WO2016040449A1 - 3-phosphoglycerate dehydrogenase inhibitors and uses thereof - Google Patents

3-phosphoglycerate dehydrogenase inhibitors and uses thereof Download PDF

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WO2016040449A1
WO2016040449A1 PCT/US2015/049140 US2015049140W WO2016040449A1 WO 2016040449 A1 WO2016040449 A1 WO 2016040449A1 US 2015049140 W US2015049140 W US 2015049140W WO 2016040449 A1 WO2016040449 A1 WO 2016040449A1
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phenyl
compound
ring
methyl
mmol
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Eddine Saiah
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Raze Therapeutics, Inc.
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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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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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and methods useful for inhibiting 3- phosphoglycerate dehydrogenase.
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • Phosphoglycerate dehydrogenase catalyzes the first step in the biosynthesis of L-serine, which is the conversion of 3 -phosphoglycerate into 3- phosphohydroxypyruvate with a reduction of nicotinamide adenine dinucleotide (NAD ) to
  • Certain cancers including human melanomas and breast cancers, can have high levels of PHGDH. These cancer cells are dependent on PHGDH for their growth and survival as PHGDH catalyzes serine production and may also be a significant source of NADPH in cancer cells. Targeting PHGDH by small molecule inhibitors could be a therapeutic strategy to reduce cancer cell growth and survival. Accordingly, there remains a need to find PHGDH inhibitors useful as therapeutic agents.
  • Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with PHGDH.
  • diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer) such as those described herein.
  • Compounds of the present invention, and compositions thereof are useful as inhibitors of PHGDH. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and compositions thereof, may inhibit the activity of PHGDH and/or inhibit the production of NADPH, and thus reduce the growth of cells in proliferative disorders such as cancer.
  • the present invention provides a compound of formula I:
  • Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring B is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6 membered saturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring D is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring;
  • each of m and q is independently 0, 1, 2, 3, 4, or 5;
  • each of n and p is independently 0, 1, 2, 3 4 or 5;
  • each of R 1 , R 2 , R 3 , and R 4 is independently halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N(R)C(0)N(R) 2 , -N(R)C(NR)N(R) 2 , -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, - S0 2 N(R)C(0)R, -S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(NR)N(R) 2 , -C(0)N(R)C(0)R or - CR ⁇ OH) ⁇
  • each R is independently hydrogen, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
  • L 1 is a covalent bond, or a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S0 2 -,
  • L 2 is -C(0)NR-, -NRC(O)-, -CH 2 N(R)-, -N(R)C(0)NR-; or
  • L is a bivalent Ci_ 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by - S0 2 NR-; -N(R)S0 2 -,-S0 2 -, -S0 2 N(R)C(0)-; -C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, or
  • L is a bivalent tetrazolylene ring
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • "cyclo aliphatic" (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a "bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary brid ed bicyclics include:
  • lower alkyl refers to a Ci_ 4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a Ci_ 4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci_s (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, CI, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a hetero aromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR*, -(CH 2 ) 0 2 CH(OR*) 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0 2 C(0)R*, -(CH 2 ) 0 2 C(0)OH, -(CH 2 ) 0 2 C(0)OR*, -(CH 2 ) 0 2 SR*, -(CH 2 )o 2 SH, -(CH 2 )o 2 NH 2 , -(CH 2 ) 0 2 NHR*, -(CH 2 ) 0 2 NR* 2 , -N0 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 - 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 _iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci ⁇ alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety, R 1 of a provided compound comprises one or more deuterium atoms.
  • an inhibitor is defined as a compound that binds to and /or inhibits PHGDH with measurable affinity.
  • an inhibitor has an IC 50 and/or binding constant of less than about 100 ⁇ , less than about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in PHGDH activity between a sample comprising a compound of the present invention, or composition thereof, and PHGDH, and an equivalent sample comprising PHGDH, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of formula I:
  • Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring B is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6 membered saturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring D is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring; each of m and q is independently 0, 1, 2, 3, 4, or 5;
  • each of n and p is independently 0, 1, 2, 3, 4 or 5;
  • each of R 1 , R 2 , R 3 , and R 4 is independently halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N(R)C(0)N(R) 2 , -N(R)C(NR)N(R) 2 , -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, - S0 2 N(R)C(0)R, -S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(NR)N(R) 2 , -C(0)N(R)C(0)R or - CR ⁇ OH) ⁇
  • each R is independently hydrogen, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
  • L 1 is a covalent bond, or a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S0 2 -,
  • L 2 is -C(0)NR-, -NRC(O)-, -CH 2 N(R)-, -N(R)C(0)NR-; or
  • L is a bivalent Ci_ 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by - S0 2 NR-; -N(R)S0 2 -,-S0 2 -, -S0 2 N(R)C(0)-; -C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, or
  • the Ring A group of formula I is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is phenyl
  • Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is pyridinyl.
  • Ring A is thiophen-2-yl.
  • Ring A is thiophen-3-yl.
  • Ring A is an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is naphthalenyl.
  • Ring A is naphthalen-l-yl.
  • Ring A is naphthalen-2-yl.
  • Ring A is quinolinyl.
  • Ring A is quinolinyl.
  • Ring A is quinolin-2-yl.
  • Ring A is quinolin-3-yl.
  • Ring A is quinolin-4-yl.
  • Ring A is quinolin-8-yl.
  • Ring A is benzothiophen-2-yl.
  • Ring A is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is pyrrolidinyl.
  • Ring A is piperidinyl.
  • Ring A is pyrrolinyl.
  • Ring A is oxazolidinyl.
  • Ring A is piperazinyl.
  • Ring A is morpholinyl.
  • the r group of formula I is 0 or 1. In some embodiments, r is 0. In other embodiments, r is 1.
  • the Ring B group of formula I is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B group of formula I is bivalent, e.g., in such instances phenyl is phenylene, heteroaryl is heteroarylene, etc.
  • Ring B is phenyl
  • Ring B is a 5 membered monocyclic heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring B is pyrazolyl.
  • Ring B is triazolyl.
  • Ring B is oxazolyl.
  • Ring B is furanyl.
  • Ring B is imidazolyl.
  • Ring B is 6 membered monocyclic heteroaryl ring having 1-2 nitrogens. In some embodiments, Ring B is pyridinyl.
  • the Ring C group of formula I is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring C group of formula I is bivalent, e.g., in such instances phenyl is phenylene, heteroaryl is heteroarylene, etc.
  • Ring C is phenyl. In some embodiments, Ring C is
  • Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring C is pyridinyl.
  • Ring C is a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring C is piperidin-l-yl.
  • Ring C is piperazin-l-yl.
  • Ring C is cycloalkyl.
  • a R substituent on a saturated carbon of cycloalkyl forms a chiral center.
  • that chiral center is in the (R) configuration.
  • that chiral center is in the (S) configuration.
  • Ring C is cyclohexyl.
  • the Ring D group of formula I is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring.
  • Ring D is phenyl
  • Ring D is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is furanyl. In some embodiments, Ring D is a 6 membered monocyclic heteroaryl ring having 1-3 nitrogens. In some embodiments, Ring D is pyridinyl. In some embodiments, Ring D is pyridin-2-yl. In some embodiments, Ring D is pyridin-3-yl. In some embodiments, Ring D is pyridin-4-yl. In some embodiments, Ring D is pyrimidinyl. In some embodiments, Ring D is pyrimidin-2-yl. In some embodiments, Ring D is triazinyl.
  • Ring D is a 5 membered monocyclic heteroaryl ring having 1- 4 heteroatoms selected from nitrogen, oxygen, or sulfur.
  • Ring D is thiazol-2-yl.
  • Ring D is lH-imidazol-2-yl.
  • Ring D is lH-pyrazol-5-yl.
  • Ring D is lH-triazol-5-yl.
  • Ring D is lH-tetrazol-5-yl.
  • Ring D is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring D is morpholino.
  • Ring D is piperidin-l-yl.
  • Ring D is piperidin-4-yl.
  • Ring D is piperazin-l-yl.
  • Ring D is 4,5-dihydro-lH-imidazol-2-yl.
  • Ring D is a 5-6 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring D is cyclopentyl. In some embodiments, Ring D is cyclohexyl.
  • the s group of formula I is 0 or 1. In some embodiments, s is 0. In other embodiments, s is 1.
  • the L 1 group of formula I is a covalent bond, or a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, - N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S0 2 -, -S0 2 N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S0 2 -.
  • L 1 is a covalent bond.
  • L 1 is a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, - N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S0 2 -, -S0 2 N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S0 2 -.
  • the L group of formula I is a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or -NR-, or
  • Ring C L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • L is a bivalent Ci_ 4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or -NR-. 2 2
  • L is -C(0)NR-. In some embodiments, L is -C(0)NR- and
  • R is hydrogen.
  • L is -N(R)C(0)-. In some embodiments, L is -
  • L is -CH 2 N(R)-.
  • Exemplary L groups include those depicted in Table 1.
  • L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the L group of formula I is a bivalent Ci_ 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -S0 2 NR-; -N(R)S0 2 -, -S0 2 -, - S0 2 N(R)C(0)-; -C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or L 3 is a bivalent tetrazolylene ring.
  • L is a bivalent Ci_ 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -S0 2 NR-; -N(R)S0 2 -, -S0 2 -, N(R)C(0)-; -C(0)N(R)S0 2 -, -C(0)NR- , -N(R)C(0)-, - N(R)C(0)NR-.
  • L is -S0 2 NR- (i.e., a Ci bivalent hydrocarbon chain wherein the methylene unit is replaced by -S0 2 NR-), -N(R)S0 2 -, -S0 2 - -S0 2 N(R)C(0)-; - C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, or -N(R)C(0)NR-.
  • L 3 is -S0 2 NR- (i.e., a Ci bivalent hydrocarbon chain wherein the methylene unit is replaced by -S0 2 NR-), -N(R)S0 2 -, -S0 2 - -S0 2 N(R)C(0)-; - C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, or -N(R)C(0)NR-.
  • L 3 is -
  • L is -S0 2 -.
  • L is -N(R)S0 2 -, - S0 2 N(R)C(0)-; -C(0)N(R)S0 2 -, -C(0)NR-, -N(R)C(0)-, or -N(R)C(0)NR-.
  • Exemplary L 3 groups include those depicted in Table 1.
  • L is a bivalent tetrazolylene ring.
  • each of R 1 , R 2 , R 3 , and R 4 group of formula I is independently halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , -N(R)C(0)R, - N(R)C(0)N(R) 2 , -N(R)C(NR)N(R) 2 , -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, -S0 2 N(R)C(0)R, - S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(NR)N(R) 2, -C(0)N(R)C(0)R or -CR ⁇ Ot ⁇ R.
  • R 1 is halogen, R, -OR, -SR, -N(R) 2 , -NHR, -C(0)R, - C(0)N(R) 2 , -N(R)C(0)R, -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, or -C(0)N(R)C(0)R.
  • R 1 is halogen.
  • R 1 is R.
  • R 1 is -OR.
  • R is -SR.
  • R is -N(R) 2 .
  • R 1 is -NHR.
  • R 1 is -C(0)R. In some embodiments, R 1 is -C(0)N(R) 2 . In some embodiments, R 1 is -N(R)C(0)R. In some embodiments, R 1 is -N0 2 . In some embodiments, R 1 is -CN. In some embodiments, R 1 is -S0 2 N(R) 2 . In some embodiments, R 1 is - N(R)S0 2 R. In some embodiments, R 1 is -C(0)N(R)C(0)R.
  • R 1 groups include those depicted in Table 1.
  • R 1 is -CH 3 , -OH, -C(0)OH, -NH 2 , -phenyl. -F, -CI, -OCH 3 , -OCH 2 CH 3 or -C(0)OH.
  • Ring A is substituted with at least one R 1 group.
  • Ring A is 3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4- trifiuoromethoxyphenyl, 4-phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2,3-difluorophenyl, 2,4-difiuorophenyl, 2,5- difluorophenyl, 2,6-difiuorophenyl, 3,4-difiuorophenyl, 2,3,4-trifluorophenyl, 2,4,5- trifiuorophenyl, 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5- trifiuorophenyl, 2,
  • two adjacent R 1 groups on Ring A are taken together with their intervening atoms to form an optionally substituted 5-6 membered saturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or
  • Ring A is:
  • the m group of formula I is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.
  • R 2 is halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, or -C(0)N(R)C(0)R.
  • R is halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, or -C(0)N(R)C(0)R.
  • R is halogen. In some embodiments, R is R. In some embodiments, R is -OR. In some
  • R is -SR. In some embodiments, R is -N(R) 2 . In some embodiments, R is - C(0)R. In some embodiments, R 2 is -C(0)N(R) 2 . In some embodiments, R 2 is -N(R)C(0)R. In
  • R is -N0 2 . In some embodiments, R is -CN. In some embodiments, R is 2 2
  • R is -N(R)S0 2 R. In some embodiments, R is - C(0)N(R)C(0)R.
  • R groups include those depicted in Table 1.
  • R is -F, -CI, -Br, -I, -CH 3 , -CH 2 CH 3, -CH 2 CH 2 CH 3, -CH(CH 3 ) 2 , -cyclopropyl, -tert-butyl, -CN, - OCH 3 , -CH 2 CH 2 OCH 3, -OCF 3 , -OCHF 2 , -CH 2 CH 2 N(CH 3 ) 2 or -phenyl.
  • Ring B is substituted with at least one R group.
  • r 0 and Ring B is 5-chloro-l-methylindolin-2-yl.
  • n group of formula I is 0, 1, 2, 3 4 or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
  • r is 0 and n is 0. In some embodiments, r is 0 and n is 1. In some embodiments, r is 0 and n is 2. In some embodiments, r is 0 and n is 3. In some embodiments, r is 0 and n is 4. In some embodiments, r is 0 and n is 5.
  • r is 1 and n is 0. In some embodiments, r is 1 and n is 1. In some embodiments, r is 1 and n is 2. In some embodiments, r is 1 and n is 3. In some embodiments, r is 1 and n is 4.
  • R 3 is halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N(R)C(0)N(R) 2 , -N(R)C(NR)N(R) 2 , -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, - S0 2 N(R)C(0)R, -S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(NR)N(R) 2 or -C(0)N(R)C(0)R or -
  • R is halogen. In some embodiments, R is R. In some embodiments,
  • R is -OR. In some embodiments, R is -SR. In some embodiments, R is -N(R) 2 .
  • R is -C(0)R. In some embodiments, R is -C(0)N(R) 2 . In some embodiments, R 3 is -N(R)C(0)R. In some embodiments, R 3 is -N(R)C(0)N(R) 2 . In some embodiments,
  • R J is -N(R)C(NR)N(R) 2 . In some embodiments, R is -N0 2 . In some
  • R is -CN. In some embodiments, R is -S0 2 N(R) 2 . In some embodiments, R is - N(R)S0 2 R. In some embodiments, R 3 is -S0 2 N(R)C(0)R. In some embodiments, R is - S0 2 N(R)C(0)N(R) 2 . In some embodiments, R 3 is - S0 2 N(R)C(NR)N(R) 2 . In some embodiments, R 3 is -C(0)N(R)C(0)R.
  • the p group of formula I is 0, 1, 2, 3, 4 or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.
  • s is 0 and p is 0. In some embodiments, s is 0 and p is 1. In some embodiments, s is 0 and p is 2. In some embodiments, s is 0 and p is 3. In some embodiments, s is 0 and p is 4. In some embodiments, s is 0 and p is 5.
  • s is 1 and p is 0. In some embodiments, s is 1 and p is 1. In some embodiments, s is 1 and p is 2. In some embodiments, s is 1 and p is 3. In some embodiments, s is 1 and p is 4.
  • R 4 is halogen, R, -OR, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , - N(R)C(0)R, -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, or -C(0)N(R)C(0)R.
  • R 4 is halogen.
  • R 4 is R.
  • R 4 is -OR.
  • R 4 is -OH.
  • R 4 is -SR.
  • R 4 is - N(R) 2 .
  • R 4 is -C(0)R. In some embodiments, R 4 is -C(0)N(R) 2 . In some embodiments, R 4 is -N(R)C(0)R. In some embodiments, R 4 is -N0 2 . In some embodiments, R 4 is -CN. In some embodiments, R 4 is -S0 2 N(R) 2 . In some embodiments, R 4 is -N(R)S0 2 R. In some embodiments, R 4 is -C(0)N(R)C(0)R.
  • R 4 groups include those depicted in Table 1.
  • R 4 is -CH 3 , -NH(CO)CH 3 , -OCH 3 , -C(0)OH, -CH 2 C(0)OH, -CH 2 C(0)OCH 3 or -OCF 3 .
  • R 4 is -CH 3 .
  • R 4 is -OCH 3 .
  • R 4 is - OCH 2 CH 3 .
  • Ring D is substituted with at least one R 4 group.
  • Ring A is 4-ethoxypyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl, 2- cyclopentan-l-ol, 2-cyclohexan-l-ol or 4-(l-methylpiperidin-3-ol).
  • the q group of formula I is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.
  • each R group of formula I is independently hydrogen, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
  • two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur.
  • R is hydrogen. In some embodiments, R is an optionally substituted Ci_ 6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur.
  • the present invention provides a compound of formula I, wherein r and s are 1 thereby forming a compound of formula II:
  • n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein Ring A is phenyl, L 1 is a covalent bond, and r and s are 1, thereby forming a compound of formula III:
  • Ring B, Ring C, Ring D, L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein Ring A is phenyl, Ring D is pyrimidinyl, L 1 is a covalent bond, r and s are 1, thereby forming a compound of formula IV:
  • Ring B, Ring C, L 2 , L 3 , R 1 , R2 , R 3 , R 4 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring D is pyrimidinyl, L 1 is a covalent bond, r and s are 1, thereb forming a compound of formula V:
  • R 5 is hydrogen or an optionally substituted
  • Ci_6 aliphatic and each of Ring C, L , L , R , R , R , R , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl, L 1 is a covalent bond, r and s are 1, thereby forming a compound of formula VI:
  • each of L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is triazinyl, L 1 is a covalent bond, r and s are 1 thereby forming a compound of formula VII:
  • each of L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalent bond
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula VIII:
  • each of L 2 , R, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula IX:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is triazinyl, L 1
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula X:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula XI:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula
  • R 7 is halogen, R, -SR, -N(R) 2 , -C(0)R, -C(0)N(R) 2 , -N(R)C(0)R, - N(R)C(0)N(R) 2 , -N(R)C(NR)N(R) 2 , -N0 2 , -CN, -S0 2 N(R) 2 , -N(R)S0 2 R, -S0 2 N(R)C(0)R, - S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(0)N(R) 2 , - S0 2 N(R)C(NR)N(R) 2 , -C(0)N(R)C(0)R or -CR ⁇ Ot ⁇ R.
  • R independently, and R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and
  • n 1 or a pharmaceutically acceptable salt thereof.
