl.
• R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 3-methylbutyl,
• R 2 is substituted with one or more -(CM alkyl), -(C 0 _ 3 alkyl)OR, -C(0)NR 2 or -NRCOR', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 2 is substituted with one or more -OH, or -CH 3 .
• R 2 is substituted with one or more -OH, -OCH 3 , or -CH 3 .
• R 2 is a substituted or unsubstituted cycloalkyl, for example, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
• R 2 is substituted with one or more -(C 1-4 alkyl), -(C 0-3 alkyl)OR, -(Co-3 alkyl)C(0)NR 2 , -NR 2 , or -NRCOR', wherein each R is independently H, or
• Ci_ 4 alkyl wherein the alkyl is optionally fluorinated
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
• R 2 is substituted with one or more -CF 3 , -(C 1-4 alkyl), -(Ci_ 6 cycloalkyl), -(Co-3 alkyl)OR, -(C 0 _ 3 alkyl)C(0)NR 2 , -NR 2 , or -NRCOR', wherein each R is
• R 2 is substituted with one or more methyl, ethyl, isopropyl, -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 , -C(0)NH 2 , - NHC(0)CH 3 , or -NHC(0)CH 2 CH 3 .
• R 2 is substituted with one or more methyl, ethyl, isopropyl, -cyclopropyl, -CF 3 , -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 , -C(0)NH 2 , - NHC(0)CH 3 , or -NHC(0)CH 2 CH 3 .
• R 2 is a substituted or unsubstituted alkylcycloalkyl, for example, a substituted or unsubstituted
• R 2 is -(CH 2 )cyclopropyl, -(CH 2 )cyclobutyl, -CH(CH 3 )cyclopropyl, -CH(CH 3 )cyclobutyl, -CH(CH 2 CH 3 )cyclopropyl,
• R 2 is a substituted or unsubstituted non-aromatic heterocyclyl, for example, tetrahydrofuranyl,
• R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinonyl or
• R 2 is substituted with one or more -(C 1-4 alkyl), -(C 0-3 alkyl)OR, or -C(0)R', wherein each R is independently H, or Ci_4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_4 alkyl, wherein the alkyl is optionally fluorinated.
• R 2 is a substituted or unsubstituted Ci_ 8 alkyl
• R 5 is -CF 3 , -(Ci_4 alkyl), -(Ci_ 6 cycloalkyl), -(C 0 _ 3 alkyl)OR, -(Co-3 alkyl)C(0)NR 2 , -NR 2 , or -NRCOR', wherein the cycloalkyl is optionally
• R 6 is H, or -C(0)R'
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• n 0-2.
• R 5 is methyl, ethyl, isopropyl, -cyclopropyl,
• R 6 ' is H or -C(0)CH 3 , -C(0)CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , or -C(0)CH 2 CH(CH 3 ) 2 .
• R 1 is a cycloalkyl, optionally substituted with one or more halogen, -CF 3 , -(C 1-4 alkyl), -(C 1-6 cycloalkyl), -NR 2 , -(C 0-3 alkyl)OR, -(Co-3 alkyl)OR", -NRC(0)R', -C(0)R', -C(0)NR 2 , -C(0)OR', or -NRS(0) 2 R', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, each
• ATI- 2 514175vl R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R" is independently a Ci_ 6 cycloalkyl., wherein the cycloalkyl is optionally fluorinated.
• the compound is selected from Table 2.
• R 3 is substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl-(non-aromatic heterocyclyl); and
• R 4 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.
• the compound is not
• R 3 is a branched
• Ci_8 alkyl for example, R 3 is isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl,
• R 3 is isopropyl, sec-butyl, isobutyl, tert-butyl, 2,3-dimethylbutyl, isopentyl, 2-methylpentyl, neopentyl, tert-pentyl, or
• R 3 is tert-butyl.
• R 3 is a substituted or unsubstituted cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[l . l . l]pentyl, or bicyclo[2.2.2]octyl.
• R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[l . l . l]pentyl, bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl.
• R 3 is cyclobutyl or cyclohexyl.
• the cycloalkyl is substituted with one or more halogen, -CF 3 , -(Ci_ 4 alkyl), -(Ci_ 6 cycloalkyl), -NR 2 ,
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R" is independently a Ci_ 6 cycloalkyl, wherein the cycloalkyl is optionally fluorinated.
• the cycloalkyl is substituted with one or more methyl, ethyl, t-butyl, cyclopropyl, -CF 3 , -F, -OH, -OCH 3 , -OCHF 2 , -OCF 3 ,
• the cycloalkyl is substituted with one or more halogen, -(Ci_ 4 alkyl), -NR 2 , -(C 0-3 alkyl)OR, -NRC(0)R', -C(0)R',
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• the cycloalkyl is substituted with one or more methyl, ethyl, t-butyl, -F, -OH, -OCH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CF 3 , -O(cyclopropyl), -CH 2 OH, -CH 2 OCH 3 ,
• the cycloalkyl is substituted with one or more methyl, -F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 , -OCH 2 CF 3 , -NH(CH 3 ), -NHC(0)CH 3 , -C(0)N(CH 3 ) 2 , or -C(CH 3 ) 2 C(0)N(CH 3 ) 2 .