  • the compound of formula I is
  • the compound of formula I is
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalen -C(0)NR-, L is -S0 2 N(R)-, r and s are 1, thereby forming a compound of formula XII:
  • each of R, independently, and R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula XIII:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula XIV:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein wherein Ring A is pyridinyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is
  • L is a covalent bond
  • L is -C(0)NR-
  • L is -S0 2 N(R)-
  • r and s are 1, thereby forming a compound of formula XV:
  • each of R, independently, and R 1 , R2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of formula I, wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, L 1 is a covalent bond, L 2 is - C(0)NR-, r is 1 and s is 0, and R 11 is an acidic moiety, thereby forming a compound of formula XVI:
  • each of R, R 1 , R2 , R 3 , R 5 , m, n and p is as defined above and described in embodiments herein, both singly and in combination.
  • the acidic moiety, R 11 is -OH, -C0 2 H or -S0 2 NHR or -B(OH) 2 .
  • the present invention provides a compound of formula I, wherein Ring C is phenyl, Ring D is pyrimidinyl, r is 0 and s is 1 , thereby forming a compound of formula XVII:
  • Ring B is indolyl.
  • Ring B is pyrazolo[l,5-a]pyridyl.
  • Ring B is 1,3-benzodiazolyl.
  • Ring B is pyrrolo[2,3-b]pyridyl. In some embodiments, Ring B is
  • the present invention provides a compound of formula I, wherein Ring B is indolyl, Ring C is phenyl, Ring D is pyrimidinyl, r is 0 and s is 1, thereby forming a compound of formula XVIII:
  • R 6 is hydrogen. In other embodiments, R 6 is Ci_4-alkyl.
  • the present invention provides a compound of formula I, wherein Ring B is indolyl, Ring C is phenyl, Ring D is triazinyl, r is 0 and s is 1 , thereby forming a compound of formula XIX:
  • R 6 is hydrogen or an optionally substituted
  • Ci_6 aliphatic, each R, independently, and each of R , R , R , n, p and q is as defined above and described in embodiments herein, both singly and in combination.
  • R 6 is hydrogen.
  • R 6 is Ci_4-alkyl.
  • R 6 is methyl.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or XVI wherein m is 1, 2 or 3 and each R 1 is independently selected from -OH, -CF 3 , -OCi_ 4 -alkyl, -OCF 3 , -OCHF 2 , -C0 2 H, NH 2 , -CI, -Br, -F, and -I.
  • one R 1 is -OH.
  • one R is -CH 3 .
  • two R 1 groups are -CH 3 .
  • the present invention provides a compound of formulae I, II,
  • n 1, 2 or 3 and each R is independently selected from -OH, -CF 3 , -OCi_ 4 -alkyl, -OCF 3 , -
  • the present invention provides a compound of formulae I, II,
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein p is 1, 2 or 3 and each R is independently selected from-CF 3 , -OCi_ 4 -alkyl, -OCF 3 , -OCHF 2 , -CI, -Br, and -F.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVII, XVIII or XIX wherein q is 0.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVII, XVIII or XIX wherein q is 1, 2 or 3 and each R 4 is independently selected from-CF 3 , -OCi_4-alkyl, -OCF 3 , -OCHF 2 , -CI, -Br, and -F. In some embodiments, q is 1 and R 4 is -CH 3 . In some embodiments, q is 2 and both R 4 groups are -CH 3 .
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 2 is -C(0)NR- and the R of-C(0)NR- is hydrogen.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 2 is -C(0)NR- and the R of-C(0)NR- is not hydrogen.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 2 is -C(0)NR- and the R of -C(0)NR- is Ci_ 4 -alkyl. In some embodiments, the R of -C(0)NR- is CH 3 .
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 3 is -S0 2 N(R)- and the R of -S0 2 N(R)- is hydrogen.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 3 is -S0 2 N(R)- and the R of -S0 2 N(R)- is not hydrogen.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L 3 is -S0 2 N(R)- and the R of -S0 2 N(R)- is Ci_ 4 -alkyl. In some embodiments, the R of - -S0 2 N(R)- is CH 3 .
  • the present invention provides a compound of formulae V, VI,
  • the present invention provides a compound of formulae V, VI,
  • the present invention provides a compound of formulae V, VI,
  • the present invention provides a compound of formulae VIII,
  • the present invention provides a compound of formulae VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein at least one R is not hydrogen.
  • the present invention provides a compound of formulae VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein at least two R groups are not hydrogen.
  • the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein the compound is not any of Compounds I-l - 1-16, 1-22 - 1-31, 1-33, 1-40 - 1-46, 1-49 - 1-59, 1-67 - 1-72, 1-79, 1 - 80 or 1-92.
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof, wherein the compound is not Compound 1-1.
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof, wherein the compound is not any of Compounds 1-1 to 1-16, 1-22 to 1-31, 1-33, 1-40 to 1-46, 1-49 to 1-59, 1-67 to 1-72, 1-79, 1 - 80 or I- 92.
  • the compound is 1-21.
  • the compound is 1-32.
  • the compound is 1-73.
  • the compound is 1-76.
  • the compound is 1-78.
  • the compound is 1-84.
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • LG includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4- methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2- (phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R 1 , R 2 , R 3 , R 4 , m, n, p and q is as defined above and below and in classes and subclasses as described herein.
  • the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme I, above.
  • a compound of formula G-l is contacted with a group of the formula G-2 to couple Rings A and B, e.g., via Suzuki coupling, forming a compound of formula G-3.
  • PG is 2-(trimethylsilyl)ethoxy]methyl.
  • the compound of formula G-l is contacted with the group of the formula G-2 and Pd(PPh 3 ) 4 .
  • PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R 1 , R 2 , R 3 , R 4 , m, n, p and q is as defined above and below and in classes and subclasses as described herein.
  • the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme II, above.
  • a compound of formula G-4 is contacted with a group of the formula G-5 to couple Rings B and C, e.g., via amide bond formation, yielding a compound of formula G-3.
  • PG is 2-(trimethylsilyl)ethoxy]methyl.
  • the -C0 2 H group of G-5 is converted to -C0 2 C1, prior to being contacted with G-4.
  • the compound of formula G-4 is contacted with the group of the formula G-5 and (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU) to yield the compound of formula G-3.
  • PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R 1 , R 2 , R 3 , R 4 , m, n, p and q is as defined above and below and in classes and subclasses as described herein.
  • the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme III, above.
  • a compound of formula G-6 is contacted with a group of the formula G-7 to couple Rings C and D, e.g., via sulfonamide bond formation, yielding a compound of formula G-3.
  • the compound of formula G-6 is contacted with the group of the formula G- 7 and a base such as DIPEA.
  • compositions are provided.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropy
  • a "pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • inhibitors or residue thereof means that a metabolite or residue thereof is also an inhibitor of PHGDH, or a mutant thereof.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • the activity of a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of PHGDH, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to PHGDH.
  • Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof, are set forth in the Examples below.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the present invention provides a method for treating a PHGDH-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • PHGDH-mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which PHGDH, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which PHGDH, or a mutant thereof, are known to play a role.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
  • the present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by targeting PHGDH of the serine biosynthetic pathway.
  • cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases. Such disorders may be diagnosed using methods known in the art.
  • Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macro globulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcom
  • Cancers includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia,
  • the present invention provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein.
  • the tumor comprises any of the cancers described herein.
  • the tumor comprises melanoma cancer.
  • the tumor comprises breast cancer.
  • the tumor comprises lung cancer.
  • the tumor comprises small cell lung cancer (SCLC).
  • the tumor comprises non-small cell lung cancer (NSCLC).
  • the tumor is treated by arresting further growth of the tumor.
  • the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the size of the tumor prior to treatment.
  • tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the quantity of tumors prior to treatment.
  • proliferative diseases include, e.g., obesity, benign prostatic hyperplasia, psoriasis, abnormal keratinization, lymphoproliferative disorders (e.g., a disorder in which there is abnormal proliferation of cells of the lymphatic system), chronic rheumatoid arthritis, arteriosclerosis, restenosis, and diabetic retinopathy.
  • lymphoproliferative disorders e.g., a disorder in which there is abnormal proliferation of cells of the lymphatic system
  • chronic rheumatoid arthritis e.g., arteriosclerosis, restenosis, and diabetic retinopathy.
  • Proliferative diseases that are hereby incorporated by reference include those described in U.S. Pat. Nos. 5,639,600 and 7,087,648. Inflammatory Disorders and Diseases
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
  • Compounds according to the invention are useful in the treatment of heteroimmune diseases.
  • heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
  • Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget' s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity
  • the inflammatory disease which can be treated according to the methods of this invention is an disease of the skin.
  • the inflammatory disease of the skin is selected from contact dermatitits, atompic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.
  • the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease.
  • the TH17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).
  • the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.
  • the invention provides a method of treating a metabolic disease.
  • the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome or obesity.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, 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, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adj
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • 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 sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 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 sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention relates to a method of inhibiting PHGDH activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Another embodiment of the present invention relates to a method of inhibiting PHGDH in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the present invention provides a method for treating a disorder mediated by PHGDH, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • a compound of the current invention may also be used to advantage in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angio genie compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors;
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AromasinTM.
  • Formestane is marketed under the trade name LentaronTM.
  • Fadrozole is marketed under the trade name AfemaTM.
  • Anastrozole is marketed under the trade name ArimidexTM.
  • Letrozole is marketed under the trade names FemaraTM or FemarTM.
  • Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen is marketed under the trade name NolvadexTM.
  • Raloxifene hydrochloride is marketed under the trade name EvistaTM.
  • Fulvestrant can be administered under the trade name FaslodexTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CasodexTM).
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name ZoladexTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CamptosarTM.
  • Topotecan is marketed under the trade name HycamptinTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CaelyxTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name EtopophosTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name AcriblastinTM or AdriamycinTM.
  • Epirubicin is marketed under the trade name FarmorubicinTM.
  • Idarubicin is marketed, under the trade name ZavedosTM.
  • Mitoxantrone is marketed under the trade name Novantron.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TaxolTM.
  • Docetaxel is marketed under the trade name TaxotereTM.
  • Vinblastine sulfate is marketed under the trade name Vinblastin R.PTM.
  • Vincristine sulfate is marketed under the trade name FarmistinTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CyclostinTM. Ifosfamide is marketed under the trade name HoloxanTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine is marketed under the trade name XelodaTM.
  • Gemcitabine is marketed under the trade name GemzarTM.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CarboplatTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark EloxatinTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angio genie compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I
  • BCR-Abl kinase and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD 173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin;
  • c-Met receptor compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to ⁇ , ⁇ , ⁇ , ⁇ , PI3K-C2a, PBK-C2P, ⁇ - C2y, Vps34, pl lO-a, ⁇ 110- ⁇ , ⁇ 110- ⁇ , ⁇ 110- ⁇ , ⁇ 85- ⁇ , ⁇ 85- ⁇ , ⁇ 55- ⁇ , ⁇ 150, plOl, and ⁇ 87.
  • ⁇ inhibitors useful in this invention include but are not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • BTK inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib
  • BTK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • PBK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (ThalomidTM) and TNP-470.
  • ThilomidTM thalidomide
  • TNP-470 TNP-470.
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP- 18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or a- ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox- 2 inhibitors such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DidronelTM.
  • Clodronic acid is marketed under the trade name BonefosTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name ArediaTM.
  • Alendronic acid is marketed under the trade name FosamaxTM.
  • Ibandronic acid is marketed under the trade name BondranatTM.
  • Risedronic acid is marketed under the trade name ActonelTM.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier as used herein refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or Rl 15777 (ZarnestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine ammopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine ammopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine ammopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VelcadeTM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 - ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DMl, erbitux, bevacizumab (AvastinTM), rituximab (Pvituxan ® ), PR064553 (anti-CD40) and 2C4 Antibody.
  • trastuzumab HerceptinTM
  • Trastuzumab-DMl erbitux
  • bevacizumab AvastinTM
  • rituximab Pierismab
  • PR064553 anti-CD40
  • compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • the term "ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X- rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1 , pp. 248-275 (1993).
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate
  • AngiostatinTM EndostatinTM
  • anthranilic acid amides ZD4190; ZD6474; SU5416; SU6668
  • bevacizumab or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab
  • VEGF aptamer such as Macugon
  • FLT-4 inhibitors, FLT-3 inhibitors VEGFR-2 IgGI antibody
  • Angiozyme RI 4610)
  • Bevacizumab AvastinTM
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy include treatment with compounds, such as VisudyneTM and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • a compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • HATU (460mg, 1.2 mmol) and DIPEA (0.42 ml, 2.4 mmol) were added at Rt to a stirred solution of 3-(propan-2-yl)-lH-pyrazole-5-carboxylic acid (120mg, 0.8 mmol) in DMF (HPLC grade, 7 ml) followed by 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide (200mg, 0.8 mmol). The resulting mixture was stirred at Rt for 20h.
  • Step 1 Synthesis of 4-amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ benzene-l-sulfonamide, 9.1
  • Step 2A Synthesis of 3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ ) sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 9.2
  • HATU 300mg, 0.79 mmol
  • DIPEA 0.27 ml, 1.58 mmol
  • HATU 300mg, 0.79 mmol
  • DIPEA 0.27 ml, 1.58 mmol
  • 4-amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene-l- sulfonamide 9.1, 200 mg, 0.53 mmol
  • DMF dry, 20 ml
  • 5 -phenyl- lH-pyrazole- 3-carboxylic acid 99mg, 0.53 mmol
  • Step 3 Synthesis of 3-Phenyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH- pyrazole-5-carboxamide, 1-32
  • Step 1 Synthesis of 4-amino-N-(4,6-dimethylpyrimidin-2-yl)-N- ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ benzene-l-sulfonamide, 10.1
  • SEMC1 (1.18 ml, 6.66 mmol) was added drop wise at rt to a stirred suspension of 4- amino-N-(4,6-dimethylpyrimidin-2-yl)-N-sodiobenzene-l -sulfonamide (2.00g, 6.66 mmol) in MeCN (HPLC grade, 50ml). The mixture was stirred at rt for 20h. The solvent was removed in vacuo and the remaining material was partitioned between DCM (150ml) and water (100ml). The aqueous layer was extracted further with DCM (2 x 70ml).
  • Step 2A Synthesis of N- ⁇ 4-[(4,6-dimethylpyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ ) sulfamoyl]phenyl ⁇ -3-phenyl-lH-pyrazole-5-carboxamide, 10.2
  • HATU (294mg, 0.77 mmol) and DIPEA (0.27 ml, 1.55 mmol) were added at rt to a stirred solution of 4-amino-N-(4,6-dimethylpyrimidin-2-yl)-N- ⁇ [2-
  • Step 3 Synthesis of N- ⁇ 4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl ⁇ -3- phenyl-lH-pyrazole-5-carboxamide, 1-73
  • Step 2B Synthesis of N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-indole-2-carboxamide, 11.1
  • reaction crude was partitioned between DCM (75ml) and water (75ml).
  • the aqueous layer was further extracted with DCM (2 x 50ml) and the combined layers dried over Na 2 S0 4 .
  • the solvent was removed in vacuo to afford a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 248mg (60%) of N- ⁇ 4- [(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ - 1 H-indole-2- carboxamide 11.1 as a colourless solid.
  • Step 3 N- ⁇ 4- [(pyrimidin-2-yl)sulfamoyl] phenyl ⁇ -lH-indole-2-carboxamide 1-78
  • Step 2B Synthesis of N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) sulfamoyl] phenyl ⁇ - lH-indole-3-carboxamide 12.1
  • Step 3 Synthesis of N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH-indole-3- carboxamide, 1-82
  • Step 2B Synthesis of N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) sulfamoyl] phenyl ⁇ pyrazolo[l,5-a]pyridine-2-carboxamide 13.1
  • Methanesulfonyl chloride (0.04ml, 0.55mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene- 1 -sulfonamide (9.1, 150mg, 0.39mmol), pyrazolo[l,5-a]pyridine-2-carboxylic acid (60mg, 0.39mmol) and 3-picoline (0.12 ml, 1.18mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 15h.
  • reaction mixture was partitioned between DCM (50ml) and water (50ml).
  • the aqueous layer was further extracted with DCM (2x 30ml) and the combined layers dried over Na 2 S0 4 .
  • the solvent was removed in vacuo to afford a material which was purified by flash column chromatography (heptane/EtOAc 75/25 to 0/100) to obtain 190mg (87%) of N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) sulfamoyl]phenyl ⁇ pyrazolo[l,5-a]pyridine-2-carboxamide 13.1 as an off white solid.
  • Step 3 Synthesis of N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ pyrazolo[l,5- a]pyridine-2-carboxamide, 1-83
  • Example 14 Synthesis of l-methyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH- indole-2-carboxamide, 1-84
  • Step 2B Synthesis of l-Methyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-indole-2-carboxamide 14.1
  • Methanesulfonyl chloride (40 ⁇ 1, 0.51mmol) was added to a stirred solution of 1- methyl-lH-indole-2-carboxylic acid (90mg, 0.51mmol), 4-amino-N-(pyrimidin-2-yl)-N- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ benzene-l-sulfonamide (9.1, 205mg, 0.54mmol) and 3-picoline (50 ⁇ 1, 0.51mmol) in MeCN (dry, 10 ml) at 0°C. The reaction was allowed to reach rt and stirred for 15h.
  • Step 3 Synthesis of l-Methyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH- indole-2-carboxamide, 1-84
  • Methanesulfonyl chloride (0.05 ml, 0.65 mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene- 1 -sulfonamide (9.1, 176mg, 0.46 mmol), l-ethyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (lOOmg, 0.46 mmol) and 3-picoline (0.14ml, 1.39 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 30 minutes.
  • reaction mixture was partitioned between DCM (75ml) and water (50ml).
  • the aqueous layer was further extracted with DCM (2x 40ml) and the combined layers dried over Na 2 S0 4 , filtered and concentrated in vacuo to afford a material which was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 39mg (19%) of 1 -ethyl-3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ - lH-pyrazole-5- carboxamide 1-89 as a white solid.
  • Step 1 Synthesis of ethyl 3-bromo-lH-pyrazole-5-carboxylate 16.1
  • Step 2 Synthesis of ethyl 5-bromo-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH- pyrazole-3-carboxylate, 16.2
  • SEMC1 (0.62g, 3.75 mmol) was added to a mixture of ethyl 5-bromo-lH-pyrazole-3- carboxylate (16.1, 0.55g, 2.5 mmol) and DIPEA (0.87 ml, 4.99 mmol) in DCM (HPLC grade, 20 ml) at 0°C. After addition, the reaction mixture was allowed to reach rt and stirred for 20h. The mixture was diluted with DCM (30 ml), washed with sat. aq.
  • Step 3 Synthesis of 3-bromo-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-pyrazole- 5-carboxylic acid 16.3
  • LiOH (179mg, 7.49 mmol) was added at rt to a stirred solution of ethyl 3-bromo-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-pyrazole-5-carboxylate (16.2, 872mg, 2.5 mmol) in THF (HPLC grade, 10 ml) and water (distilled, 2 ml). The mixture was stirred for 3h at rt. Additional LiOH (60mg, 2.5mmol) was added and the mixture stirred for 20h. The mixture was concentrated in vacuo, diluted with water (20ml) and washed with EtOAc (20 ml).
  • Step 4 Synthesis of 3-bromo-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ ) sulfamoyl]phenyl ⁇ -l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-pyrazole-5- carboxamide 16.4
  • Step 5 Synthesis of 2-[5-( ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ ) sulfamoyl]phenyl ⁇ carbamoyl)-l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-pyrazol-3-yl]benzoic acid 16.5
  • Step 6 Synthesis of 2-[5-( ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ carbamoyl)-lH- pyrazol-3-yl] benzoic acid, 1-74
  • Example 17 Synthesis of 3-(2-aminopyridin-3-yl)-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-p razole-5-carboxamide, 1-75
  • Step 5 Synthesis of 3-(2-aminopyridin-3-yl)-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl) ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH- pyrazole-5-carboxamide 17.1
  • Step 6 Synthesis of 3-(2-aminopyridin-3-yl)-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 1-75
  • Step 1 Synthesis of methyl 3-iodo-l-methyl-lH-pyrazole-5-carboxylate 18.1
  • Step 2 Synthesis of lithio 3-iodo-l-methyl-lH-pyrazole-5-carboxylate 18.2
  • Step 3 Synthesis of l-methyl-3-phenyl-lH-pyrazole-5-carboxylic acid 18.3
  • Step 4 Synthesis of l-methyl-3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 18.4
  • Step 5 Synthesis of l-methyl-3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ - lH-pyrazole-5-carboxamide, 1-76
  • Step 1 Synthesis of N- ⁇ 4-[(4-methoxy-6-methylpyrimidin-2-yl)sulfamoyl] phenyl ⁇ acetamide 19.1
  • Step 2 Synthesis of 4-amino-N-(4-methoxy-6-methylpyrimidin-2-yl)benzene-l- sulfonamide 19.2
  • Step 3 Synthesis of N- ⁇ 4-[(4-methoxy-6-methylpyrimidin-2- yl)sulfamoyl]phenyl ⁇ -l-methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-90
  • Example 20 Synthesis of N- ⁇ 4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl ⁇ -l- methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-85
  • Step 1 Synthesis of N- ⁇ 4-[(5-methoxypyrimidin-2-yl)sulfamoyl] phenyl ⁇ acetamide 20.1
  • Step 2 Synthesis of 4-amino-N-(5-methoxypyrimidin-2-yl)benzene-l- sulfonamide hydrochloride 20.2
  • Step 3 Synthesis of 4-amino-N-(5-methoxypyrimidin-2-yl)-N- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ benzene-l-sulfonamide 20.3
  • Step 4 Synthesis of N- ⁇ 4-[(5-methoxypyrimidin-2-yl)( ⁇ [2-(trimethylsilyl) ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ -l-methyl-3-phenyl-lH-pyrazole-5-carboxamide 20.4
  • Step 5 Synthesis of N- ⁇ 4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl ⁇ -l- methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-85
  • Example 22 Synthesis of 3-(2-Hydroxyphenyl)-l-methyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-p razole-5-carboxamide, 1-95
  • Step 1 Synthesis of 3-(2-methoxyphenyl)-l-methyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 22.2
  • Methanesulfonyl chloride (0.05 ml, 0.6 mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene- 1 -sulfonamide (22.1 , 164mg, 0.43mmol), 3 -(2-methoxyphenyl)-l -methyl- lH-pyrazole-5-carboxylic acid (lOOmg, 0.43 mmol) and 3-picoline (0.13ml, 1.29 mmol) in MeCN (dry, 5ml) at 0°C.
  • Step 2 Synthesis of 3-(2-hydroxyphenyl)-l-methyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl] phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-95
  • Example 23 Synthesis of l-[2-(dimethylamino)ethyl]-3-ph [(pyrimidin-2-yl)sulfamoyl] henyl ⁇ -lH-pyrazole-5-carboxamide, 1-93
  • Step 1 Synthesis of methyl l-[2-(dimethylamino)ethyl]-3-phenyl-lH-pyrazole-5- carboxylate 23.1
  • Step 2 Synthesis of lithio l-[2-(dimethylamino)ethyl]-3-phenyl-lH-pyrazole-5- carboxylate 23.2
  • Step 3 Synthesis of l-[2-(dimethylamino)ethyl]-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)( ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 23.3
  • Step 4 Synthesis of l-[2-(dimethylamino)ethyl]-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-93
  • Example 24 Synthesis of l-methyl-5-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl] phenyl ⁇ -lH-pyrazole-3-carboxamide, 1-98
  • Step 3 Synthesis of l-methyl-5-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-3-carboxamide 24.1
  • Step 4 Synthesis of l-methyl-5-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ - lH-pyrazole-3-carboxamide, 1-98
  • Example 25 Synthesis of l-(2-methoxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 1-87
  • Step 1 Synthesis of methyl l-(2-methoxyethyl)-3-phenyl-lH-pyrazole-5- carboxylate and methyl l-(2-methoxyethyl)-5-phenyl-lH-pyrazole-3-carboxylate 25.1
  • Step 2 Synthesis of lithio l-(2-methoxyethyl)-3-phenyl-lH-pyrazole-5- carboxylate 25.2
  • Step 3 Synthesis of l-(2-methoxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 25.3
  • Methanesulfonyl chloride (0.04 ml, 0.56 mmol) was added to a mixture of 4-amino- N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene-l-sulfonamide (15 lmg, 0.4 mmol), lithio 1 -(2 -methoxyethyl)-3 -phenyl- lH-pyrazole-5-carboxylate (25.2, lOOmg, 0.4 mmol) and 3-picoline (0.12ml, 1.19 mmol) in MeCN (dry, 5ml) at 0°C.
  • reaction mixture was allowed to reach rt and stirred for 30 minutes.
  • the reaction mixture was diluted with DCM (75ml) and water (50ml).
  • the aqueous layer was further extracted with DCM (2 x 40ml) and the combined layers dried over Na 2 S0 4 .
  • Evaporation of the solvent afforded a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 216mg (72%) of l-(2-methoxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2-
  • Step 4 Synthesis of l-(2-methoxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-87
  • Example 26 Synthesis of l-(2-hydroxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl] phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-96
  • Step 5 Synthesis of l-(2-hydroxyethyl)-3-phenyl-N- ⁇ 4-[(pyrimidin-2- yl)sulfamoyl] phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-96
  • Step 1 Synthesis of methyl 3-phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.1
  • Step 2 Synthesis of lithio 3-phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.2
  • Step 3 Synthesis of 3-phenyl-l-(propan-2-yl)-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 27.3
  • Step 4 Synthesis of 3-phenyl-l-(propan-2-yl)-N- ⁇ 4-[(pyrimidin-2-yl) sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-88
  • Triethylamine (0.20 ml, 1.40 mmol) was added at rt to a stirred solution of 4-amino- N-(pyrimidin-2-yl)benzene-l -sulfonamide (300mg, 1.20 mmol) in DCM (HPLC grade, 10ml), followed by 4-chlorobenzoyl chloride (0.11 ml, 0.90 mmol). The mixture was stirred at rt for 5 minutes. The reaction mixture was filtered through celite and evaporated to dryness.
  • Example 29 Synthesis of 4-chloro-N-methyl-N- ⁇ 4- [(pyrimidin-2- yl)sulfamoyl] henyl ⁇ benzamide, 1-39
  • Step 1 Synthesis of 4-(methylamino)-N-(pyrimidin-2-yl)benzene-l-sulfonamide 29.1
  • Step 2 Synthesis of 4-chloro-N-methyl-N- ⁇ 4- [(pyrimidin-2-yl)sulfamoyl] phenyl ⁇ benzamide, 1-39
  • DIPEA 129.7 ⁇ , 0.74 mmol
  • DCM 4-(methylamino)-N- (pyrimidin-2-yl)benzene-l -sulfonamide
  • 29.1 150 mg, 0.57 mmol
  • DCM HPLC grade, 10 ml
  • 4-chlorobenzoyl chloride 99 mg, 0.57 mmol
  • DCM HPLC grade, 5ml
  • Example 30 Synthesis of 3-(2-hydroxyphenyl)-N- ⁇ 4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-63
  • Step 1 Synthesis of 4-Amino-N-methyl-N-(pyrimidin-2-yl)benzene-l- sulfonamide 30.1
  • lodomethane (0.50 ml, 8.0 mmol) was added to a mixture of 4-amino-N-(pyrimidin- 2-yl)benzene-l -sulfonamide (2.00g, 8.0 mmol) and K 2 C0 3 (1.10 g, 8.0 mmol) in DMF (HPLC grade, 35 ml) at 0°C.
  • the reaction mixture was allowed to reach rt and stirred for lh.
  • the mixture was diluted with water (100 ml) then extracted with DCM (3 x 100 ml).
  • Step 2B Synthesis of 3-(2-methoxyphenyl)-N- ⁇ 4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-p razole-5-carboxamide, 1-60
  • DIPEA (0.79 ml, 4.54 mmol) and HATU (0.86g, 2.27 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (0.33g, 1.51 mmol) in DMF (HPLC grade, 15ml), followed by 4-amino-N-methyl-N-(pyrimidin-2-yl)benzene-l- sulfonamide (30.1, 0.40g, 1.51 mmol). The mixture was stirred for 20h at rt then 23h at 60°C.
  • reaction mixture was diluted with water (100 ml), extracted with DCM (3 x 75ml) and the combined organics dried over Na 2 S0 4 .
  • the solvent was removed in vacuo and the crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 0.25g (36%) of 3-(2-methoxyphenyl)-N- ⁇ 4-[methyl(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH- pyrazole-5-carboxamide 1-60 as a light brown solid.
  • Step 3 Synthesis of 3-(2-hydroxyphenyl)-N- ⁇ 4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide, 1-63
  • Triethylamine (0.09 ml, 0.68 mmol) was added at rt to a stirred solution of 4-amino- N-methyl-N-(pyrimidin-2-yl)benzene-l -sulfonamide (30.1 150mg, 0.57 mmol) in DCM (HPLC grade, 7ml), followed by 4-chlorobenzoyl chloride (0.07 ml, 0.57 mmol). The mixture was stirred for 14h at rt. The reaction mixture was diluted with water (75 ml) then extracted with DCM (3 x 50ml) and the combined organics dried over Na 2 S0 4 .
  • Example 32 Synthesis of N- ⁇ 4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -3-phenyl-lH-pyrazole-5-carboxamide, 1-47
  • DIPEA (0.42 ml, 2.39 mmol) and HATU (460m g, 1.2 mmol) were added at rt to a stirred solution of 5 -phenyl- lH-pyrazole-3-carboxylic acid (150mg, 0.8 mmol) in DMF (HPLC grade, 7ml), followed by 4-amino-N-methyl-N-(pyrimidin-2-yl)benzene-l -sulfonamide (30.1, 210mg, 0.8 mmol). The mixture was stirred for 15h at rt. The reaction mixture was diluted with sat. aq.
  • Step 1 Synthesis of 3-amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ benzene-l-sulfonamide 33.1
  • DIPEA (0.35 ml, 2 mmol) and DMAP (20mg, 0.20 mmol) were added to a stirred solution of 3-amino-N-(pyrimidin-2-yl)benzenesulfonamide (500mg, 2.0 mmol) in DCM (HPLC grade, 5 ml) at 0°C, followed by SEMC1 (0.35 ml, 2.0 mmol). The mixture was stirred at rt for 62h. The reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined organics were dried over Na 2 S0 4 and evaporated to dryness.
  • Step 2A Synthesis of 4-chloro-N- ⁇ 3-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ ) sulfamoyl]phenyl ⁇ benzamide 33.2
  • DIPEA (0.25 ml, 1.4 mmol) and HATU (270mg, 0.71 mmol) were added at rt to a stirred solution of 4-chlorobenzoic acid (70mg, 0.47 mmol) in DCM (HPLC grade, 10ml) followed by 3 -amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene- 1 - sulfonamide (33.1, 180mg, 0.47 mmol).
  • the mixture was stirred for 21h at rt, then re-treated with 4-chlorobenzoic acid (40mg, 0.26 mmol), DIPEA (0.32 ml, 1.84 mmol) and HATU (360mg, 0.95 mmol) and stirred for 24h at rt.
  • the reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined layers were dried over Na 2 S0 4 and evaporated to dryness.
  • Step 3A Synthesis of 4-chloro-N- ⁇ 3-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ benzamide, 1-64
  • Example 34 Synthesis of l-[5-(2-Hydroxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide 1-77
  • Step 1 Synthesis of N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,3- dihydro-lH-indole-5-sulfonamide 34.1
  • DIPEA (0.32 ml, 1.81 mmol) and DMAP (20mg, 0.18 mmol) were added to a stirred solution of N-(pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide (500mg, 1.81 mmol) in DCM (HPLC grade, 15 ml) at 0°C followed by SEMC1 (0.32 ml, 1.81 mmol). The mixture was stirred at rt for 90h. The reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined layers were dried over Na 2 S0 4 and evaporated to dryness.
  • Step 2B Synthesis of l-[5-(2-Methoxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,3-dihydro-lH-indole-5-sulfonamide 34.2
  • DIPEA (0.21 ml, 1.23 mmol) and HATU (230mg, 0.62 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (90mg, 0.41 mmol) in DMF (7.5ml), followed by N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,3- dihydro-lH-indole-5 -sulfonamide (34.1, 170mg, 0.41 mmol).
  • Step 3B Synthesis of l-[5-(2-Hydroxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide, 1-77
  • Step 2B Synthesis of 5-phenyl-N- ⁇ 3-[(pyrimidin-2-yl)( ⁇ 2- [(trimethylsilyl)oxy] ethyl ⁇ ) sulfamoyl]phenyl ⁇ -lH-pyrazole-3-carboxamide 35.1
  • DIPEA (0.35 ml, 2 mmol) and HATU (380mg, 1.0 mmol) were added at rt to a stirred solution of 5 -phenyl- 1 H-pyrazole-3 -carboxylic acid (130mg, 0.67 mmol) in DMF (HPLC grade, 10ml), followed by 3-amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ benzene- 1-sulfonamide (33.1, 250mg, 0.67 mmol). The mixture was stirred for 20h at rt and then filtered, diluted with water (75 ml) and extracted into DCM (3 x 50 ml).
  • Step 3C Synthesis of 5-phenyl-N- ⁇ 3-[(pyrimidin-2-yl)sulfamoyl]phenyl ⁇ -lH- pyrazole-3-carboxamide, 1-61
  • Example 36 Synthesis of 5-(2-hydroxyphenyl)-N- ⁇ 3-[(pyrimidin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-3-carboxamide, 1-81
  • Step 2B Synthesis of 4-(2-methoxyphenyl)-N- ⁇ 3-[(pyrimidin-2-yl)( ⁇ [2- trimethylsilyl)ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-pyrazole-3-carboxamide 36.1
  • DIPEA (0.21 ml, 1.23 mmol) and HATU (230mg, 0.62 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (90mg, 0.41 mmol) in DMF (7.5ml), followed by 3-amino-N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ benzene- 1-sulfonamide (33.1, 160mg, 0.41 mmol). The mixture was stirred for 65h.
  • Step 3B Synthesis of 5-(2-hydroxyphenyl)-N- ⁇ 3-[(pyrimidin-2-yl)sulfamoyl] phenyl ⁇ - lH-pyrazole-3-carboxamide, 1-81
  • Example 37 Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indole-5-sulfonamide, 1-65
  • Step 2B Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2-yl)- N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,3-dihydro-lH-indole-5-sulfonamide 37.1
  • DIPEA (0.16 ml, 0.89 mmol) and HATU (170mg, 0.45 mmol) were added at rt to a stirred solution of 5 -phenyl- lH-pyrazole-3-carboxylic acid (60mg, 0.30 mmol) in DMF (HPLC grade, 10ml) followed by N-(pyrimidin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,3-dihydro- lH-indole-5 -sulfonamide (34.1, 120mg, 0.30 mmol).
  • Step 3C Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indole-5-sulfonamide, 1-65
  • Example 38 Synthesis of l-methyl-3-phenyl-N-[4-(phenylformamido) sulfonylphenyl] -lH-pyrazole-5-carboxamide, 1-94
  • Step 1 Synthesis of N-(4-aminobenzenesulfonyl)-N- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ benzamide 38.1
  • DIPEA (0.47 ml, 2.7 mmol) and DMAP (22mg, 0.18 mmol) were added to a solution of N-(4-aminobenzenesulfonyl)benzamide (500mg, 1.81 mmol) in DCM (HPLC grade, 10 ml), followed by SEMCl (0.35 ml, 2.0 mmol). The mixture was stirred at rt for 2.5h. Water (20ml) was added and the mixture extracted with DCM (2 x 20 ml).
  • Step 2 Synthesis of l-methyl-3-phenyl-N- ⁇ 4-[(l-phenyl-N- ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ formamido)sulfonyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 38.2
  • Step 3 Synthesis of l-methyl-3-phenyl-N-[4-(phenylformamido)sulfonylphenyl]- lH-pyrazole-5-carboxamide, 1-94
  • Example 39 Synthesis of 3-(2-hydroxyphenyl)-N-[4-(phenylsulfamoyl)phenyl]- lH-pyrazole-5-carboxamide 1-37
  • Step 1 Synthesis of 3-(2-hydroxyphenyl)-lH-pyrazole-5-carbonyl chloride 39.1
  • Step 2 Synthesis of 3-(2-hydroxyphenyl)-N-[4-(phenylsulfamoyl)phenyl]-lH- pyrazole-5-carboxamide, 1-37
  • DIPEA 256 ⁇ , 1.47 mmol
  • reaction mixture was concentrated in vacuo and the remaining material was purified by flash column chromatography (DCM/MeOH 100/0 to 95/5) and prep HPLC (MeCN/water, 0.1% formic acid) to obtain 5mg (1%) of 3-(2-hydroxyphenyl)-N- ⁇ 4-[(pyridin-2- yl)sulfamoyl]phenyl ⁇ -lH-pyrazole-5-carboxamide 1-37 as a white powder.
  • Example 40 Synthesis of 4-chloro-N- ⁇ 4-[(pyridin-2- yl)sulfamoyl]phenyl ⁇ benzamide 1-62
  • Step 4 Synthesis of 4-chloro-N- ⁇ 4-[(pyridin-2-yl)( ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ benzamide 40.2 [00485] To a solution of 4-amino-N-(pyridin-2-yl)-N- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ benzene-l -sulfonamide (40.1, lOOmg, 0.26 mmol) in DCM (2 ml) was added DIPEA (50 ⁇ , 0.29 mmol).
  • Step 5 Synthesis of 4-chloro-N- ⁇ 4-[(pyridin-2-yl)sulfamoyl]phenyl ⁇ benzamide, I- 62
  • Example 41 was prepared according to the reaction sequence in Scheme XVIII.