• R 3 is a substituted or unsubstituted non-aromatic heterocyclyl, for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, l ,4-dioxaspiro[4.5]decanyl, or piperidyl.
• the non-aromatic heterocyclyl is oxetanyl, tetrahydrofuranyl,
• R 3 is tetrahydropyranyl.
• the piperidyl is substituted with -C(0)R', or -C(0)OR', wherein R' is Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 3 is a substituted or unsubstituted alkylcycloalkyl, for example, (C 1-3 alkyl)cyclopropyl, (C 1-3 alkyl)cyclobutyl, (C 1-3 alkyl)cyclopentyl, or (Ci_3 alkyl)cyclohexyl.
• R 3 is -(CH 2 )cyclopropyl, -(CH 2 )cyclobutyl, -(CH 2 )cyclopentyl, -(CH 2 )cyclohexyl, -CH(CH 3 )cyclopropyl, -CH(CH 3 )cyclobutyl, -CH(CH 3 )cyclopentyl, or -CH(CH 3 )cyclohexyl.
• R 3 is -(CH 2 )cyclopropyl, -CH(CH 3 )cyclopropyl, -CH(CH 3 )cyclobutyl, -CH(CH 3 )cyclohexyl, or
• R 3 is a substituted or unsubstituted alkyl- (non-aromatic heterocyclyl), for example, -(Ci_ 4 alkyl)tetrahydrofuranyl, or
• R 3 is selected from branched Ci_ 8 alkyl
• R 3' is halogen, -CF 3 , -(Ci_ 4 alkyl), -(Ci_ 6 cycloalkyl), -NR 2 , -(C 0 _ 3 alkyl)OR,
• R 4' is -C(0)R', or -C(0)OR'
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R" is independently a Ci_ 6 cycloalkyl, wherein the cycloalkyl is optionally fluorinated;
• n 0-2.
• R 3 is methyl, ethyl, t-butyl, cyclopropyl -CF 3 , -F,
• R 3 is selected from branched Ci_ 8 alkyl
• R 3' is halogen, -(C M alkyl), -NR 2 , -(C 0 _ 3 alkyl)OR, -NRC(0)R', -C(0)R', -(Co-3 alkyl)C(0)NR 2 , -C(0)OR', or -NRS(0) 2 R';
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• n 0-2.
• R 3 is methyl, ethyl, t-butyl, -F, -OH, -OCH 3 ,
• R 4 is a substituted or unsubstituted Ci_g alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, or tert-pentyl.
• R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 3-methylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 2,3,3-trimethylbutyl, tert-pentyl, isopentyl, 3-pentyl, 3-methylpentyl, 2-methylpentyl, or 2,4-dimethylpentyl.
• R 4 is isopropyl, isobutyl, isopentyl, tert-butyl, or tert-pentyl.
• R 4 is substituted with one or more -(Ci_ 4 alkyl), -(Co- 3 alkyl)OR, -C(0)NR 2 or -NRCOR', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 4 is substituted with one or more -OH, or -CH 3 .
• R 4 is a substituted or unsubstituted cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
• R 4 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[l . l .l]pentyl.
• R 4 is substituted with one or more halogen, -CF 3 , -(C 1-4 alkyl),
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and wherein the cycloalkyl is optionally fluorinated.
• R 4 is substituted with one or more methyl, ethyl, isopropyl, -cyclopropyl, -CF 3 , -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 ,
• R 4 is substituted with one or more halogen, -(C 1-4 alkyl), -(C 0-3 alkyl)OR, -(C 0-3 alkyl)C(0)NR 2 , -NR 2 , or -NRCOR', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 4 is substituted with one or more F, methyl, ethyl, isopropyl, -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 , -OCH 2 CF 3 , -C(0)NH 2 , -C(0)NHCH 3 , -C(0)N(CH 3 ) 2 , -CH 2 C(0)NH 2 , -CH 2 C(0)NHCH 3 ,
• R 4 is substituted with one or more methyl, ethyl, -F, -CH 2 OH, or -OH.
• R 4 is a substituted or unsubstituted non-aromatic heterocyclyl, for example, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinonyl or l,4-dioxaspiro[4.5]decanyl.
• R 4 is tetrahydrofuranyl or tetrahydropyranyl.
• R 4 is substituted with one or more -(Ci_ 4 alkyl), -(Co- 3 alkyl)OR, or -C(0)R', wherein each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated, and each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated.
• R 4 is a substituted or unsubstituted Ci_ 8 alkyl
• R 5 is -CF 3 , -(Ci_4 alkyl), -(Ci_ 6 cycloalkyl), -(C 0-3 alkyl)OR, -(Co-3 alkyl)C(0)NR 2 , -NR 2 , or -NRCOR', wherein the cycloalkyl is optionally
• R 6 is H, or -C(0)R'
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• n 0-2.
• R 5 is methyl, ethyl, isopropyl, -cyclopropyl,
• R 6 ' is H or -C(0)CH 3 , -C(0)CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , or -C(0)CH 2 CH(CH 3 ) 2 .
• R 4 is a substituted or unsubstituted Ci_g alkyl
• R 5 is halogen, -(C M alkyl), -(C0-3 alkyl)OR, -(C 0 _ 3 alkyl)C(0)NR 2 , -NR 2 , or
• each R is independently H, or Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated;
• n 0-2.