  • Step 1 Synthesis of methyl 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoate 41.1
  • Methanesulfonyl chloride (0.05 ml, 0.69 mmol) was added to a mixture of methyl 4- aminobenzoate (75mg, 0.49 mmol), l-methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (100 mg, 0.49 mmol) and 3-picoline (0.14 ml, 1.48 mmol) in MeCN (dry, 5ml) at 0°C. After addition, the reaction mixture was allowed to reach rt and stirred for 17h. The reaction mixture was diluted with DCM (50ml) and water (50ml).
  • Step 2 Synthesis of 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoic acid, I- 86
  • Example 42 The compound of Example 42 was prepared according to the reaction sequence in Scheme XIX.
  • Step 1 Synthesis of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate 42.1
  • Step 2 Synthesis of benzyl N- ⁇ l-[(pyrimidin-2-yl)sulfamoyl]piperidin-4- yl ⁇ carbamate 42.2
  • Step 3 Synthesis of 4-amino-N-(pyrimidin-2-yl)piperidine-l-sulfonamide hydrochloride 42.3
  • Step 4 Synthesis of 3-phenyl-N- ⁇ l-[(pyrimidin-2-yl)sulfamoyl] piperidin-4-yl ⁇ - lH-pyrazole-5-carboxamide, 1-91
  • Example 43 The compound of Example 43 was prepared according to the reaction sequence in Scheme XX.
  • Example 43 Synthesis of 5-chloro-l-methyl-N-(4-(N-(pyrimidin-2- yl)sulfamoyl)phenyl)-lH-indole-2-carboxamide 1-102
  • Step 1 Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylate 43.1
  • Step 2 Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylic acid 43.2
  • Step 3 Synthesis of 5-chloro-l-methyl-N- ⁇ 4-[(pyrimidin-2-yl)( ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ )sulfamoyl]phenyl ⁇ -lH-indole-2-carboxamide 43.3
  • Step 4 Synthesis of 5-chloro-l-methyl-N- ⁇ 4-[(pyrimidin-2-yl)sulfamoyl] phenyl ⁇ - lH-indole-2-carboxamide 1-102
  • Example 44 Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase coupled assay
  • PHGDH activity was determined by detecting the NADH produced during the reaction.
  • Diaphorase was used to catalyze the oxidation of NADH with the concomitant reduction of resazurin to the fluorescent product resorufin.
  • Resorufm fluorescence quantitatively reflected the production of NADH by the PHGDH reaction.
  • PSAT1 phosphoserine aminotransferase
  • PSPH phosphoserine phosphatase
  • the plate was then incubated at 30°C for 60 minutes and resorufin fluorescence was measured at emission wavelength 598nM following excitation at 525nM.
  • the positive control consisted of the complete reaction mixture with 4% DMSO and was set to 0% inhibition and negative control consisted of the reaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition. Percent inhibition with the compounds was then calculated by normalizing the fluorescence observed at a given compound concentration to the positive and negative controls. The IC 50 was calculated by plotting the % inhibition versus concentration and using hyperbolic fit to determine compound concentration corresponding to 50% inhibition.
  • Table 2 shows the activity of selected compounds of this invention in the full-length PHGDH activity inhibition assay.
  • the compound numbers correspond to the compound numbers in Table 1.
  • Compounds having an activity designated as "A” provided an IC 50 ⁇ 50 ⁇ ; compounds having an activity designated as “B” provided an IC 50 of 50-100 ⁇ ; and compounds having an activity designated as “C” provided an IC 50 of > 100 ⁇ .
  • “NA” stands for "not assayed.”

Abstract

The present invention provides compounds, compositions and methods useful for treating a variety of diseases, disorders or conditions, associated with PHGDH.

Description

3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES
THEREOF
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds and methods useful for inhibiting 3- phosphoglycerate dehydrogenase. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
BACKGROUND OF THE INVENTION
[0002] Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the biosynthesis of L-serine, which is the conversion of 3 -phosphoglycerate into 3- phosphohydroxypyruvate with a reduction of nicotinamide adenine dinucleotide (NAD ) to
NADH.
[0003] Certain cancers, including human melanomas and breast cancers, can have high levels of PHGDH. These cancer cells are dependent on PHGDH for their growth and survival as PHGDH catalyzes serine production and may also be a significant source of NADPH in cancer cells. Targeting PHGDH by small molecule inhibitors could be a therapeutic strategy to reduce cancer cell growth and survival. Accordingly, there remains a need to find PHGDH inhibitors useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0004] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as PHGDH inhibitors. Such compounds have the general formula I:
Figure imgf000002_0001
I or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
[0005] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with PHGDH. Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer) such as those described herein.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Certain Embodiments of the Invention:
[0006] Compounds of the present invention, and compositions thereof, are useful as inhibitors of PHGDH. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and compositions thereof, may inhibit the activity of PHGDH and/or inhibit the production of NADPH, and thus reduce the growth of cells in proliferative disorders such as cancer.
[0007] In certain embodiments the present invention provides a compound of formula I:
Figure imgf000003_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6 membered saturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring D is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring;
each of m and q is independently 0, 1, 2, 3, 4, or 5;
each of n and p is independently 0, 1, 2, 3 4 or 5;
r is 0 or 1; where if r = 0, n is 0, 1, 2, 3, 4 or 5; and if r = 1, n is 0, 1, 2, 3 or 4;
s is 0 or 1; where if s = 0, p is 0, 1, 2, 3, 4 or 5; and if s = 1, p is 0, 1, 2, 3 or 4;
each of R1, R2, R3, and R4 is independently halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N(R)C(0)N(R)2, -N(R)C(NR)N(R)2, -N02, -CN, -S02N(R)2, -N(R)S02R, - S02N(R)C(0)R, -S02N(R)C(0)N(R)2, - S02N(R)C(NR)N(R)2 , -C(0)N(R)C(0)R or - CR^OH)^
each R is independently hydrogen, or an optionally substituted group selected from Ci_6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
L1 is a covalent bond, or a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S02-,
-S02N(R)-, -C(0)-, -0C(0)-, -C(0)0-, -0-, -S-, -SO-, or -S02-;
L2 is -C(0)NR-, -NRC(O)-, -CH2N(R)-, -N(R)C(0)NR-; or
L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
L is a bivalent Ci_6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by - S02NR-; -N(R)S02-,-S02-, -S02N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, or
- N(R)C(0)NR-, or L is a bivalent tetrazolylene ring;
with the provision that the compound is not 3-(2-hydroxy-3,4-dimethylphenyl)-N-(4-(N-
(pyrimidin-2-yl)sulfamoyl)phenyl)-lH-pyrazole-5-carboxamide, i compound 1-1 in
Table 1 below.
2. Compounds and Definitions:
[0008] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0009] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cyclo aliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0010] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary brid ed bicyclics include:
Figure imgf000006_0001
Figure imgf000007_0001
[0011] The term "lower alkyl" refers to a Ci_4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
[0012] The term "lower haloalkyl" refers to a Ci_4 straight or branched alkyl group that is substituted with one or more halogen atoms.
[0013] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ΝΗ (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
[0014] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.
[0015] As used herein, the term "bivalent Ci_s (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
[0016] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0017] The term "alkenylene" refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0018] As used herein, the term "cyclopropylenyl" refers to a bivalent cyclopropyl group of the following structure:
Figure imgf000008_0001
[0019] The term "halogen" means F, CI, Br, or I.
[0020] The term "aryl" used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
[0021] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a hetero aromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
[0022] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or (as in N-substituted pyrrolidinyl).
[0023] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical," are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cyclo aliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
[0024] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
[0025] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0026] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2)o-4R0; -(CH2)o-40R°; -0(CH2)o_4R°, -O- (CH2)0 4C(0)OR°; -(CH2)0 4CH(OR°)2; -(CH2)0^SR°; -(CH2)0^Ph, which may be substituted with R°; -(CH2)o-40(CH2)0-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o_40(CH2)0_i-pyridyl which may be substituted with R°; -N02; -CN; -N3; -(CH2)o 4N(R°)2; -(CH2)0 4N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)0 4N(R0)C(0)NR°2; -N(R°)C(S)NR°2; -(CH2)0 4N(R°)C(0)OR°; -N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0)NR°2; -N(R°)N(R°)C(0)OR0; -(CH2)0 4C(0)R°; -C(S)R°; -(CH2)0 4C(0)OR°; -(CH2)0 4C(0)SR°; -(CH2)o^C(0)OSiR°3; -(CH2)0 4OC(0)R°; -OC(O)(CH2)0^SR-, SC(S)SR°; -(CH2)0 4SC(0)R°; -(CH2)o 4C(0)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)0 4OC(0)NR°2; -C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH2C(0)R°; -C(NOR°)R°; -(CH2)0^SSR°; -(CH2)0 4S(0)2R°; -(CH2)o^S(0)2OR°; -(CH2)0 4OS(0)2R°; -S(0)2NR°2; -(CH2)0 4S(0)R°; -N(R°)S(0)2NR°2; -N(R°)S(0)2R°; -N(OR°)R°; -C(NH)NR°2; -P(0)2R°; -P(0)R°2; -OP(0)R°2; -OP(0)(OR°)2; SiR°3; -(Ci^ straight or branched alkylene)0-N(R°)2; or -(Ci_4 straight or branched alkylene)C(0)0-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci_6 aliphatic, -CH2Ph, -O(CH2)0 iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0027] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0 2R*, -(haloR*), -(CH2)0 2OH, -(CH2)0 2OR*, -(CH2)0 2CH(OR*)2; -O(haloR'), -CN, -N3, -(CH2)0 2C(0)R*, -(CH2)0 2C(0)OH, -(CH2)0 2C(0)OR*, -(CH2)0 2SR*, -(CH2)o 2SH, -(CH2)o 2NH2, -(CH2)0 2NHR*, -(CH2)0 2NR*2, -N02, -SiR*3, -OSiR*3, -C(0)SR* -(Ci-4 straight or branched alkylene)C(0)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from Ci_4 aliphatic, -CH2Ph, -O(CH2)0 iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
[0028] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR* 2, =NNHC(0)R*, =NNHC(0)OR*, =NNHS(0)2R*, =NR*, =NOR*, -0(C(R* 2))2 30- or -S(C(R* 2))2_3S- wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -0(CR 2)2-30-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0029] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH2, -NHR*, -NR*2, or -N02, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH2Ph, -O(CH2)0_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0030] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R†, -NR† 2, -C(0)R†, -C(0)OR†, -C(0)C(0)R†, -C(0)CH2C(0)R†, -S(0)2R†, -S(0)2NR† 2, -C(S)NR† 2, -C(NH)NR† 2, or -N(R†)S(0)2R†; wherein each R† is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0031] Suitable substituents on the aliphatic group of R† are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH2, -NHR*, -NR*2, or -N02, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0032] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0033] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci^alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0034] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a warhead moiety, R1, of a provided compound comprises one or more deuterium atoms.
[0035] As used herein, the term "inhibitor" is defined as a compound that binds to and /or inhibits PHGDH with measurable affinity. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 100 μΜ, less than about 50 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
[0036] The terms "measurable affinity" and "measurably inhibit," as used herein, means a measurable change in PHGDH activity between a sample comprising a compound of the present invention, or composition thereof, and PHGDH, and an equivalent sample comprising PHGDH, in the absence of said compound, or composition thereof.
3. Description of Exemplary Embodiments:
[0037] In certain embodiments the present invention provides a compound of formula I:
Figure imgf000014_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6 membered saturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring D is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring; each of m and q is independently 0, 1, 2, 3, 4, or 5;
each of n and p is independently 0, 1, 2, 3, 4 or 5;
r is 0 or 1; where if r = 0, n is 0, 1, 2, 3, 4 or 5; and if r = 1, n is 0, 1, 2, 3 or 4;
s is 0 or 1; where if s = 0, p is 0, 1, 2, 3, 4 or 5; and if s = 1, p is 0, 1, 2, 3 or 4;
each of R1, R2, R3, and R4 is independently halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N(R)C(0)N(R)2, -N(R)C(NR)N(R)2, -N02, -CN, -S02N(R)2, -N(R)S02R, - S02N(R)C(0)R, -S02N(R)C(0)N(R)2, - S02N(R)C(NR)N(R)2, -C(0)N(R)C(0)R or - CR^OH)^
each R is independently hydrogen, or an optionally substituted group selected from Ci_6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
L1 is a covalent bond, or a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S02-,
-S02N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S02-;
L2 is -C(0)NR-, -NRC(O)-, -CH2N(R)-, -N(R)C(0)NR-; or
L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
L is a bivalent Ci_6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by - S02NR-; -N(R)S02-,-S02-, -S02N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, or
- N(R)C(0)NR-, or L is a bivalent tetrazolylene ring; with the provision that the compound is not 3-(2-hydroxy-3,4-dimethylphenyl)-N-(4-(N- (pyrimidin-2-yl)sulfamoyl)phenyl)-lH-pyrazole-5-carboxamide, i.e., compound 1-1 in Table 1 below.
[0038] As defined generally above, the Ring A group of formula I is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0039] In some embodiments, Ring A is phenyl.
[0040] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is thiophen-2-yl. In some embodiments, Ring A is thiophen-3-yl.
[0041] In some embodiments, Ring A is an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is naphthalenyl. In some embodiments, Ring A is naphthalen-l-yl. In some embodiments, Ring A is naphthalen-2-yl. In some embodiments, Ring A is quinolinyl. In some embodiments, Ring A is quinolinyl. In some embodiments, Ring A is quinolin-2-yl. In some embodiments, Ring A is quinolin-3-yl. In some embodiments, Ring A is quinolin-4-yl. In some embodiments, Ring A is quinolin-8-yl. In some embodiments, Ring A is benzothiophen-2-yl.
[0042] In some embodiments, Ring A is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is pyrrolidinyl. In some embodiments, Ring A is piperidinyl. In some embodiments, Ring A is pyrrolinyl. In some embodiments, Ring A is oxazolidinyl. In some embodiments, Ring A is piperazinyl. In some embodiments, Ring A is morpholinyl.
[0043] As defined generally above, the r group of formula I is 0 or 1. In some embodiments, r is 0. In other embodiments, r is 1.
[0044] As defined generally above, the Ring B group of formula I is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0045] One of ordinary skill in the art will appreciate that when r = 1 , the Ring B group of formula I is bivalent, e.g., in such instances phenyl is phenylene, heteroaryl is heteroarylene, etc.
[0046] In some embodiments, Ring B is phenyl.
[0047] In some embodiments, Ring B is a 5 membered monocyclic heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is pyrazolyl. In some embodiments, Ring B is triazolyl. In some embodiments, Ring B is oxazolyl. In some embodiments, Ring B is furanyl. In some embodiments, Ring B is imidazolyl.
[0048] In some embodiments, Ring B is 6 membered monocyclic heteroaryl ring having 1-2 nitrogens. In some embodiments, Ring B is pyridinyl.
[0049] In some embodiments, Ring B is an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, r = 0 and Ring B is an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B is indolyl. In some embodiments, Ring B is pyrazolo[l,5-a]pyridyl. In some embodiments, Ring B is 1,3- benzodiazolyl. In some embodiments, Ring B is not 1,3-benzodiazolyl. In some embodiments, Ring B is pyrrolo[2,3-b]pyridyl. In some embodiments, Ring B is benzothiophenyl. In some embodiments, r = 0 and Ring B is indolyl. In some embodiments, r = 0 and Ring B is pyrazolo[l,5-a]pyridyl. In some embodiments, r = 0 and Ring B is not 1,3-benzodiazolyl. In some embodiments, Ring B is r = 0 and pyrrolo[2,3-b]pyridyl. In some embodiments, r = 0 and Ring B is benzothiophenyl.
[0050] As defined generally above, the Ring C group of formula I is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0051] One of ordinary skill in the art will appreciate that when s = 1, the Ring C group of formula I is bivalent, e.g., in such instances phenyl is phenylene, heteroaryl is heteroarylene, etc. 0052] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is
Figure imgf000018_0001
[0053] In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring C is pyridinyl.
[0054] In some embodiments, Ring C is a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring C is piperidin-l-yl. In some embodiments, Ring C is piperazin-l-yl.
[0055] In some embodiments, Ring C is cycloalkyl. One of ordinary skill in the art will appreciate that a R substituent on a saturated carbon of cycloalkyl forms a chiral center. In some embodiments, that chiral center is in the (R) configuration. In other embodiments, that chiral center is in the (S) configuration. In some embodiments, Ring C is cyclohexyl.
[0056] As defined generally above, the Ring D group of formula I is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring.
[0057] In some embodiments, Ring D is phenyl.
[0058] In some embodiments, Ring D is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is furanyl. In some embodiments, Ring D is a 6 membered monocyclic heteroaryl ring having 1-3 nitrogens. In some embodiments, Ring D is pyridinyl. In some embodiments, Ring D is pyridin-2-yl. In some embodiments, Ring D is pyridin-3-yl. In some embodiments, Ring D is pyridin-4-yl. In some embodiments, Ring D is pyrimidinyl. In some embodiments, Ring D is pyrimidin-2-yl. In some embodiments, Ring D is triazinyl.
[0059] In some embodiments, Ring D is a 5 membered monocyclic heteroaryl ring having 1- 4 heteroatoms selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is thiazol-2-yl. In some embodiments, Ring D is lH-imidazol-2-yl. In some embodiments, Ring D is lH-pyrazol-5-yl. In some embodiments, Ring D is lH-triazol-5-yl. In some embodiments, Ring D is lH-tetrazol-5-yl.
[0060] In some embodiments, Ring D is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D is morpholino. In some embodiments, Ring D is piperidin-l-yl. In some embodiments, Ring D is piperidin-4-yl. In some embodiments, Ring D is piperazin-l-yl. In some embodiments, Ring D is 4,5-dihydro-lH-imidazol-2-yl.
[0061] In some embodiments, Ring D is a 5-6 membered saturated monocyclic carbocyclic ring. In some embodiments, Ring D is cyclopentyl. In some embodiments, Ring D is cyclohexyl.
[0062] As defined generally above, the s group of formula I is 0 or 1. In some embodiments, s is 0. In other embodiments, s is 1.
[0063] As defined generally above, the L1 group of formula I is a covalent bond, or a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, - N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S02-, -S02N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S02-. In some embodiments, L1 is a covalent bond. In other embodiments, L1 is a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, - N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S02-, -S02N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S02-.
[0064] As defined generally above, the L group of formula I is a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or -NR-, or
L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0065] In some embodiments L is a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or -NR-. 2 2
[0066] In some embodiments, L is -C(0)NR-. In some embodiments, L is -C(0)NR- and
2 2
R is hydrogen. In some embodiments, L is -N(R)C(0)-. In some embodiments, L is -
2 2
N(R)C(0)NR-. In some embodiments, L is -CH2N(R)-. Exemplary L groups include those depicted in Table 1.
[0067] In some embodiments L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0068] As defined generally above, the L group of formula I is a bivalent Ci_6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -S02NR-; -N(R)S02-, -S02-, - S02N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, or L3 is a bivalent tetrazolylene ring.
[0069] In some embodiments, L is a bivalent Ci_6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -S02NR-; -N(R)S02-, -S02-, N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR- , -N(R)C(0)-, - N(R)C(0)NR-.
[0070] In some embodiments, L is -S02NR- (i.e., a Ci bivalent hydrocarbon chain wherein the methylene unit is replaced by -S02NR-), -N(R)S02-, -S02- -S02N(R)C(0)-; - C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, or -N(R)C(0)NR-. In some embodiments, L3 is -
3 3
S02NR-. In some embodiments, L is -S02- In some embodiments, L is -N(R)S02-, - S02N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, or -N(R)C(0)NR-. Exemplary L3 groups include those depicted in Table 1.
[0071] In some embodiments, L is a bivalent tetrazolylene ring.
[0072] As defined generally above, each of R1, R2, R3, and R4 group of formula I is independently halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, -N(R)C(0)R, - N(R)C(0)N(R)2, -N(R)C(NR)N(R)2, -N02, -CN, -S02N(R)2, -N(R)S02R, -S02N(R)C(0)R, - S02N(R)C(0)N(R)2, - S02N(R)C(NR)N(R)2, -C(0)N(R)C(0)R or -CR^Ot^R.
[0073] In some embodiments, R1 is halogen, R, -OR, -SR, -N(R)2, -NHR, -C(0)R, - C(0)N(R)2, -N(R)C(0)R, -N02, -CN, -S02N(R)2, -N(R)S02R, or -C(0)N(R)C(0)R. In some embodiments, R1 is halogen. In some embodiments, R1 is R. In some embodiments, R1 is -OR. In some embodiments, R is -SR. In some embodiments, R is -N(R)2. In some embodiments, R1 is -NHR. In some embodiments, R1 is -C(0)R. In some embodiments, R1 is -C(0)N(R)2. In some embodiments, R1 is -N(R)C(0)R. In some embodiments, R1 is -N02. In some embodiments, R1 is -CN. In some embodiments, R1 is -S02N(R)2. In some embodiments, R1 is - N(R)S02R. In some embodiments, R1 is -C(0)N(R)C(0)R.
[0074] Exemplary R1 groups include those depicted in Table 1. In some embodiments, R1 is -CH3, -OH, -C(0)OH, -NH2, -phenyl. -F, -CI, -OCH3, -OCH2CH3 or -C(0)OH.
[0075] In some embodiments, Ring A is substituted with at least one R1 group. In some embodiments, Ring A is 3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4- trifiuoromethoxyphenyl, 4-phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- fiuorophenyl, 3 -fluorophenyl, 4-fiuorophenyl, 2,3-difluorophenyl, 2,4-difiuorophenyl, 2,5- difluorophenyl, 2,6-difiuorophenyl, 3,4-difiuorophenyl, 2,3,4-trifluorophenyl, 2,4,5- trifiuorophenyl, 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5- trifiuorophenyl, 2-methyl-N,N-dimethylamino-phenyl, 5-methylfuran-2-yl, 5-methylthiophen-2- yl. In some embodiments, Ring A is 4-fiuorophenyl.
[0076] In some embodiments two adjacent R1 groups on Ring A are taken together with their intervening atoms to form an optionally substituted 5-6 membered saturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur. In some embodiments, Ring A is:
Figure imgf000021_0001
[0077] As defined generally above, the m group of formula I is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.
[0078] In some embodiments, R2 is halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N02, -CN, -S02N(R)2, -N(R)S02R, or -C(0)N(R)C(0)R. In some embodiments,
2 2 2
R is halogen. In some embodiments, R is R. In some embodiments, R is -OR. In some
2 2 2 embodiments, R is -SR. In some embodiments, R is -N(R)2. In some embodiments, R is - C(0)R. In some embodiments, R2 is -C(0)N(R)2. In some embodiments, R2 is -N(R)C(0)R. In
2 2 2 some embodiments, R is -N02. In some embodiments, R is -CN. In some embodiments, R is 2 2
-S02N(R)2. In some embodiments, R is -N(R)S02R. In some embodiments, R is - C(0)N(R)C(0)R.
2 2
[0079] Exemplary R groups include those depicted in Table 1. In some embodiments, R is -F, -CI, -Br, -I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -cyclopropyl, -tert-butyl, -CN, - OCH3, -CH2CH2OCH3, -OCF3, -OCHF2, -CH2CH2N(CH3)2 or -phenyl.
[0080] In some embodiments, Ring B is substituted with at least one R group. In some embodiments, r = 0 and Ring B is 5-chloro-l-methylindolin-2-yl.
[0081] As defined generally above, the n group of formula I is 0, 1, 2, 3 4 or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
[0082] In some embodiments, r is 0 and n is 0. In some embodiments, r is 0 and n is 1. In some embodiments, r is 0 and n is 2. In some embodiments, r is 0 and n is 3. In some embodiments, r is 0 and n is 4. In some embodiments, r is 0 and n is 5.
[0083] In some embodiments, r is 1 and n is 0. In some embodiments, r is 1 and n is 1. In some embodiments, r is 1 and n is 2. In some embodiments, r is 1 and n is 3. In some embodiments, r is 1 and n is 4.
[0084] In some embodiments, R3 is halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N(R)C(0)N(R)2, -N(R)C(NR)N(R)2, -N02, -CN, -S02N(R)2, -N(R)S02R, - S02N(R)C(0)R, -S02N(R)C(0)N(R)2, - S02N(R)C(NR)N(R)2 or -C(0)N(R)C(0)R or -
1 3 3
CR OF R. In some embodiments, R is halogen. In some embodiments, R is R. In some
3 3 3 embodiments, R is -OR. In some embodiments, R is -SR. In some embodiments, R is -N(R)2.
3 3
In some embodiments, R is -C(0)R. In some embodiments, R is -C(0)N(R)2. In some embodiments, R3 is -N(R)C(0)R. In some embodiments, R3 is -N(R)C(0)N(R)2. In some
3 3
embodiments, RJ is -N(R)C(NR)N(R)2. In some embodiments, R is -N02. In some
3 3 3 embodiments, R is -CN. In some embodiments, R is -S02N(R)2. In some embodiments, R is - N(R)S02R. In some embodiments, R3 is -S02N(R)C(0)R. In some embodiments, R is - S02N(R)C(0)N(R)2. In some embodiments, R3 is - S02N(R)C(NR)N(R)2. In some embodiments, R3 is -C(0)N(R)C(0)R.
[0085] In some embodiments, s = 0 and R3 is -S02NH2, -S02NHC(NH)NH2, - S02NHC(0)NH2, -S02NHC(0)NHCH3, -S02NHC(0)NHCH(CH3)2, S02NHC(0)NHC(OH)(CH3)2, -S02NHC(0)NHC(OAc)(CH3)2, -C(CF3)2(OH), -C(CH3)(OH) (CF3), -C(CH3)2(OH) or -C(CONH2)(OH)CF3, -C(CONH2)(OH)CH3.
[0086] As defined generally above, the p group of formula I is 0, 1, 2, 3, 4 or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.
[0087] In some embodiments, s is 0 and p is 0. In some embodiments, s is 0 and p is 1. In some embodiments, s is 0 and p is 2. In some embodiments, s is 0 and p is 3. In some embodiments, s is 0 and p is 4. In some embodiments, s is 0 and p is 5.
[0088] In some embodiments, s is 1 and p is 0. In some embodiments, s is 1 and p is 1. In some embodiments, s is 1 and p is 2. In some embodiments, s is 1 and p is 3. In some embodiments, s is 1 and p is 4.
[0089] In some embodiments, R4 is halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N02, -CN, -S02N(R)2, -N(R)S02R, or -C(0)N(R)C(0)R. In some embodiments, R4 is halogen. In some embodiments, R4 is R. In some embodiments, R4 is -OR. In some embodiments, R4 is -OH. In some embodiments, R4 is -SR. In some embodiments, R4 is - N(R)2. In some embodiments, R4 is -C(0)R. In some embodiments, R4 is -C(0)N(R)2. In some embodiments, R4 is -N(R)C(0)R. In some embodiments, R4 is -N02. In some embodiments, R4 is -CN. In some embodiments, R4 is -S02N(R)2. In some embodiments, R4 is -N(R)S02R. In some embodiments, R4 is -C(0)N(R)C(0)R.
[0090] Exemplary R4 groups include those depicted in Table 1. In some embodiments, R4 is -CH3, -NH(CO)CH3, -OCH3, -C(0)OH, -CH2C(0)OH, -CH2C(0)OCH3 or -OCF3. In some embodiments, R4 is -CH3. In some embodiments, R4 is -OCH3. In some embodiments, R4 is - OCH2CH3.
[0091] In some embodiments, Ring D is substituted with at least one R4 group. In some embodiments, Ring A is 4-ethoxypyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl, 2- cyclopentan-l-ol, 2-cyclohexan-l-ol or 4-(l-methylpiperidin-3-ol).
[0092] As defined generally above, the q group of formula I is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.
[0093] In some embodiments, at least one of r and s is 1. In some embodiments, r is 1 and s is 0. In some embodiments, r is 0 and s is 1. In some embodiments, r is 1 and s is 1. [0094] As defined generally above, each R group of formula I is independently hydrogen, or an optionally substituted group selected from Ci_6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
[0095] two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur.
[0096] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted Ci_6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0097] In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur.
[0098] In certain embodiments, the present invention provides a compound of formula I, wherein r and s are 1 thereby forming a compound of formula II:
Figure imgf000024_0001
II
or a pharmaceutically acceptable salt thereof, wherein each of Ring A, Ring B, Ring C, Ring D,
2 3 1 2 3 4
m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[0099] In certain embodiments, the present invention provides a compound of formula I, wherein Ring A is phenyl, L1 is a covalent bond, and r and s are 1, thereby forming a compound of formula III:
Figure imgf000025_0001
III
or a pharmaceutically acceptable salt thereof, wherein each of Ring B, Ring C, Ring D, L 2 , L 3 , R1, R2, R3, R4, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00100] In certain embodiments, the present invention provides a compound of formula I, wherein Ring A is phenyl, Ring D is pyrimidinyl, L1 is a covalent bond, r and s are 1, thereby forming a compound of formula IV:
Figure imgf000025_0002
IV
or a pharmaceutically acceptable salt thereof, wherein each of Ring B, Ring C, L 2 , L 3 , R 1 , R2 , R 3 , R4, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00101] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring D is pyrimidinyl, L1 is a covalent bond, r and s are 1, thereb forming a compound of formula V:
Figure imgf000025_0003
V
or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or an optionally substituted
2 3 1 2 3 4
Ci_6 aliphatic, and each of Ring C, L , L , R , R , R , R , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00102] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl, L1 is a covalent bond, r and s are 1, thereby forming a compound of formula VI:
Figure imgf000026_0001
VI
or a pharmaceutically acceptable salt thereof, wherein each of L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00103] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is triazinyl, L1 is a covalent bond, r and s are 1 thereby forming a compound of formula VII:
Figure imgf000026_0002
VII
or a pharmaceutically acceptable salt thereof, wherein each of L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00104] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 3
L is a covalent bond, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula VIII:
Figure imgf000026_0003
VIII
or a pharmaceutically acceptable salt thereof, wherein each of L 2 , R, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00105] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 2 3
L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula IX:
Figure imgf000027_0001
IX
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00106] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is triazinyl, L1
2 3
is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula X:
Figure imgf000027_0002
X
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00107] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 2 3
L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula XI:
Figure imgf000028_0001
XI
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00108] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 2 3
L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula
Figure imgf000028_0002
XIa
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 2 , R 3 , R 4 , R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination and R7 is halogen, R, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, -N(R)C(0)R, - N(R)C(0)N(R)2, -N(R)C(NR)N(R)2, -N02, -CN, -S02N(R)2, -N(R)S02R, -S02N(R)C(0)R, - S02N(R)C(0)N(R)2, - S02N(R)C(NR)N(R)2 , -C(0)N(R)C(0)R or -CR^Ot^R. In some embodiments, m = 0. In one embodiment, the compound of formula I is
Figure imgf000028_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, m = 0 and n = 1. In one embodiment, the compound of formula I is
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, m = 0 and q = 0. In one embodiment, the compound of formula I is
Figure imgf000029_0002
or a pharmaceutically acceptable salt thereof.
[00109] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 2 3
L is a covalen -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula XII:
Figure imgf000029_0003
XII
[00110] or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R1, R2, R3, R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is
1 2 3
triazinyl, L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula XIII:
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00111] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is pyrimidinyl,
1 2 3
L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula XIV:
Figure imgf000030_0002
XIV
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00112] In certain embodiments, the present invention provides a compound of formula I, wherein wherein Ring A is pyridinyl, Ring B is pyrazolyl, Ring C is phenyl, Ring D is
1 2 3
pyrimidinyl, L is a covalent bond, L is -C(0)NR-, L is -S02N(R)-, r and s are 1, thereby forming a compound of formula XV:
Figure imgf000031_0001
XV
or a pharmaceutically acceptable salt thereof, wherein each of R, independently, and R 1 , R2 , R 3 , R4, R5, m, n, p and q is as defined above and described in embodiments herein, both singly and in combination.
[00113] In certain embodiments, the present invention provides a compound of formula I, wherein Ring A is phenyl, Ring B is pyrazolyl, Ring C is phenyl, L 1 is a covalent bond, L 2 is - C(0)NR-, r is 1 and s is 0, and R11 is an acidic moiety, thereby forming a compound of formula XVI:
Figure imgf000031_0002
XVI
or a pharmaceutically acceptable salt thereof, wherein each of R, R 1 , R2 , R 3 , R 5 , m, n and p is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the acidic moiety, R11, is -OH, -C02H or -S02NHR or -B(OH)2.
[00114] In certain embodiments, the present invention provides a compound of formula I, wherein Ring C is phenyl, Ring D is pyrimidinyl, r is 0 and s is 1 , thereby forming a compound of formula XVII:
Figure imgf000032_0001
XVII
or a pharmaceutically acceptable salt thereof, wherein each R, independently, and each of R 2 , R 3 , R4, n, p and q is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, Ring B is indolyl. In some embodiments, Ring B is pyrazolo[l,5-a]pyridyl. In some embodiments, Ring B is 1,3-benzodiazolyl. In some
embodiments, Ring B is pyrrolo[2,3-b]pyridyl. In some embodiments, Ring B is
benzothiophenyl.
[00115] In certain embodiments, the present invention provides a compound of formula I, wherein Ring B is indolyl, Ring C is phenyl, Ring D is pyrimidinyl, r is 0 and s is 1, thereby forming a compound of formula XVIII:
Figure imgf000032_0002
XVIII
or a pharmaceutically acceptable salt thereof, wherein each R, independently, and each of R 2 , R 3 , R4, R6, n, p and q is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, R6 is hydrogen. In other embodiments, R6 is Ci_4-alkyl.
[00116] In certain embodiments, the present invention provides a compound of formula I, wherein Ring B is indolyl, Ring C is phenyl, Ring D is triazinyl, r is 0 and s is 1 , thereby forming a compound of formula XIX:
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen or an optionally substituted
2 3 4
Ci_6 aliphatic, each R, independently, and each of R , R , R , n, p and q is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, R6 is hydrogen. In other embodiments, R6 is Ci_4-alkyl. In some embodiments, R6 is methyl.
[00117] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or XVI wherein m is 1, 2 or 3 and each R1 is independently selected from -OH, -CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -C02H, NH2, -CI, -Br, -F, and -I. In some embodiments, one R1 is -OH. In some embodiments, one R is -CH3. In some embodiments, two R1 groups are -CH3.
[00118] In some embodiments, the present invention provides a compound of formulae I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein n is 1, 2 or 3 and each R is independently selected from -OH, -CF3, -OCi_4-alkyl, -OCF3, -
OCHF2, -CH2CH2OCH3, -CH2CH2N(CH3)2, -C02H, NH2, -CI, -Br, and -F.
[00119] In some embodiments, the present invention provides a compound of formulae I, II,
III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein p is O.
[00120] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein p is 1, 2 or 3 and each R is independently selected from-CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -CI, -Br, and -F.
[00121] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVII, XVIII or XIX wherein q is 0.
[00122] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVII, XVIII or XIX wherein q is 1, 2 or 3 and each R4 is independently selected from-CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -CI, -Br, and -F. In some embodiments, q is 1 and R4 is -CH3. In some embodiments, q is 2 and both R4 groups are -CH3.
[00123] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L2 is -C(0)NR- and the R of-C(0)NR- is hydrogen.
[00124] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L2 is -C(0)NR- and the R of-C(0)NR- is not hydrogen.
[00125] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L2 is -C(0)NR- and the R of -C(0)NR- is Ci_4-alkyl. In some embodiments, the R of -C(0)NR- is CH3.
[00126] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L3 is -S02N(R)- and the R of -S02N(R)- is hydrogen.
[00127] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L3 is -S02N(R)- and the R of -S02N(R)- is not hydrogen.
[00128] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein L3 is -S02N(R)- and the R of -S02N(R)- is Ci_4-alkyl. In some embodiments, the R of - -S02N(R)- is CH3.
[00129] In some embodiments, the present invention provides a compound of formulae V, VI,
VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or XVI wherein R5 is hydrogen.
[00130] In some embodiments, the present invention provides a compound of formulae V, VI,
VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or XVI wherein R5 is not hydrogen.
[00131] In some embodiments, the present invention provides a compound of formulae V, VI,
VII, VIII, IX, X, XI, XII, XIII, XIV, XV, or XVI wherein R5 is Ci_4-alkyl.
[00132] In some embodiments, the present invention provides a compound of formulae VIII,
IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein each R is hydrogen. [00133] In some embodiments, the present invention provides a compound of formulae VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein at least one R is not hydrogen.
[00134] In some embodiments, the present invention provides a compound of formulae VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein at least two R groups are not hydrogen.
[00135] In some embodiments, the present invention provides a compound of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX wherein the compound is not any of Compounds I-l - 1-16, 1-22 - 1-31, 1-33, 1-40 - 1-46, 1-49 - 1-59, 1-67 - 1-72, 1-79, 1 - 80 or 1-92.
[00136] Exemplary compounds of the invention are set forth in Table 1, below. Table 1. Exemplary Compounds
Figure imgf000035_0001

Figure imgf000036_0001
Figure imgf000037_0001

Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
40
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
1-143
Figure imgf000047_0001
Figure imgf000048_0001
1-156
[00137] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof, wherein the compound is not Compound 1-1. In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof, wherein the compound is not any of Compounds 1-1 to 1-16, 1-22 to 1-31, 1-33, 1-40 to 1-46, 1-49 to 1-59, 1-67 to 1-72, 1-79, 1 - 80 or I- 92. In one embodiment, the compound is 1-21. In one embodiment, the compound is 1-32. In one embodiment, the compound is 1-73. In one embodiment, the compound is 1-76. In one embodiment, the compound is 1-78. In one embodiment, the compound is 1-84.