• R 5 is F, methyl, ethyl, isopropyl, -CH 2 OH, -OH,
• R 5 ' is F, -OH, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 , -OCH 2 CF 3 , -NH(CH 3 ), -NHC(0)CH 3 ,
• R 4 is a substituted or unsubstituted
• R 3 is a cycloalkyl, optionally substituted with one or more halogen, -CF 3 ,
• each R is independently H, or
• Ci_ 4 alkyl wherein the alkyl is optionally fluorinated
• each R' is independently Ci_ 4 alkyl, wherein the alkyl is optionally fluorinated
• each R" is independently a Ci_ 6 cycloalkyl, wherein the cycloalkyl is optionally fluorinated.
• Diaminopyrimidine Compounds set forth in Table 1 , Table 2, and Table 3 were tested in the JNK inhibitor assays described herein and were found to have activity as JNK inhibitors.
• the Diaminopyrimidine Compound is a compound as described herein, wherein the compound at a concentration of 10 ⁇ inhibits JNK1 by at least about 50% or more.
• Diaminopyrimidine Compounds can be made using conventional organic syntheses and commercially available starting materials.
• Diaminopyrimidine Compounds of formula (I) can be prepared as outlined in Schemes 1-9 shown below as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired products.
• compounds of formula (I), wherein R 1 and R 2 are as defined herein can be prepared starting from an appropriately derivatized 4-chloro-2- alkylthiopyrimidine carboxylate ester (wherein each R x is independently a Ci_ 2 alkyl), by treatment with R 2 NH 2 at elevated temperature (for example 60-80 °C) in an organic solvent (for example, ethanol, methanol, isopropanol, THF, NMP, DMF, DMSO, or dioxane), in the presence of a base (for example, DIEA, TEA, N-methylmorpholine, l ,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate).
• an organic solvent for example, ethanol, methanol, isopropanol, THF, NMP, DMF, DMSO, or dioxane
• a base for example, DIE
• Hydrolysis of the ester is achieved by treatment with an aqueous base, such as for example aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide, in a cosolvent such as ethanol, methanol, isopropanol, THF, or dioxane.
• aqueous base such as for example aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide
• a cosolvent such as ethanol, methanol, isopropanol, THF, or dioxane.
• Amide formation is accomplished by reaction with NH 4 C1 in the presence of a coupling agent (such as, for example, HATU, CDI, HBTU, EDC optionally in combination with HOBt, or ethyl chloroformate), in an organic solvent, such as NMP, DMF, DMSO, dioxane, THF, DCM, or chloroform, in the presence of a base (such as DIEA, TEA, or potassium carbonate).
• a coupling agent such as, for example, HATU, CDI, HBTU, EDC optionally in combination with HOBt, or ethyl chloroformate
• organic solvent such as NMP, DMF, DMSO, dioxane, THF, DCM, or chloroform
• a base such as DIEA, TEA, or potassium carbonate
• ATI- 2 514175vl moiety is achieved by treatment in an organic solvent (such as, for example, acetone, DCM, NMP, DMF, or chloroform) with an oxidant such as mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l,2-oxaziridine.
• an organic solvent such as, for example, acetone, DCM, NMP, DMF, or chloroform
• an oxidant such as mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l,2-oxaziridine.
• R 2 NH 2 in a solvent (such as dioxane, NMP, DMF, DMSO, THF, or water), in the presence
• a solvent such as dioxane, NMP, DMF, DMSO, THF, or water
• ATI- 2 514175vl of an organic base such as DIEA, TEA, l,8-diazabicyclo[5.4.0]undec-7-ene, or N-methylmorpholine
• elevated temperature e.g. 80- 110 °C
• N-methylmorpholine, sodium bicarbonate, cesium carbonate, or potassium phosphate at low temperature (for example, -70 °C) provides introduction of the R 2 sidechain.
• a base for example, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, l,8-diazabicyclo[5.4.0]undec-7-ene,
• R 2 R 4 , compounds of formula (IB)).
• ATI- 2 514175vl the presence of a base (such as, for example, DIEA, TEA, N-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate), at a temperature between 50 °C and 90 °C) introduces the R 1 sidechain.
• a base such as, for example, DIEA, TEA, N-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate
• ATI- 2 514175vl introduces the R 1 sidechain.
• Introduction of the carbonitrile moiety is achieved by treatment with zinc and dicyanozinc in a solvent (such as DMF, DMSO, NMP, or DMA) in the presence of a catalyst such as Pd(O), at elevated temperature (for example, between 80 °C - 100 °C).
• a solvent such as DMF, DMSO, NMP, or DMA
• Pd(O) a catalyst
• conversion to the amide moiety by treatment with peroxide, followed by oxidation to the sulfone/sulfoxide, and treatment with R 2 NH 2 provides the compounds of formula (I).
• Diaminopyrimidine Compounds of Formula (IB), wherein R 3 and R 4 are as defined herein, can be made as outlined in Schemes 7, 8 and 9 shown below, as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired roduct.
• coupling with R 4 NH 2 is performed at a temperature between room temperature and 1 10 °C.