4. General Methods of Providing the Present Compounds
[00138] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
[00139] In the Schemes below, where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.
[00140] As used herein, the phrase "leaving group" (LG) includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. [00141] As used herein, the phrase "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4- methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2- (phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
[00142] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
[00143] In certain embodiments, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme I set forth below: Scheme I
Figure imgf000050_0001
PG Deprotection
S-1
[00144] In Scheme I above, PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, m, n, p and q is as defined above and below and in classes and subclasses as described herein.
[00145] In one aspect, the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme I, above. In some embodiments, at step S-1, a compound of formula G-l is contacted with a group of the formula G-2 to couple Rings A and B, e.g., via Suzuki coupling, forming a compound of formula G-3. In some embodiments, PG is 2-(trimethylsilyl)ethoxy]methyl. In some embodiments, the compound of formula G-l is contacted with the group of the formula G-2 and Pd(PPh3)4.
[00146] In certain embodiments, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme II set forth below:
Scheme II
Figure imgf000050_0002
PG Deprotection
[00147] In Scheme II above, PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, m, n, p and q is as defined above and below and in classes and subclasses as described herein. [00148] In one aspect, the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme II, above. In some embodiments, at step S-2, a compound of formula G-4 is contacted with a group of the formula G-5 to couple Rings B and C, e.g., via amide bond formation, yielding a compound of formula G-3. In some embodiments, PG is 2-(trimethylsilyl)ethoxy]methyl. In some embodiments, the -C02H group of G-5 is converted to -C02C1, prior to being contacted with G-4. In some embodiments, the compound of formula G-4 is contacted with the group of the formula G-5 and (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU) to yield the compound of formula G-3.
[00149] In certain embodiments, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme III set forth below:
Scheme III
Figure imgf000051_0001
Sulfonamide bond
formation
S-3
[00150] In Scheme III above, PG is a protecting group and each of Ring A, Ring B, Ring C, Ring D, R1, R2, R3, R4, m, n, p and q is as defined above and below and in classes and subclasses as described herein.
[00151] In one aspect, the present invention provides methods for preparing compounds of formula G-3 according to the process depicted in Scheme III, above. In some embodiments, at step S-3, a compound of formula G-6 is contacted with a group of the formula G-7 to couple Rings C and D, e.g., via sulfonamide bond formation, yielding a compound of formula G-3. In some embodiments, the compound of formula G-6 is contacted with the group of the formula G- 7 and a base such as DIPEA.
[00152] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification.
5. Uses, Formulation and Administration
Pharmaceutically acceptable compositions
[00153] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
[00154] The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.
[00155] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00156] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
[00157] As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of PHGDH, or a mutant thereof.
[00158] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00159] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. [00160] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00161] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00162] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00163] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[00164] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00165] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
[00166] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00167] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
[00168] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
[00169] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
Uses of Compounds and Pharmaceutically Acceptable Compositions
[00170] Compounds and compositions described herein are generally useful for the inhibition of PHGDH or a mutant thereof.
[00171] The activity of a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of PHGDH, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to PHGDH. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof, are set forth in the Examples below.
[00172] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
[00173] Provided compounds are inhibitors of PHGDH and are therefore useful for treating one or more disorders associated with activity of PHGDH. Thus, in certain embodiments, the present invention provides a method for treating a PHGDH-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
[00174] As used herein, the terms "PHGDH-mediated" disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which PHGDH, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which PHGDH, or a mutant thereof, are known to play a role.
[00175] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
Cellular Proliferative Disorders
[00176] The present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by targeting PHGDH of the serine biosynthetic pathway. Cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases. Such disorders may be diagnosed using methods known in the art. Cancer
[00177] Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macro globulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). In some embodiments, the cancer is melanoma or breast cancer.
[00178] Cancers includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
[00179] In some embodiments, the present invention provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein. In some embodiments, the tumor comprises any of the cancers described herein. In some embodiments, the tumor comprises melanoma cancer. In some embodiments, the tumor comprises breast cancer. In some embodiments, the tumor comprises lung cancer. In some embodiments the the tumor comprises small cell lung cancer (SCLC). In some embodiments the the tumor comprises non-small cell lung cancer (NSCLC).
[00180] In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the quantity of tumors prior to treatment.
Other Proliferative Diseases
[00181] Other proliferative diseases include, e.g., obesity, benign prostatic hyperplasia, psoriasis, abnormal keratinization, lymphoproliferative disorders (e.g., a disorder in which there is abnormal proliferation of cells of the lymphatic system), chronic rheumatoid arthritis, arteriosclerosis, restenosis, and diabetic retinopathy. Proliferative diseases that are hereby incorporated by reference include those described in U.S. Pat. Nos. 5,639,600 and 7,087,648. Inflammatory Disorders and Diseases
[00182] It has recently been reported that PHGDH gene expression, dictated by IL-2R signaling, is a crucial event for DNA synthesis during S phase of activated T cells. Jun do Y et al., Cell Immunol. 2014 Feb;287(2):78-85. Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
[00183] Compounds according to the invention are useful in the treatment of heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
[00184] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
[00185] Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
[00186] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
[00187] Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
[00188] Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget' s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.
[00189] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is an disease of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dermatitits, atompic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
[00190] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.
[00191] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease. In some embodiments the TH17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).
[00192] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.
Metabolic Disease
[00193] In some embodiments the invention provides a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome or obesity.
[00194] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.
[00195] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[00196] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00197] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00198] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00199] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00200] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[00201] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00202] 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 sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 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 sugar as well as high molecular weight polethylene glycols and the like.
[00203] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[00204] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00205] According to one embodiment, the invention relates to a method of inhibiting PHGDH activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
[00206] According to another embodiment, the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
[00207] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[00208] Another embodiment of the present invention relates to a method of inhibiting PHGDH in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
[00209] According to another embodiment, the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by PHGDH, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
[00210] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."
[00211] A compound of the current invention may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angio genie compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17- AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNFIOIO, CNF2024, CNFIOIO from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD 181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
[00212] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
[00213] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.
[00214] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.
[00215] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed, under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.
[00216] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.
[00217] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.
[00218] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
[00219] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.
[00220] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™. [00221] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angio genie compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD 173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safmgol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD 184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- {[(2,5- dihydroxyphenyl)methyl] amino} -benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El . l, E2.4, E2.5, E6.2, E6.4, E2.l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB- 1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL- 147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).
[00222] The term "PI3K inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to ΡΒΚα, ΡΒΚγ, ΡΒΚδ, ΡΒΚβ, PI3K-C2a, PBK-C2P, ΡΒΚ- C2y, Vps34, pl lO-a, ρ110-β, ρ110-γ, ρ110-δ, ρ85-α, ρ85-β, ρ55-γ, ρ150, plOl, and ρ87. Examples of ΡΒΚ inhibitors useful in this invention include but are not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
[00223] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.
[00224] The term "BTK inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
[00225] The term "SYK inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib
[00226] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
[00227] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794,
WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.
[00228] Further examples of PBK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
[00229] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
[00230] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.
[00231] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP- 18770, and MLN9708.
[00232] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
[00233] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or a- γ- or δ-tocotrienol.
[00234] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
[00235] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578. [00236] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.
[00237] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or Rl 15777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
[00238] The term "methionine ammopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine ammopeptidase. Compounds which target, decrease or inhibit the activity of methionine ammopeptidase include, but are not limited to, bengamide or a derivative thereof.
[00239] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.
[00240] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.
[00241] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
[00242] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
[00243] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
[00244] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Pvituxan®), PR064553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
[00245] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
[00246] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X- rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993).
[00247] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
[00248] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).
[00249] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.
[00250] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
[00251] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone. [00252] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
[00253] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).
[00254] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
[00255] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
[00256] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
[00257] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
[00258] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
[00259] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.
[00260] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
[00261] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.
EXEMPLIFICATION [00262] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
Scheme IV
Figure imgf000079_0001
[00263] Each compound of Examples 1-8 was prepared according to the reaction sequence in Scheme IV or an adaptation thereof.
[00264] Example 1. Synthesis of 5-(propan-2-yl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide, 1-17
Figure imgf000079_0002
1-17
[00265] HATU (460mg, 1.2 mmol) and DIPEA (0.42 ml, 2.4 mmol) were added at Rt to a stirred solution of 3-(propan-2-yl)-lH-pyrazole-5-carboxylic acid (120mg, 0.8 mmol) in DMF (HPLC grade, 7 ml) followed by 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide (200mg, 0.8 mmol). The resulting mixture was stirred at Rt for 20h. The solvent was removed in vacuo and the remaining material was purified by prep HPLC (MeCN/Water, 0.1% formic acid) to afford lOmg (3%) of 5-(propan-2-yl)-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-3- carboxamide 1-17 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.29 (s, 1H), 8.48 (d, J = 4.8 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.01 (s, 1H), 6.54 (s, 1H), 3.11 - 2.77 (m, 1H), 1.25 (d, J = 6.9 Hz, 6H).
[00266] Example 2. Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-l,2,4- triazole-3-carboxamide, 1-18
Figure imgf000080_0001
1-18
[00267] Compound 1-18 was prepared according to the reaction sequence in Scheme IV with several adaptations. The solvent was removed in vacuo, the remaining material was triturated from H2O/CH3CN 1 : 1 (20ml), washed with small volumes of DMSO/CH3CN 1 :2, collected and dried to afford 190mg (65%) of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-l,2,4-triazole-3- carboxamide 1-18 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 14.84 (s, 1H), 11.70 (s, 1H), 10.83 (s, 1H), 8.66 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 8.9 Hz, 2H), 7.04 (t, J = 4.9 Hz, 1H).
[00268] Example 3. Synthesis of 4-methyl-5-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl] phenyl}-lH-pyrazole-3-carboxamide 1-19
Figure imgf000080_0002
1-19
[00269] Compound 1-19 was prepared according to the reaction sequence in Scheme IV with several adaptations. The solvent was removed in vacuo and the remaining material was triturated from H20/CH3CN 1 : 1 (20ml), washed with small volumes of DMSO/CH3CN 1 :2, collected and dried to afford 57mg (15%) of 4-methyl-5-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 1-19 as a colourless solid.1H NMR (500 MHz, DMSO-d6) δ 13.56 (s, 1H), 11.66 (s, 1H), 10.38 (s, 1H), 8.51 (d, J = 4.2 Hz, 2H), 8.16 - 7.67 (m, 4H), 7.56 (dd, J = 19.6, 6.9 Hz, 4H), 7.46 (d, J = 7.0 Ηζ,ΙΗ), 7.04 (s, 1H), 2.37 (s, 3H).
[00270] Example 4. Synthesis of 5-phenyl-N-{4-[(pyridin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-3-carboxamide, 1-38
Figure imgf000080_0003
1-38 [00271] Compound 1-38 was prepared according to the reaction sequence in Scheme IV with several adaptations. The reaction crude was partitioned between DCM (100ml) and sat. NaHC03 (70ml) and the two layers were separated. The aqueous layer was extracted further with DCM (1 x 50ml), the combined extracts were dried over Na2S04 and evaporated to dryness to obtain a material that was purified by HPLC (MeCN /Water +0.1% Formic Acid) to afford 13mg (4%) of 5-phenyl-N-{4-[(pyridin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 1-38 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 13.89 (s, 1H), 10.41 (s, 1H), 8.42 (s, 1H), 8.05 - 7.96 (m, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.84 - 7.76 (m, 4H), 7.70 - 7.56 (m, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.29 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.90 - 6.66 (m,
1H).
[00272] Example 5. Synthesis of 3-cyclopropyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}- lH-pyrazole-5-carboxamide, 1-20
Figure imgf000081_0001
1-20
[00273] Compound 1-20 was prepared according to the reaction sequence in Scheme IV and purified by prep HPLC (MeCN/Water, 0.1 % formic acid) afforded 4mg (2%) of 3-cyclopropyl- N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-20 as a an orange- brown solid. 1H NMR (500 MHz, DMSO-d6) δ 13.16 (s, 1H), 11.60 (s, 1H), 10.26 (s, 1H), 8.45 (s, 2H), 8.01-7.77 (m, 4H), 6.87 (d, J = 106.7 Hz, 1H), 6.40 (d, J = 1.8 Hz, 1H), 1.98-1.88 (m, 1H), 0.99-0.88 (m, 2H), 0.78-0.63 (m, 2H).
[00274] Example 6. Synthesis of 3-phenyl-N- {4- [(pyrimidin-2-yl)sulfamoyl] phenyl}- 1,2- oxazole-5-carboxamide, 1-34
Figure imgf000081_0002
-34
[00275] Compound 1-34 was prepared according to the reaction sequence in Scheme IV with several adaptations. The solvent was removed in vacuo. The crude material was suspended in DMSO:MeCN (1 :2) (20ml) and the product filtered off to afford 196mg (58%) of 3-phenyl-N- {4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-l,2-oxazole-5-carboxamide 1-34 as a cream solid. 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 11.15 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 8.07-7.92 (m, 6H), 7.86 (s, 1H), 7.61-7.52 (m, 3H), 7.05 (t, J = 4.8 Hz, 1H).
[00276] Example 7. Synthesis of 3-(2-fluorophenyl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-35
Figure imgf000082_0001
1-35
[00277] Compound 1-35 was prepared according to the reaction sequence in Scheme IV with several adaptations. The crude product was purified using flash column chromatography (DCM/MeOH 100/0 to 90/10) and then by prep HPLC (MeCN /Water, 0.1% formic acid) to afford 2mg (0.5%) of 3-(2-fluorophenyl)-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide 1-35 as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.44 (s, 3H), 8.12 (d, J = 4.7 Hz, 2H), 7.97 (t, 1H), 7.77 (s, 3H), 7.52-7.43 (m, 1H), 7.39-7.30 (m, 2H), 6.46-6.33 (m, 2H).
[00278] Example 8. Synthesis of 3-(2-methoxyphenyl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-36
Figure imgf000082_0002
1-36
[00279] Compound 1-36 was prepared according to the reaction sequence in Scheme IV with several adaptations. The solvent was removed in vacuo. The crude material was suspended in DMSO:MeCN (1 :2) (20ml), the product filtered off and washed with water (10 ml) and MeOH (2 ml) to afford 22mg (6%) of 3-(2-methoxyphenyl)-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}- lH-pyrazole-5-carboxamide 1-36 as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.52 (s, 1H), 11.68 (s, 1H), 10.39 (s, 1H), 8.50 (d, J = 4.0 Hz, 2H), 7.98 (dd, 4H), 7.75 (d, 1H), 7.46-7.33 (m, 1H), 7.18 (d, J = 11.6 Hz, 2H), 7.11-7.00 (m, 2H), 3.92 (s, 3H).
Scheme V
ArCOOH
MF
Figure imgf000083_0001
(step 2B)
Figure imgf000083_0002
[00280] Each compound of Examples 9-15 was prepared according to the reaction sequence in Scheme V or an adaptation thereof.
[00281] Example 9. Synthesis of 3-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide, 1-32
Figure imgf000083_0003
[00282] Step 1: Synthesis of 4-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzene-l-sulfonamide, 9.1
[00283] DIPEA (2.78 ml, 15.98 mmol), DMAP (0.20g, 1.6 mmol) and SEMCl (2.83 ml, 15.98 mmol) were added sequentially at rt to a stirred solution of 4-amino-N-(pyrimidin-2- yl)benzenesulfonamide (4.00g, 15.98 mmol) in DCM (HPLC grade, 100 ml). The resulting mixture was stirred at rt for 20h. The solvent was removed in vacuo and the remaining material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to afford 3.38g (53%) of 4-amino-N-(pyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 - sulfonamide 9.1 as a sticky yellow solid.
[00284] Step 2A: Synthesis of 3-phenyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl}) sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 9.2
[00285] HATU (300mg, 0.79 mmol) and DIPEA (0.27 ml, 1.58 mmol) were added at rt to a stirred solution of 4-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l- sulfonamide (9.1, 200 mg, 0.53 mmol) in DMF (dry, 20 ml) followed by 5 -phenyl- lH-pyrazole- 3-carboxylic acid (99mg, 0.53 mmol). The resulting mixture was stirred at rt for 20h. The solvent was removed in vacuo and the remaining material was partitioned between DCM (100ml) and water (70ml). The two layers were separated, the aqueous layer was extracted further with DCM (2 x 30ml) and the combined extracts were dried over Na2S04. Evaporation of the solvent afforded a material that was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) and triturated from DMSO:MeCN:water 1 :2: 1 to obtain 163mg (54%) of 3-phenyl-N-{4- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} ) sulfamoyl]phenyl} - 1 H-pyrazole-5- carboxamide 9.2 as a colourless solid.
[00286] Step 3: Synthesis of 3-Phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide, 1-32
[00287] 4M HC1 in dioxane (10ml) was added at rt to a stirred suspension of 3-phenyl-N-{4- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H-pyrazole-5- carboxamide (9.2, 160 mg, 0.29 mmol) in MeOH (HPLC grade, 5ml). The mixture was stirred at rt for lh. The solvent was removed in vacuo and the remaining material was triturated from MeOH to obtain 89mg (72%) of 3-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide 1-32 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 13.85 (s, 1H), 11.65 (s, 1H), 10.46 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.98 (d, J = 22.5 Hz, 4H), 7.84 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.1 Hz, 2H), 7.39 (s, 1H), 7.23 (s, 1H), 7.05 (t, J = 4.8 Hz, 1H).
[00288] Example 10. Synthesis of N-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}- 3-phenyl-lH-pyrazole-5-carboxamide 1-73
Figure imgf000084_0001
1-73 [00289] Step 1: Synthesis of 4-amino-N-(4,6-dimethylpyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy] methyl} benzene-l-sulfonamide, 10.1
[00290] SEMC1 (1.18 ml, 6.66 mmol) was added drop wise at rt to a stirred suspension of 4- amino-N-(4,6-dimethylpyrimidin-2-yl)-N-sodiobenzene-l -sulfonamide (2.00g, 6.66 mmol) in MeCN (HPLC grade, 50ml). The mixture was stirred at rt for 20h. The solvent was removed in vacuo and the remaining material was partitioned between DCM (150ml) and water (100ml). The aqueous layer was extracted further with DCM (2 x 70ml). The combined layers were dried over Na2S04 and evaporated to obtain a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 20/80) to afford 1.82g (65%) of 4-amino-N-(4,6- dimethylpyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide 10.1 as a sticky yellow oil.
[00291] Step 2A: Synthesis of N-{4-[(4,6-dimethylpyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl}) sulfamoyl]phenyl}-3-phenyl-lH-pyrazole-5-carboxamide, 10.2
[00292] HATU (294mg, 0.77 mmol) and DIPEA (0.27 ml, 1.55 mmol) were added at rt to a stirred solution of 4-amino-N-(4,6-dimethylpyrimidin-2-yl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (10.1, 211 mg, 0.52 mmol) in DMF (dry, 15 ml) followed by 5 -phenyl- lH-pyrazole-3-carboxylic acid (97mg, 0.52 mmol). The resulting mixture was stirred at rt for 48h. The solvent was removed in vacuo and the remaining solid was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) and triturated from DMSO:CH3CN:water 1 :2: 1 to obtain 63mg (18%) of N-{4-[(4,6-dimethylpyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl } -3 -phenyl- 1 H-pyrazole-5 -carboxamide 10.2 as a pale yellow solid.