• compounds of formula (IB) can be prepared starting from an appropriately derivatized 4-chloro-2-alkylthiopyrimidine-carbonitrile (wherein each R x is independently a Ci_ 2 alkyl), by treatment with R 4 NH 2 at elevated temperature (for example 50 °C - 90 °C) in an organic solvent (for example, n-butanol, NMP, DMF, DMSO, or dioxane), in the presence of a base (for example, DIEA, TEA,
• Oxidation of the alkylthiol moiety is achieved by treatment in an organic solvent (such as, for example, DCM, NMP, DMF, or DMA) with an oxidant such as mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l ,2-oxaziridine.
• a solvent such as, for example, dioxane, DMSO, NMP, DMF, THF, or n-butanol
• an organic base such as DIEA, TEA, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine
• R 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that R is not 1-aminocyclohexyl;
• R 2 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl;
• R x is a Ci_2 alkyl
• n 1 or 2.
• the compound of formula (I) is not 2-(2-aminoethyl-amino)- 4-(methylamino)pyrimidine-5-carboxamide; 2-(2-aminopropylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-amino-2-oxoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-aminoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; (S)-2-(2-aminopropylamino)-4- (cyclobutylamino)pyrimidine-5 -carboxamide; (R)-2-( 1 -amino-3 -methyl- 1 -oxobutan-2- ylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-
• ATI-2514175vl (methylamino)pyrimidine-5 -carboxamide; or 2-( 1 -acetylpiperidin-4-ylamino)-4- (cyclopropylamino)pyrimidine-5-carboxamide.
• the solvent is dioxane, DMSO, NMP, DMF, THF, or water.
• the base is DIEA, TEA, l,8-diazabicyclo[5.4.0]undec-7-ene, or N-methylmorpholine.
• the contacting is performed at elevated temperature, for example, from about 80 °C to about 100 °C.
• the methods further comprise preparing a compound of formula (la):
• oxidant selected from mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l,2-oxaziridine.
• the solvent is acetone, DCM, NMP, DMF, or chloroform.
• the method is performed at a temperature between about 0 °C to about 20 °C.
• the methods further comprise preparing a compound of formula (lb):
• the solvent is NMP, DMF, DMSO, dioxane, THF,
• the coupling agent is HATU, CDI, HBTU, EDC/HOBt, or ethyl chloro formate
• the base is DIE A, TEA, or potassium carbonate.
• the methods further comprise preparing a compound of formula (Ic)
• the aqueous base is aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide.
• the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.
• the methods further comprise preparing a compound of formula (Id)
• the organic solvent is ethanol, methanol, isopropanol, THF, NMP, DMF, DMSO, or dioxane.
• the base is DIEA, TEA, N-methylmorpholine, l,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate.
• the contacting is performed at elevated temperature, for example, from about 60 °C to about 80 °C.
• the methods further comprise preparing a compound of formula (lb)
• ATI- 2 514175vl with peroxide in the presence of a base, in a solvent.
• the solvent is DMSO, NMP, DMF, ethanol, or methanol.
• the base is sodium hydroxide or potassium hydroxide.
• the methods further comprise preparing a compound of formula (If)
• the organic solvent is n-butanol, NMP, DMF, DMSO, dioxane, or ethanol.
• the base is DIEA, TEA, N-methylmorpholine,
• the contacting is performed at elevated temperature, for example, from about 50 °C to about 90 °C.
• R 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 1-aminocyclohexyl;
• R 2 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl;
• R x is a Ci_ 2 alkyl
• n 1 or 2.
• the compound of formula (I) is not 2-(2-aminoethyl- amino)-4-(methylamino)pyrimidine-5-carboxamide; 2-(2-aminopropylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-amino-2-oxoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-aminoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; (S)-2-(2-aminopropylamino)-4- (cyclobutylamino)pyrimidine-5 -carboxamide; (R)-2-( 1 -amino-3 -methyl- 1 -oxobutan-2- ylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-
• the solvent is dioxane, DMSO, NMP, DMF, THF, or water.
• the base is DIEA, TEA, l ,8-diazabicyclo[5.4.0]undec-7-ene, or N-methylmorpholine.
• the contacting is performed at elevated temperature, for example, from about 80 °C to about 1 10 °C.
• the methods further comprise preparing a compound of formula (II a):
• oxidant selected from mCPBA, oxone,hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l,2-oxaziridine.
• the solvent is acetone, DCM, NMP, DMF, or chloroform.
• the oxidizing is performed at low temperature, for example, at about 0 °C.
• the methods further comprise preparing a compound of formula (lib):
• the solvent is NMP, DMF, DMSO, dioxane, THF,
• the coupling agent is HATU, CDI, HBTU, EDC/HOBt, or ethyl chloro formate
• the base is DIE A, TEA, or potassium carbonate.
• the methods further comprise preparing a compound of formula (lie)
• the aqueous base is aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide.
• the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.
• the methods further comprise preparing a compound of formula (lid)
• the organic solvent is dioxane, THF, NMP, DMF,
• the base is DIEA, TEA,
• the contacting is performed at elevated temperature, for example, from about 80 °C to about 100 °C.
• the methods further comprise preparing a compound of formula (He)
• the solvent is THF, DCM, or dioxane.
• the catalyst is triethylbenzylammonium chloride, tetrabutylammonium chloride, or tetrabutylammonium bromide. In some embodiments, the contacting is performed under cooling for example, about -10 °C.
• the methods further comprise preparing a compound of formula (lib):
• the solvent is DMSO, NMP, DMF, ethanol, or methanol.
• the base is sodium hydroxide or potassium hydroxide.
• the methods further comprise preparing a compound of formula (Ilg)
• the catalyst is Pd(0).
• the solvent is DMF, DMSO, NMP, or DMA.
• the contacting is performed at elevated temperature, for example at a temperature between about 80 °C and about 100 °C.
• the methods further comprise preparing a compound of formula (Ilh)
• the organic solvent is n-butanol, NMP, DMF,
• the contacting is performed at elevated temperature, for example at a temperature between about 80 °C and about 100 °C.
• R 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 1-aminocyclohexyl; and
• ATI- 2 514175vl R 2 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl.
• the compound of formula (I) is not 2-(2-aminoethyl- amino)-4-(methylamino)pyrimidine-5-carboxamide; 2-(2-aminopropylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-amino-2-oxoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-aminoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; (S)-2-(2-aminopropylamino)-4- (cyclobutylamino)pyrimidine-5 -carboxamide; (R)-2-( 1 -amino-3 -methyl- 1 -oxobutan-2- ylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-
• the solvent is NMP, DMF, DMSO, dioxane, THF,
• the coupling agent is HATU, CDI, HBTU, EDC/HOBt, or ethyl chloro formate
• the base is DIE A, TEA, or potassium carbonate.
• the methods further comprise preparing a compound of formula (Ilia):
• the aqueous base is aqueous sodium hydroxide, potassium hydroxide, or lithium hydroxide.
• the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.
• the method further comprise preparing a compound of formula (Illb):
• the organic solvent is THF, NMP, DMF, DMSO, dioxane, ethanol, methanol, or isopropanol.
• the organic base is DIEA, TEA, l,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate.
• the contacting is performed at elevated temperature, for example, about 70 °C.
• the methods further comprise preparing a compound of formula (IIIc)
• the solvent is ethyl ether, THF, DCM, toluene, or methyl tert-butyl ether.
• the base is DIEA, TEA, l ,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, sodium bicarbonate, cesium carbonate, or potassium phosphate.
• the contacting is performed at low temperature, for example, about -70 ° C.
• R 1 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkylheterocyclyl, provided that R 1 is not 1-aminocyclohexyl; and
• R 2 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted saturated cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl.
• the compound of formula (I) is not 2-(2-aminoethyl- amino)-4-(methylamino)pyrimidine-5-carboxamide; 2-(2-aminopropylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-amino-2-oxoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; 2-(2-aminoethylamino)-4- (cyclohexylamino)pyrimidine-5-carboxamide; (S)-2-(2-aminopropylamino)-4- (cyclobutylamino)pyrimidine-5 -carboxamide, (R)-2-( 1 -amino-3 -methyl- 1 -oxobutan-2-
• the solvent is DMSO, NMP, DMF, ethanol or methanol.
• the strong aqueous base is such as sodium hydroxide or potassium hydroxide.
• the methods further comprise preparing a compound of formula (IVa):
• the organic solvent is 1-butanol, THF, NMP, DMF,
• the contacting is performed at elevated temperature, for example, about 120 °C.
• the methods further comprise preparing a compound of formula (IVb):
• the organic solvent is ethanol, methanol, isopropanol or THF.
• the base is DIEA, TEA, l,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate.
• the contacting is performed at low temperature, for example, about -60 °C.
• the methods further comprise preparing a compound of formula (IVa):
• the organic solvent is DCM, NMP, DMF, or DMA.
• the base is DIEA, TEA, l,8-diazabicyclo[5.4.0]undec-7-ene, or
• the contacting is performed at a temperature between room temperature and about 130 °C.
• the methods further comprise preparing a compound of formula (IVd):
• oxidant selected from mCPBA, oxone,hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l ,2-oxaziridine.
• the solvent is DCM, NMP, DMF, or DMA.
• the oxidizing is performed at a temperature from about 0 °C to about room temperature.
• R 3 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl-(non-aromatic heterocyclyl); and
• ATI- 2 514175vl R 4 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.
• the compound is not 4-(isopentylamino)-2-(3-(2- methylpiperidin-l-yl)propylamino)pyrimidine-5-carbonitrile; (2S,2'S)-dimethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(4-methylpentanoate); (2S,2'S)-diethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(3-methylbutanoate); 4-(cycloheptylamino)-2- (3-(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5-carbonitrile; 4-(4-methylcyclo- hexylamino)-2-(3 -(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5 -carbonitrile; 4-(4-methyl
• the organic solvent is 1-butanol, THF, NMP, DMF,
• the contacting is performed at elevated temperature, for example, from about 50 °C to about 90 °C.
• the methods further comprise preparing a compound of formula (Va):
• the organic solvent is ethanol, methanol,
• the base is DIEA, TEA, l ,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate, or
• the contacting is performed at low temperature, for example, from about -70 °C to about 20 °C.
• R 3 is substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl-(non-aromatic heterocyclyl); and
• R 4 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.