[00293] Step 3: Synthesis of N-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-3- phenyl-lH-pyrazole-5-carboxamide, 1-73
[00294] Trituration from MeOH afforded lOmg (21%) of N-{4-[(4,6-dimethylpyrimidin-2- yl)sulfamoyl]phenyl}-3-phenyl-lH-pyrazole-5-carboxamide 1-73 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 13.87 (s, 1H), 11.38 (s, 1H), 10.47 (d, J = 71.9 Hz, 1H), 7.96 (d, J = 9.9 Hz, 4H), 7.83 (d, J = 7.5 Hz, 2H), 7.45 (dt, J = 44.9, 7.3 Hz, 3H), 7.22 (s, 1H), 6.74 (s, 1H), 2.25 (s, 6H). [00295] Example 11. Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-indole-2- carboxamide, 1-78
Figure imgf000086_0001
1-78
[00296] Step 2B: Synthesis of N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide, 11.1
[00297] Methanesulfonyl chloride (0.09ml, l .lmmol) was added to a stirred mixture of 4- amino-N-(pyrimidi n-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 -sulfonamide (9.1, 300mg, 0.79 mmol), lH-indole-2-carboxylic acid (130mg, 0.79mmol) and 3-picoline (0.23ml, 2.37mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for lh. The reaction crude was partitioned between DCM (75ml) and water (75ml). The aqueous layer was further extracted with DCM (2 x 50ml) and the combined layers dried over Na2S04. The solvent was removed in vacuo to afford a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 248mg (60%) of N-{4- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H-indole-2- carboxamide 11.1 as a colourless solid.
[00298] Step 3 : N-{4- [(pyrimidin-2-yl)sulfamoyl] phenyl}-lH-indole-2-carboxamide 1-78
[00299] Evaporation of the solvent afforded 128mg (62%) of N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-indole-2-carboxamide 1-78 as a pale cream solid. 1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 11.66 (s, 1H), 10.51 (s, 1H), 8.51 (d, J = 4.7 Hz, 2H), 7.99 (s, 4H), 7.69 (d, J = 7.8 Hz, 1H), 7.47 (d, 2H), 7.24 (t, 1H), 7.12 - 7.01 (m, 2H).
[00300] Example 12. Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-indole-3- carboxamide, 1-82
Figure imgf000087_0001
1-82
[00301] Step 2B: Synthesis of N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl] phenyl}- lH-indole-3-carboxamide 12.1
[00302] The product obtained after flash column chromatography was purified by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to afford 58mg (14%) of N-{4-[(pyrimidin-2- yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-indole-3-carboxamide 12.1 as a light brown crystalline solid.
[00303] Step 3: Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-indole-3- carboxamide, 1-82
[00304] Evaporation of the solvent afforded an off-white solid that was triturated from MeOH to afford 25mg (55% yield) of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-indole-3- carboxamide 1-82 as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 11.61 (s, 1H), 10.04 (s, 1H), 8.50 (d, J = 4.7 Hz, 2H), 8.33 (d, J = 3.0 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.94 (s, 4H), 7.48 (d, J = 7.9 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.04 (s, 1H).
[00305] Example 13. Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}pyrazolo[l,5- a]pyridine-2-carboxamide, 1-83
Figure imgf000087_0002
1-83
[00306] Step 2B: Synthesis of N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl] phenyl}pyrazolo[l,5-a]pyridine-2-carboxamide 13.1
[00307] Methanesulfonyl chloride (0.04ml, 0.55mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 -sulfonamide (9.1, 150mg, 0.39mmol), pyrazolo[l,5-a]pyridine-2-carboxylic acid (60mg, 0.39mmol) and 3-picoline (0.12 ml, 1.18mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 15h. The reaction mixture was partitioned between DCM (50ml) and water (50ml). The aqueous layer was further extracted with DCM (2x 30ml) and the combined layers dried over Na2S04. The solvent was removed in vacuo to afford a material which was purified by flash column chromatography (heptane/EtOAc 75/25 to 0/100) to obtain 190mg (87%) of N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl]phenyl}pyrazolo[l,5-a]pyridine-2-carboxamide 13.1 as an off white solid.
[00308] Step 3: Synthesis of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}pyrazolo[l,5- a]pyridine-2-carboxamide, 1-83
[00309] Evaporation of the solvent afforded a material that was triturated from MeOH to obtain 141mg (99% yield) of N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}pyrazolo[l,5-a]pyridine- 2-carboxamide 1-83 as a cream solid. 1H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 10.76 (s, 1H), 8.74 (dd, 1H), 8.51 (d, J = 4.8 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.83 (d, J= 8.9 Hz, 1H), 7.34 (t, 1H), 7.17 (s, 1H), 7.09 (td, J= 6.9, 1.3 Hz, 1H), 7.05 (t, 1H).
[00310] Example 14. Synthesis of l-methyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- indole-2-carboxamide, 1-84
Figure imgf000088_0001
1-84
[00311] Step 2B: Synthesis of l-Methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide 14.1
[00312] Methanesulfonyl chloride (40μ1, 0.51mmol) was added to a stirred solution of 1- methyl-lH-indole-2-carboxylic acid (90mg, 0.51mmol), 4-amino-N-(pyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (9.1, 205mg, 0.54mmol) and 3-picoline (50μ1, 0.51mmol) in MeCN (dry, 10 ml) at 0°C. The reaction was allowed to reach rt and stirred for 15h. The reaction mixture was concentrated to dryness and purified using flash column chromatography (heptane/EtOAc 100/0 to 50/50) to afford 166mg (60% yield) of 1-methyl-N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl] phenyl} - 1 H-indole-2- carboxamide 14.1as an off white resin. [00313] Step 3: Synthesis of l-Methyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- indole-2-carboxamide, 1-84
[00314] Evaporation of the solvent afforded an off-white solid that was triturated from MeOH to obtain 62mg (49% yield) l-methyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-indole-2- carboxamide 1-84 as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 11.70 (br. s, 1H), 10.63 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.97 (s, 4H), 7.71 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.35 - 7.30 (m, 1H), 7.17 - 7.12 (m, 1H), 7.05 (t, J = 4.9 Hz, 1H), 4.00 (s, 3H).
[00315] Example 15. Steps 2B/3: Synthesis of l-Ethyl-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-89
Figure imgf000089_0001
1-89
[00316] Methanesulfonyl chloride (0.05 ml, 0.65 mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 -sulfonamide (9.1, 176mg, 0.46 mmol), l-ethyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (lOOmg, 0.46 mmol) and 3-picoline (0.14ml, 1.39 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 30 minutes. The reaction mixture was partitioned between DCM (75ml) and water (50ml). The aqueous layer was further extracted with DCM (2x 40ml) and the combined layers dried over Na2S04, filtered and concentrated in vacuo to afford a material which was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 39mg (19%) of 1 -ethyl-3-phenyl-N- {4-[(pyrimidin-2-yl)sulfamoyl]phenyl} - lH-pyrazole-5- carboxamide 1-89 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.63 (s, 1H), 8.50 (d, J = 4.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.82 (d, J = 7.2 Hz, 2H), 7.50 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). Scheme VI
O
Η,Ν- NaNO^
Br- SEMCI
N-NH CuBr HBr
N-NH
DIPEA, DCM (step 1 )
(step 2)
Figure imgf000090_0001
picoline, sCI acetonitrile (step 4)
Figure imgf000090_0002
Figure imgf000090_0003
[00317] Each compound of Examples 16 and 17 was prepared according to the reaction sequence in Scheme VI or an adaptation thereof.
[00318] Example 16. Synthesis of 2-[5-({4-[(pyrimidin-2-yl)sulfamoyl]phenyl} carbamoyl)-lH-pyrazol-3-yl] benzoic acid, 1-74
Figure imgf000090_0004
1-74 [00319] Step 1: Synthesis of ethyl 3-bromo-lH-pyrazole-5-carboxylate 16.1
[00320] To ethyl 3-amino-lH-pyrazole-5-carboxylate (1.08g, 6.97 mmol) was added HBr (48% aqueous, 10 ml). The mixture was cooled to 0°C and then sodium nitrite (0.54g, 7.67 mmol) in water (10 ml) was added drop wise. The mixture was stirred for 10 minutes. Copper(l+) bromide (3.00g, 20.92 mmol) was added portion wise and the mixture kept at 0°C over 15 minutes. The mixture was neutralised with sat. aq. NaHC03 at 0°C and extracted with DCM (2 x 100ml). The combined layers were washed with water (100 ml), dried over Na2S04 and evaporated to dryness to give a material which was purified by flash column chromatography (heptane/EtOAc 90/10 to 50/50) to give 0.65g (40%) of ethyl 3-bromo-lH- pyrazole-5-carboxylate 16.1 as an off-white solid.
[00321] Step 2: Synthesis of ethyl 5-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH- pyrazole-3-carboxylate, 16.2
[00322] SEMC1 (0.62g, 3.75 mmol) was added to a mixture of ethyl 5-bromo-lH-pyrazole-3- carboxylate (16.1, 0.55g, 2.5 mmol) and DIPEA (0.87 ml, 4.99 mmol) in DCM (HPLC grade, 20 ml) at 0°C. After addition, the reaction mixture was allowed to reach rt and stirred for 20h. The mixture was diluted with DCM (30 ml), washed with sat. aq. NaHC03 (30 ml) and water (30ml), then evaporated to dryness to obtain 0.87g (87%>) of ethyl 5-bromo-l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole-3-carboxylate 16.2 in mixture with the corresponding regioisomer.
[00323] Step 3: Synthesis of 3-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole- 5-carboxylic acid 16.3
[00324] LiOH (179mg, 7.49 mmol) was added at rt to a stirred solution of ethyl 3-bromo-l- {[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-carboxylate (16.2, 872mg, 2.5 mmol) in THF (HPLC grade, 10 ml) and water (distilled, 2 ml). The mixture was stirred for 3h at rt. Additional LiOH (60mg, 2.5mmol) was added and the mixture stirred for 20h. The mixture was concentrated in vacuo, diluted with water (20ml) and washed with EtOAc (20 ml). The aqueous layer was adjusted to pH 9 with 1M NH4C1 then extracted with EtOAc (3 x 20ml). The combined layers were dried over Na2S04 and evaporated to dryness to give a material which was taken up in DCM and filtered. The filtrate was evaporated to dryness to afford 505mg (63%) of 3-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-carboxylic acid 16.3 as a green oil in mixture with the corresponding regioisomer. The initial EtOAc phase was also evaporated to dryness to give a material which was dissolved in MeOH (5 ml), washed with heptane (6 x 3ml) and evaporated to dryness to afford 128mg (16%) of additional 3-bromo-l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-carboxylic acid 16.3 as a pale yellow oil in mixture with the corresponding regioisomer. The two batches were combined for further use.
[00325] Step 4: Synthesis of 3-bromo-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy] methyl}) sulfamoyl]phenyl}-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5- carboxamide 16.4
[00326] To a stirred solution of 4-amino-N-(pyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (9.1, 765mg, 2.01 mmol) and 3-bromo-l- {[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-carboxylic acid (16.3, 615 mg, 1.91 mmol) in MeCN (dry, 10 ml) was added 3-picoline (560μ1, 5.74 mmol). The mixture was cooled to 0°C and methanesulfonyl chloride (208μ1, 2.68 mmol) was added. The resulting mixture was stirred at rt for 30 minutes. The mixture was partitioned between DCM (30ml) and water (30ml). The aqueous layer was extracted with DCM (2 x 30ml) and the combined layers evaporated to dryness. The crude product was purified by flash column chromatography (heptane/EtOAc 100/0 to 40/60) to afford 790mg (60%) of 3-bromo-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 - { [2-(trimethylsilyl)ethoxy]methyl} - 1 H- pyrazole-5-carboxamide 16.4 as a white sticky solid in mixture with the corresponding regioisomer.
[00327] Step 5: Synthesis of 2-[5-({4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl]phenyl}carbamoyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-3-yl]benzoic acid 16.5
[00328] 3-Bromo-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})
sulfamoyl]phenyl} - 1 - { [2-(trimethylsilyl)ethoxy]methyl} - 1 H-pyrazole-5-carboxamide (16.4, 200mg, 0.29mmol), 2-(dihydroxyboranyl)benzoic acid (48mg, 0.29mmol), K2CO3 (85mg, 0.61mmol) and Pd(PPh3)4 (34mg, 0.03mmol) were combined in dioxane (HPLC grade, 3ml) and water (2ml) at rt. The mixture was purged with nitrogen for 5 minutes and then heated to 100°C (pre-heated block) with stirring. Further 2-(dihydroxyboranyl)benzoic acid (48mg, 0.29mmol), K2CO3 (85mg, 0.61mmol) and Pd(PPh3)4 (34mg, 0.03mmol) were added after 2h, the mixture was purged with nitrogen for 5 minutes and heating at 100°C was resumed. After 2h the crude was cooled down to rt and filtered over paper washing with small volumes of MeOH. Silica was added for dry load and purification by flash column chromatography (heptane/EtOAc 50/50 to 0/100 then MeOH/EtOAc 0/100 to 50/50) afforded 173mg (75%) of 2-[5-({4-[(pyrimidin-2- yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} carbamoyl)- 1 - { [2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazol-3-yl]benzoic acid 16.5 as a pale yellow crystalline solid in mixture with the corresponding regioisomer.
[00329] Step 6: Synthesis of 2-[5-({4-[(pyrimidin-2-yl)sulfamoyl]phenyl}carbamoyl)-lH- pyrazol-3-yl] benzoic acid, 1-74
[00330] 4M HC1 in dioxane (7ml) was added at rt to a stirred solution of 2-[5-({4-[(pyrimidin- 2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} carbamoyl)- 1 - { [2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazol-3-yl]benzoic acid (16.5, 170mg, 0.23mmol) in dioxane (HPLC grade, 3ml). The mixture was stirred at rt further. After 20h the solvent was removed in vacuo and the remaining material was triturated from MeOH to obtain 26mg (24%) of 2-[5-({4-[(pyrimidin-2-yl)sulfamoyl]phenyl}carbamoyl)-lH-pyrazol-3-yl]benzoic acid 1-74 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 13.71 (s, 1H), 13.05 (s, 1H), 11.68 (s, 1H), 10.49 (s, 1H), 8.51 (d, J = 4.7 Hz, 2H), 8.01 (s, 2H), 7.96 (s, 2H), 7.85 (s, 1H), 7.60 (d, J = 18.9 Hz, 3H), 7.05 (t, J = 4.6 Hz, 1H), 6.85 (s, 1H).
[00331] Example 17. Synthesis of 3-(2-aminopyridin-3-yl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-75
Figure imgf000093_0001
1-75
[00332] Step 5: Synthesis of 3-(2-aminopyridin-3-yl)-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl) ethoxy]methyl})sulfamoyl]phenyl}-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH- pyrazole-5-carboxamide 17.1
[00333] 3-Bromo-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl] phenyl} - 1 - { [2-(trimethylsilyl)ethoxy]methyl} - 1 H-pyrazole-5-carboxamide (16.5, 200mg, 0.29mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (129mg, 0.58mmol), K2CO3 (84.89mg, 0.61mmol) and Pd(PPh3)4 (33.8mg, 0.03mmol) were combined in dioxane (3ml) and water (2ml) at rt. The mixture was purged with nitrogen for 5 minutes and then heated to 100°C (pre -heated block) with stirring. After 2.5h the crude was cooled down to rt and filtered over paper washing with small volumes of MeOH. Silica was added for dry load and purification by flash column chromatography (heptane/EtOac 100/0 to 0/100 then MeOH/EtOAc 0/100 to 50/50) afforded lOOmg (49%) of 3-(2-aminopyridin-3-yl)-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 - { [2-(trimethylsilyl)ethoxy]methyl} - 1 H- pyrazole-5-carboxamide 17.1 as the pale yellow glassy solid.
[00334] Step 6: Synthesis of 3-(2-aminopyridin-3-yl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-75
[00335] 4M HCI in dioxane (6 ml) was added at rt to a stirred solution of 3-(2-aminopyridin- 3 -yl)-N- {4- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 - { [2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-carboxamide (17.1, lOOmg, 0.14mmol) in MeOH (HPLC grade, 2ml). The mixture was stirred at rt further. After 20h the solvent was removed in vacuo and the remaining material was triturated from MeOH to obtain 39mg (57%) of 3-(2- aminopyridin-3-yl)-N- {4-[(pyrimidin-2-yl)sulfamoyl]phenyl} -lH-pyrazole-5-carboxamide 1-75 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 14.52 (s, 1H), 11.74 (s, 1H), 10.92 (s, 1H), 8.51 (d, J = 4.8 Hz, 4H), 8.37 (s, 1H), 8.08 (d, J = 5.7 Hz, 1H), 8.00 (s, 4H), 7.81 (s, 1H), 7.13 - 6.89 (m, 2H).
Scheme VII
Figure imgf000094_0001
[00336] The compound of Example 18 was prepared according to the reaction sequence in Scheme VII.
[00337] Example 18. Synthesis of l-methyl-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-76
Figure imgf000095_0001
1-76
[00338] Step 1: Synthesis of methyl 3-iodo-l-methyl-lH-pyrazole-5-carboxylate 18.1
[00339] To a solution of methyl 3 -amino- 1 -methyl- lH-pyrazole-5-carboxylate (l .OOg, 6.45 mmol) in 12M HC1 (24 ml) at 0°C was added a solution of sodium nitrite (0.90g, 12.89 mmol) in water (distilled, 5 ml) over 3 minutes. A solution of KI (2.68g, 16.11 mmol) in water (distilled, 5 ml) was added dropwise to the reaction mixture, which was kept at 0°C over 15 minutes. The reaction mixture was allowed to warm up to rt and water (25ml) was added. The crude was added to DCM (50ml) and washed with saturated Na2S03 (50ml) and water (50 ml). The aqueous layer was extracted further with DCM (3 x 50 ml). The combined layers were washed with water (20 ml) and evaporated to afford a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 75/25) to obtain 0.52g (21%) of methyl 3-iodo-l- methyl-lH-pyrazole-5-carboxylate 18.1 as a colourless oil which solidified on standing.
[00340] Step 2: Synthesis of lithio 3-iodo-l-methyl-lH-pyrazole-5-carboxylate 18.2
[00341] LiOH (0.14 g, 5.81 mmol) was added in one portion to a stirred solution of methyl 3- iodo-1 -methyl- lH-pyrazole-5-carboxylate (18.1, 0.52g, 1.94 mmol) in THF (HPLC grade, 10 ml)/water (distilled, 2ml) at rt. After 10 minutes the reaction crude was filtered over paper and the remaining solid was washed with THF (3 x 8ml). Evaporation of the solvent afforded 0.43 g (64%) of lithio 3 -iodo-1 -methyl- lH-pyrazole-5-carboxylate 18.2 as a colourless powder.