• the compound is not 4-(isopentylamino)-2-(3-(2- methylpiperidin-l-yl)propylamino)pyrimidine-5-carbonitrile; (2S,2'S)-dimethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(4-methylpentanoate); (2S,2'S)-diethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(3-methylbutanoate); 4-(cycloheptylamino)-2- (3-(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5-carbonitrile; 4-(4-methylcyclo- hexylamino)-2-(3 -(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5 -carbonitrile; 4-(4-methyl
• the organic solvent is 1-butanol, NMP, DMF,
• the base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, l ,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, DIEA, or TEA.
• the contacting is performed at elevated temperature, for example, from about 25 °C to about 1 10 °C.
• the methods further comprise preparing a compound of formula (Via):
• the organic solvent is ethanol, methanol, isopropanol or THF.
• the base is DIEA, TEA, l ,8-diazabicyclo[5.4.0]undec-7- ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate, or potassium phosphate.
• the contacting is performed at low
• R 3 is substituted or unsubstituted Ci_g alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted
• R 4 is substituted or unsubstituted Ci_ 8 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl;
• R x is Ci_2 alkyl
• n 1 or 2.
• the compound is not 4-(isopentylamino)-2-(3-(2- methylpiperidin-l-yl)propylamino)pyrimidine-5-carbonitrile; (2S,2'S)-dimethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(4-methylpentanoate); (2S,2'S)-diethyl 2,2'-(5- cyanopyrimidine-2,4-diyl)bis(azanediyl)bis(3-methylbutanoate); 4-(cycloheptylamino)-2- (3-(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5-carbonitrile; 4-(4-methylcyclo- hexylamino)-2-(3 -(2-methylpiperidin- 1 -yl)propylamino)pyrimidine-5 -carbonitrile; 4-(4-methyl
• the solvent is dioxane, DMSO, NMP, DMF, THF, or n-butanol.
• the base is DIEA, TEA, l ,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine.
• the contacting is performed at elevated temperature, for example, from about 25 °C to about 1 10 °C.
• the methods further comprise preparing a compound of formula (Vila):
• oxidant selected from mCPBA, oxone, hydrogen peroxide, or 3-phenyl-2-(phenylsulfonyl)-l ,2-oxaziridine.
• the solvent is DCM, NMP, DMF, or DMA.
• the oxidizing is performed at low temperature, for example, about 0 °C.
• the methods further comprise preparing a compound of formula (Vllb)
• the organic solvent is n-butanol, NMP, DMF, DMSO, or dioxane.
• the base is DIEA, TEA, N-methylmorpholine,
• the contacting is performed at elevated temperature, for example, from about 50 °C to about 90 °C.
• Diaminopyrimidine Compounds are active against protein kinases, particularly JNK1 and/or JNK2. Accordingly, provided herein are many uses of the Diaminopyrimidine Compounds, including the treatment or prevention of those diseases set forth below.
• the methods provided herein comprise the administration of an effective amount of one or more Diaminopyrimidine Compound(s) to a subject in need thereof.
• ATI- 2 514175vl Diaminopyrimidine Compound ATI- 2 514175vl Diaminopyrimidine Compound.
• the kinase is JNKl, JNK2, or mutants or isoforms thereof, or a combination thereof.
• the Diaminopyrimidine Compound is a compound from Table 1, 2 or 3.
• liver fibrotic disorders such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, and liver fibrosis coincident with chronic or repeated alcohol ingestion
• alcoholic hepatitis with infection (e.g. viral infection such as HCV), with liver transplant, or with drug induced liver injury (e.g. acetaminophen toxicity), comprising administering to a subject in need thereof an effective amount of a Diaminopyrimidine Compound.
• infections e.g. viral infection such as HCV
• drug induced liver injury e.g. acetaminophen toxicity
• methods for treating or preventing diabetes or metabolic syndrome leading to liver fibrotic disorders such as non-alcoholic steatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, and hepatitis, comprising administering to a subject in need thereof an effective amount of a Diaminopyrimidine Compound.
• the lupus is lupus erythematosus (such as discoid lupus erythematosus, or cutaneous lupus erythematosus) or systemic lupus.
• Diaminopyrimidine Compound examples include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis;
• irritable bowel syndrome mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; Type II diabetes; obesity; atherosclerosis; restenosis following angioplasty; left ventricular pressure
• ATI-2514175vl hypertrophy myocardial infarction; stroke; ischemic damages of heart, lung, gut, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of the organ for transplantation; organ failure or loss of limb (e.g., including, but not limited to, that resulting from ischemia-reperfusion injury, trauma, gross bodily injury, car accident, crush injury or transplant failure); graft versus host disease; endotoxin shock; multiple organ failure; psoriasis; burn from exposure to fire, chemicals or radiation;
• eczema dermatitis; skin graft; ischemia; ischemic conditions associated with surgery or traumatic injury (e.g., vehicle accident, gunshot wound or limb crush); epilepsy;
• tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterine.
• Diaminopyrimidine Compounds can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
• preparations such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
• Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose,
• an excipient e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate
• a binder e.g., cellulose, methylcellulose, hydroxymethylcellulose
• polypropylpyrrolidone polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch
• a disintegrator e.g., starch, carboxymethylcellulose
• hydroxypropylstarch low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate
• a lubricant e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate
• a flavoring agent e.g., citric acid, menthol, glycine or orange powder
• a preservative e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben
• a stabilizer e.g., citric acid, sodium citrate or
• the effective amount of the Diaminopyrimidine Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration.
• the dose of a Diaminopyrimidine Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.
• the Diaminopyrimidine Compounds can be administered one to four times a day in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration.
• the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight, about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight.
• one dose is given per day.
• the amount of the Diaminopyrimidine Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
• application of a topical concentration provides intracellular exposures or concentrations of about 0.01 - 10 ⁇ .
• kits for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of a Diaminopyrimidine Compound to a subject in need thereof.
• kits for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about
• ATI-2514175vl 1200 mg/day about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of a Diaminopyrimidine Compound to a subject in need thereof.
• the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of a Diaminopyrimidine Compound to a subject in need thereof.
• unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about
• unit dosage formulations comprising about 100 mg or 400 mg of a Diaminopyrimidine Compound.
• unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg,
• a Diaminopyrimidine Compound can be administered once, twice, three, four or more times daily.
• doses of 600 mg or less are administered as a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.
• a Diaminopyrimidine Compound can be administered orally for reasons of convenience. In one embodiment, when administered orally, a Diaminopyrimidine Compound is administered with a meal and water. In another embodiment, the
• Diaminopyrimidine Compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
• juice e.g., apple juice or orange juice
• the Diaminopyrimidine Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
• the mode of administration is left to the discretion of the health-care practitioner, and can depend in- part upon the site of the medical condition.
• Diaminopyrimidine Compound without an additional carrier, excipient or vehicle.
• compositions comprising an effective amount of a Diaminopyrimidine Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
• a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
• the composition is a pharmaceutical composition.
• compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
• compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
• the solutions are prepared from water-soluble salts, such as the hydrochloride salt.
• all of the compositions are prepared according to known methods in pharmaceutical chemistry.
• Capsules can be prepared by mixing a
• Diaminopyrimidine Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
• suitable carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
• Tablets can be prepared by direct compression, by wet granulation, or by dry granulation.
• Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound.
• Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
• Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like.
• Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye.
• the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable
• Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate.
• Tablets can be coated with sugar as a flavor and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
• the compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.
• the effect of the Diaminopyrimidine Compound can be delayed or prolonged by proper formulation.
• Diaminopyrimidine Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
• the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets.
• Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the Diaminopyrimidine Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
• ATI-2514175vl aqueous ammonia (1 mL) was stirred at room temperature under a hydrogen balloon overnight. The mixture was filtered and the filtrate was concentrated and purified by reverse-phase preparatory HPLC (10% to 40% acetonitrile + 0.005% ammonia solution) to give 5-(aminomethyl)-N-((lr,4r)-4-methoxycyclohexyl)pyrimidin-4-amine (30 mg, 0.12 mmol, yield 66%).
• [00191] B 4-((l S,3S)-3-Hydroxycyclohexylamino)-2-((lr,4S)-4-methoxy- cyclohexylamino)pyrimidine-5-carboxamide.
• E. Ethyl 4-((l S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)- pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate (1.4 g, 6.0 mmol), (lS,2S)-2-aminocyclopentanol hydrochloride (0.7 g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 mL) was heated at 60 °C for 15 h.
• Ethyl 4-((lR,3S)-3-hydroxycyclohexylamino)-2-(methylthio)- pyrimidine-5-carboxylate Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (lS,3R)-3-aminocyclohexanol (2.276 g, 19.76 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) were dissolved in ethanol (75 mL) before adding DIEA (4.93 ml, 28.2 mmol) and heating to 60 °C.
• reaction was quenched by addition of 10 mL of 10% aqueous sodium thiosulfate solution. After stirring for 5 minutes, the reaction was partitioned between ethyl acetate and water. The organic layer was then washed with saturated sodium bicarbonate and brine. The combined aqueous layers were washed with ethyl acetate three times before combining the organic layers, drying over sodium sulfate, filtering, and condensing.
• ATI-2514175vl 0.577 g, 2.53 mmol
• DIEA 0.883 mL, 5.05 mmol
• DMSO DMSO
• the solvent was evaporated under reduced pressure, the residue dissolved in a minimum amount of methanol, loaded on a silica gel column and purified (0-15% ammonia saturated methanol in DCM) to afford tert-butyl (lR,4r)-4-(5- carbamoyl-4-(( 1 R,3 S)-3-hydroxycyclohexylamino)pyrimidin-2-ylamino)cyclohexyl- (methyl)carbamate (0.210 g, 0.455 mmol, 36 % yield) as a white powder; MS (ESI) m/z 463.3 [M+l] + .
• the reaction was quenched by addition of ⁇ 20 mL of water. The solution turned pale yellow upon quenching. After transferring to a separatory funnel, the organic phase was washed successively with 10% citric acid and brine. The organic layer was then dried over sodium sulfate, filtered and condensed to give a yellow oil.
• the crude material was purified on a
• the reaction was kept under nitrogen and slowly allowed to warm. After 1 h, the reaction mixture was quenched by additions of saturated sodium bicarbonate. After transferring to a separatory funnel, the organic layer was washed with water and brine, dried over sodium sulfate, filtered and condensed. The crude material was purified on a 340G SNAP Biotage column (0-80% ethyl acetate in hexane).
• ATI-2514175vl 5-aminotetrahydro-2H-pyran-3-ol (1.15 g, 9.82 mmol) as a solution in NMP (20 mL).
• DIEA 8.57 mL, 49.1 mmol
• the reaction was heated to 100 °C overnight.
• Most of the NMP was removed by evaporation at 70 °C, the residue was diluted with DCM and purified on a 340G SNAP Biotage column (0-15% methanol in DCM over 2000 mL). The product fractions were combined and concentrated to give 2.8 g (78%) of material that was -85% pure.
• the material was dissolved in DCM and repurified on a 340G SNAP Biotage column (2-15% ammonia saturated methanol in dichloromethane). The product fractions were combined and concentrated to afford a mixture of four products (two diastereomers and their corresponding enantiomers; 1.95 g), >99% pure.
• the crude material was separated by chiral SFC using an AD-H column to afford 4 compounds labeled PEAK 1 to PEAK 4, with PEAK 1 being the first eluting compound and PEAK 4 being the latest eluting compound.
• PEAK 1 1H NMR (400 MHz, DMSO- ⁇ 3 ⁇ 4) ⁇ ppm 8.41 (s, 1H), 4.38 (br. s.,
• PEAK 2 1H NMR (400 MHz, DMSO- ⁇ 3 ⁇ 4) ⁇ ppm 8.86 - 9.01 (m, 1H), 8.35
• PEAK 3 1H NMR (400 MHz, DMSO- ⁇ 3 ⁇ 4) ⁇ ppm 8.86 - 9.02 (m, 1H),
• PEAK 4 1H NMR (400 MHz, DMSO- ⁇ 3 ⁇ 4) ⁇ ppm 8.99 - 9.24 (m, 1H), 8.36
• reaction mixture was stirred for 2 h at 70 °C.
• reaction mixture was concentrated and purified by silica gel chromatography (0% - 15% ammonia saturated methanol in DCM).
• product fractions were combined and concentrated to afford 4-(3 -hydroxy-3 -methylbutylamino)-2-(( 1 r,4r)-4-methoxycyclohexylamino)- pyrimidine-5 -carboxamide (0.143 g, 60.2 %> yield, 95.8%> pure) as a pale yellow solid.
• the crude reaction mixture was quenched by addition of 75 mL of 10% aqueous sodium thiosulfate solution, stirred for 5 min, before evaporating most of the volatile solvents.
• the material was partitioned between ethyl acetate (200 mL) and water (200 mL), and the combined organic layers were washed with saturated sodium bicarbonate solution and then brine.
• the combined aqueous layers were then washed with ethyl acetate (3x), the organic layers were combined, dried over sodium sulfate, filtered, and condensed.
• Isomer 1 (2.704g, 45%) was obtained as a white solid and isomer 2 (1.866g, 31%>) as a colorless oil, which still contained a small amount of impurities. Isomer 2 was used without further purification in the next step.
• isomer 5 is 4-((lR,3R)-3-hydroxy-3-methylcyclohexylamino)-2- (( 1 r,4R)-4-methoxycyclohexylamino)pyrimidine-5 -carboxamide .
• tert-Butyl (lr,4r)-4-acetamidocyclohexylcarbamate To a stirring solution of tert-butyl (lr,4r)-4-aminocyclohexylcarbamate (1.0 g, 4.67 mmol) in ethyl acetate (30 mL) was added acetic anhydride (0.485 mL, 5.13 mmol) in one portion.
• ATI-2514175vl resulting mixture was allowed to stir overnight at room temperature. Additional acetic anhydride (0.162 mL, 1.71 mmol) was added to the mixture and the mixture was stirred for an additional hour at room temperature. The reaction mixture was then diluted with an additional 50 mL of ethyl acetate and was washed with 50 mL each of a saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The aqueous layers were combined and extracted with 50 mL ethyl acetate.
• Example 12A 4-((lR,3S)-3-Hydroxycycloheptylamino)-2-((lr,4R)-4-methoxy- cyclohexylamino)-pyrimidine-5-carboxamide, 4-((lR,3R)-3-Hydroxycyclo- heptylamino)-2-((lr,4R)-4-methoxycyclohexylamino)-pyrimidine-5-carboxamide, 4-((lS,3R)-3-Hydroxycycloheptylamino)-2-((lr,4S)-4-methoxycyclohexylamino)- pyrimidine-5-carboxamide, 4-((lS,3S)-3-Hydroxycycloheptylamino)-2-((lr,4S)-4- methoxycyclohexylamino)-pyrimidine-5-carboxamide
• A. tert-Butyl 3-oxocycloheptylcarbamate To a stirring mixture of cyclohept-2- enone (26.96 g, 245.0 mmol) and tert-butyl carbamate (28.7 g, 245 mmol) in DCM (245 mL) was added bismuth nitrate pentahydrate (22.79 g, 47.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted reaction with ethyl acetate (500 mL) and water (300 mL) and the biphasic mixture was filtered through a bed of Celite.
• PEAK 1 10.3 mg (0.027 mmol); 1H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 9.02 (d,

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