[00342] Step 3: Synthesis of l-methyl-3-phenyl-lH-pyrazole-5-carboxylic acid 18.3
[00343] Lithio 3 -iodo-1 -methyl- lH-pyrazole-5-carboxyl ate (18.2, 67mg, 0.26 mmol), phenylboronic acid (32mg, 0.26 mmol), K2C03 (76mg, 0.55 mmol) and Pd(PPh3)4 (30mg, 0.026 mmol) were combined in dioxane (HPLC grade, 3 ml) and water (distilled, 3ml) at rt. The mixture was purged with nitrogen for 5 minutes and then heated to 100°C (pre-heated block) with stirring. After lh the reaction was cooled down and filtered over paper washing with dioxane. The crude was loaded on silica for purification by flash column chromatography (heptane/EtOAc 100/0 to 0/100 then EtOAc/MeOH 100/0 to 30/70) to afford 29mg (53%) of 1- methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid 18.3 as a yellow glassy solid.
[00344] Step 4: Synthesis of l-methyl-3-phenyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 18.4
[00345] To a stirred solution of 4-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl) ethoxy]methyl}benzene-l -sulfonamide (9.1, 58mg, 0.15 mmol) and 1 -methyl-3 -phenyl- 1H- pyrazole-5-carboxylic acid (18.3, 29mg, 0.15 mmol) in MeCN (dry, 10 ml) was added 3-picoline (42μ1, 0.44 mmol). The mixture was cooled to 0°C and methanesulfonyl chloride (16μ1, 0.20 mmol) was added. The resulting mixture was allowed to reach rt and stirred for 20h. Silica was added to the reaction crude for dry loading and purification by flash column chromatography (heptane/EtOAc 100/0 to 25/75) which afforded 41mg (49%) of 1 -methyl-3 -phenyl-N- {4- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy] methyl} )sulfamoyl]phenyl} - 1 H-pyrazole-5- carboxamide 18.4 as a pale yellow crystalline solid.
[00346] Step 5: Synthesis of l-methyl-3-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}- lH-pyrazole-5-carboxamide, 1-76
[00347] 4M HC1 in dioxane (5 ml) was added at rt to a stirred solution of 1 -methyl-3 -phenyl- N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5- carboxamide (18.4, 47 mg, 0.08 mmol) in MeOH (HPLC grade, 2 ml). The mixture was stirred at rt for 20h. The solvent was removed in vacuo to obtain 35mg (97%) of 1 -methyl-3 -phenyl-N- {4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-76 as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.63 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.84 - 7.76 (m, 2H), 7.50 (s, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 4.8 Hz, 1H), 4.13 (s, 3H). cheme VIII
Figure imgf000097_0001
[00348] Each compound of Examples 19 and 20 was prepared according to the reaction sequence in Scheme VIII or an adaptation thereof.
[00349] Example 19. Synthesis of N-{4-[(4-methoxy-6-methylpyrimidin-2- yl)sulfamoyl]phenyl}-l-meth l-3-phenyl-lH-pyrazole-5-carboxamide, 1-90
Figure imgf000097_0002
1-90
[00350] Step 1: Synthesis of N-{4-[(4-methoxy-6-methylpyrimidin-2-yl)sulfamoyl] phenyl}acetamide 19.1
[00351] 4-(Acetylamino)benzenesulfonyl chloride (2.00 g, 8.56 mmol) was added at 0°C to a stirred solution of 4-methoxy-6-methylpyrimidin-2-amine (1.19 g, 8.56 mmol) in pyridine (dry, 20ml). The reaction mixture was allowed to reach rt and stirred for 15h then heated to 60°C for 2h. The solvent was removed in vacuo by azeotroping with toluene (2 x 25ml), followed by n- heptane (2 x 25ml) to afford a brown oil which was purified by flash column chromatography (MeOH/DCM 0/100 to 5/95) to obtain 0.60g (20%) of N-{4-[(4-methoxy-6-methylpyrimidin-2- yl)sulfamoyl]phenyl}acetamide 19.1 a colourless solid.
[00352] Step 2: Synthesis of 4-amino-N-(4-methoxy-6-methylpyrimidin-2-yl)benzene-l- sulfonamide 19.2
[00353] A mixture of N-{4-[(4-methoxy-6-methylpyrimidin-2-yl)sulfamoyl] phenyl} acetamide (19.1, 575 mg, 1.71 mmol) in MeOH (dry, 15ml) was flushed with nitrogen for 5 minutes. Thionyl chloride (0.12 ml, 1.71 mmol) was added at rt and the mixture was heated at 65°C for 2h. Further thionyl chloride (0.06 ml, 0.85 mmol) was added at rt and the reaction mixture was stirred at rt for lh. The solvent was removed in vacuo to afford a solid which was dissolved in 7M NH3 in MeOH (10 ml). After stirring at rt for 5 minutes the solvent was removed in vacuo to afford a material which was dissolved in MeOH (6 ml) and purified onto an SCX-2 column (MeOH then 7M NH3/MeOH) to obtain 413mg (90%) of 4-amino-N-(4- methoxy-6-methylpyrimidin-2-yl)benzene-l -sulfonamide 19.2 as a white fluffy solid.
[00354] Step 3: Synthesis of N-{4-[(4-methoxy-6-methylpyrimidin-2- yl)sulfamoyl]phenyl}-l-methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-90
[00355] Methanesulfonyl chloride (0.04 ml, 0.52 mmol) was added to a stirred mixture of 4- amino-N-(4-methoxy-6-methylpyrimidin-2-yl)benzene-l -sulfonamide (19.2, 110 mg, 0.37 mmol), l-methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (76mg, 0.37 mmol) and 3-picoline (0.11 ml, 1.12 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for lh. The reaction crude was partitioned between DCM (75ml) and water (50ml). The aqueous layer was further extracted with DCM (2x 50ml) and the combined layers were evaporated to afford a material which was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 126 mg (68%) of N-{4-[(4-methoxy-6-methylpyrimidin-2- yl)sulfamoyl]phenyl}-l-methyl-3-phenyl-lH-pyrazole-5-carboxamide 1-90 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.53 (s, 1H), 7.87 (s, 4H), 7.81 (d, J = 7.2 Hz, 2H), 7.50 (s, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 6.14 (s, 1H), 4.14 (s, 3H), 3.73 (s, 3H), 2.21 (s, 3H).
[00356] Example 20. Synthesis of N-{4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl}-l- methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-85
Figure imgf000099_0001
1-85
[00357] Step 1: Synthesis of N-{4-[(5-methoxypyrimidin-2-yl)sulfamoyl] phenyl}acetamide 20.1
[00358] To a solution of 5-methoxypyrimidin-2-amine (200 mg, 1.6 mmol) in MeCN (5 ml) was added pyridine (86 μΐ, 1.07 mmol) and the resulting solution was cooled to 0°C. A solution of 4-(acetylamino)benzenesulfonyl chloride (250 mg, 1.07 mmol) in MeCN (10ml) was added drop wise over five minutes, the resulting mixture was stirred under nitrogen at 0°C then allowed to warm to rt and stirred for 18h. The solvent was removed in vacuo and the remaining solid was purified by flash column chromatography (DCM/iPrOH 99/1 to 90/10) to afford 190 mg (41%) of N-{4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl}acetamide 20.1 as a white powder.
[00359] Step 2: Synthesis of 4-amino-N-(5-methoxypyrimidin-2-yl)benzene-l- sulfonamide hydrochloride 20.2
[00360] To a solution of N-{4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl}acetamide (20.1, 190 mg, 0.44 mmol) in MeOH (5ml) was added thionyl chloride (33 μΐ, 0.45 mmol) and the resulting mixture was stirred under nitrogen at 60°C. The reaction mixture was concentrated in vacuo to afford 140 mg (99%) of 4-amino-N-(5-methoxypyrimidin-2-yl)benzene-l -sulfonamide hydrochloride 20.2 as a yellow solid.
[00361] Step 3: Synthesis of 4-amino-N-(5-methoxypyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide 20.3
[00362] To a solution of 4-amino-N-(5-methoxypyrimidin-2-yl)benzene-l -sulfonamide hydrochloride (20.2, 150mg, 0.47 mmol) in DMF (3 ml) was added DIPEA (250 μΐ, 1.44 mmol) and DMAP (6 mg, 0.05 mmol). To this solution was added [2- (chloromethoxy)ethyl](trimethyl)silane (85μ1, 0.48 mmol) and the mixture was stirred under nitrogen at rt for 20h. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml). The organic layer was washed with water (3 x 10ml) and sat. aq. NaCl (5ml). The organic layer was dried over Na2S04 and evaporated to dryness to afford a yellow oil which was purified by flash column chromatography (heptane/EtOAc 60/40 to 20/80) to obtain 80mg (39%) of 4-amino-N-(5 -methoxypyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 - sulfonamide 20.3as a white gum.
[00363] Step 4: Synthesis of N-{4-[(5-methoxypyrimidin-2-yl)({[2-(trimethylsilyl) ethoxy] methyl})sulfamoyl]phenyl}-l-methyl-3-phenyl-lH-pyrazole-5-carboxamide 20.4
[00364] To a solution of 4-amino-N-(5-methoxypyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzene-l -sulfonamide (20.3, 80 mg, 0.19 mmol) and l-methyl-3 -phenyl- lH-pyrazole- 5-carboxylic acid (40mg, 0.2 mmol) in MeCN (5ml) was added 3-picoline (60μ1, 0.62 mmol). To this solution was added methanesulfonyl chloride (22μ1, 0.28 mmol) and the mixture was stirred at 0°C for 24h. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml). The organic layer was washed with water (10ml), 0.2N aqueous HCl (10ml), followed by sat. aq. NaCl (10ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford 120mg (98%) of N-{4-[(5-methoxypyrimidin-2-yl)({[2-
(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl } - 1 -methyl-3 -phenyl- 1 H-pyrazole-5 - carboxamide 20.4 as a white crystalline powder.
[00365] Step 5: Synthesis of N-{4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl}-l- methyl-3-phenyl-lH-pyrazole-5-carboxamide, 1-85
[00366] To N-{4-[(5-methoxypyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl] phenyl}-l-methyl-3-phenyl-lH-pyrazole-5-carboxamide (20.4, 130 mg, 0.21 mmol) was added 4M HCl (2 ml) and the resulting mixture was stirred under nitrogen at rt for 17h. The reaction mixture was concentrated in vacuo and the remaining solid was triturated from MeCN (10ml), filtered and dried to afford as 40mg (40%) of N-{4-[(5-methoxypyrimidin-2- yl)sulfamoyl]phenyl}-l-methyl-3-phenyl-lH-pyrazole-5-carboxamide 1-85 as a beige solid. 1H NMR (500 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.62 (s, 1H), 8.30 (s, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 9.0 Hz, 2H), 7.82 - 7.79 (m, 2H), 7.50 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 4.13 (s, 3H), 3.80 (s, 3H). Sche
Figure imgf000101_0001
acetonitrile
[00367] The compound of Example 21 was prepared according to the reaction sequence in Scheme IX.
[00368] Example 21. Synthesis of N-(4-(N-acetylsulfamoyl)phenyl)-l-methyl-3 -phenyl- 1H- pyrazole-5-carboxamide, 1-97
Figure imgf000101_0002
1-97
[00369] Methanesulfonyl chloride (0.05 ml, 0.65 mmol) was added to a stirred mixture of N- [(4-aminophenyl)sulfonyl]acetamide (100 mg, 0.47 mmol), l-methyl-3 -phenyl- lH-pyrazole-5- carboxylic acid (94mg, 0.47 mmol) and 3-picoline (0.14ml, 1.4 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for lh. The reaction crude was partitioned between DCM (75ml) and water (50ml). The aqueous layer was further extracted with DCM (2 x 50ml) and the combined layers were evaporated to afford a material which was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 102mg (55%) of N-[4-(acetamidosulfonyl)phenyl] -l-methyl-3 -phenyl- lH-pyrazole-5-carboxamide 1-97 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.68 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 7.52 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, 1H), 4.15 (s, 3H), 1.92 (s, 3H). cheme X
Figure imgf000102_0001
[00370] Thecompound of Example 22 was prepared according to the reaction sequence in Scheme X.
[00371] Example 22. Synthesis of 3-(2-Hydroxyphenyl)-l-methyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-95
Figure imgf000102_0002
1-95
[00372] Step 1: Synthesis of 3-(2-methoxyphenyl)-l-methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 22.2
[00373] Methanesulfonyl chloride (0.05 ml, 0.6 mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 -sulfonamide (22.1 , 164mg, 0.43mmol), 3 -(2-methoxyphenyl)-l -methyl- lH-pyrazole-5-carboxylic acid (lOOmg, 0.43 mmol) and 3-picoline (0.13ml, 1.29 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 2h. The reaction crude was partitioned between DCM (75ml) and water (50ml). The aqueous layer was further extracted with DCM (2x 50ml) and the combined layers were evaporated to afford a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 278 mg (80%) of 3-(2- methoxyphenyl)- 1 -methyl-N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]
methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 22.2 as a glassy solid. [00374] Step 2: Synthesis of 3-(2-hydroxyphenyl)-l-methyl-N-{4-[(pyrimidin-2- yl)sulfamoyl] phenyl}-lH-pyrazole-5-carboxamide, 1-95
[00375] 1M BC13 in DCM (0.34 ml) was added to a stirred solution of 3-(2-methoxyphenyl)- 1 -methyl-N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H- pyrazole-5-carboxamide (22.2, 93mg, 0.16 mmol) in DCM (dry, 5ml) at -78°C. The reaction mixture was stirred at -78°C for 30 minutes then allowed to reach rt and stirred for 4h. The reaction crude was partitioned between DCM (50ml) and water (25ml). The aqueous layer was further extracted with DCM (3 x 30ml) and the combined layers were evaporated to afford a material which was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 25mg (36%) of 3-(2-hydroxyphenyl)- 1 -methyl-N- {4-[(pyrimidin-2-yl)sulfamoyl]phenyl} - lH-pyrazole- 5-carboxamide 1-95 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.70 (s, 1H), 10.10 (s, 1H), 8.50 (d, J = 4.5 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 6.7 Hz, 1H), 7.63 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 4.15 (s, 3H).
Scheme XI
Figure imgf000103_0001
Figure imgf000103_0002
[00376] Each compound of Examples 23-27 was prepared according to the reaction sequence in Scheme XI or an adaptation thereof. [00377] Example 23. Synthesis of l-[2-(dimethylamino)ethyl]-3-ph [(pyrimidin-2-yl)sulfamoyl] henyl}-lH-pyrazole-5-carboxamide, 1-93
Figure imgf000104_0001
1-93
[00378] Step 1: Synthesis of methyl l-[2-(dimethylamino)ethyl]-3-phenyl-lH-pyrazole-5- carboxylate 23.1
[00379] A suspension of methyl 3 -phenyl- lH-pyrazole-5-carboxylate (0.60g, 2.97 mmol), K2C03 (1.23g, 8.9 mmol) and KI (0.99g, 5.93 mmol) in MeCN (dry, 35 ml) was stirred at rt for 10 minutes. (2-Chloroethyl)dimethylamine hydrochloride (0.85g, 5.93 mmol) was added, the reaction was heated to 120°C in a sealed tube and stirred for 48h. The reaction mixture was cooled down to rt, the solvent was removed in vacuo and 1M HCl (10ml) was added. The aqueous layer was washed with EtOAc (2 x 10ml), basified to pH 14 with 1M NaOH solution (6ml) and further extracted with EtOAc (2 x 10ml). The combined layers were evaporated to dryness to afford a material which was purified by flash column chromatography (EtO Ac/Heptane) to obtain 0.16g (20%) of methyl l-[2-(dimethylamino)ethyl] -3 -phenyl- 1H- pyrazole-5-carboxylate 23.1 as a yellow oil.
[00380] Step 2: Synthesis of lithio l-[2-(dimethylamino)ethyl]-3-phenyl-lH-pyrazole-5- carboxylate 23.2
[00381] 2M LiOH (1.27 ml) was added in one portion to a stirred solution of methyl l-[2- (dimethylamino)ethyl] -3 -phenyl- lH-pyrazole-5-carboxylate (23.1, 232mg, 0.85 mmol) in THF (HPLC grade, 5 ml)/water (distilled, 1ml) at rt. After 2h the solvent was removed under reduced pressure to yield 240 mg (quant.) of lithio l-[2-(dimethylamino)ethyl]-3-phenyl-lH-pyrazole-5- carboxylate 23.2 as a colourless solid.
[00382] Step 3: Synthesis of l-[2-(dimethylamino)ethyl]-3-phenyl-N-{4-[(pyrimidin-2- yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 23.3
[00383] To a stirred solution of 4-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl) ethoxy]methyl}benzene-l -sulfonamide (77mg, 0.2 mmol) and lithio l-[2-(dimethylamino)ethyl]- 3-phenyl-lH-pyrazole-5-carboxylate (23.2, 50mg, 0.19 mmol) in MeCN (dry, 5ml) was added 3-picoline (56μ1, 0.58 mmol). The mixture was cooled to 0°C and methanesulfonyl chloride (21 μΐ, 0.27 mmol) was added. The resulting mixture was allowed to reach rt and stirred for 20h. The solvent was removed in vacuo and the crude material purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100 then DCM/MeOH 100/0 to 90/10) to obtain 11 mg (95%) of l-[2-(dimethylamino)ethyl]-3-phenyl-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl) ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 23.3 as a pale yellow oil.
[00384] Step 4: Synthesis of l-[2-(dimethylamino)ethyl]-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-93
[00385] 4M HC1 in dioxane (5.5 ml) was added at rt to a stirred solution of of l-[2- (dimethylamino)ethyl]-3-phenyl-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]
methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-93 (23.3, 114 mg, 0.18 mmol) in MeOH (HPLC grade, 2 ml). The reaction mixture was stirred at rt for 20h. The solvent was removed in vacuo to yield a pale yellow oil which was triturated from MeCN/water, filtered and dried to afford 20mg (22%) of l-[2-(dimethylamino)ethyl]-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide hydrochloric salt 1-93 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 10.76 (s, 1H), 9.59 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 7.2 Hz, 2H), 7.67 (s, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 4.4 Hz, 1H), 4.91 (t, J = 6.1 Hz, 2H), 3.64 (s, 2H), 2.86 (s, 6H).
[00386] Example 24. Synthesis of l-methyl-5-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl] phenyl}-lH-pyrazole-3-carboxamide, 1-98
Figure imgf000105_0001
1-98
[00387] Step 3: Synthesis of l-methyl-5-phenyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 24.1
[00388] Methanesulfonyl chloride (0.03 ml, 0.35 mmol) was added to a stirred mixture of 4- amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l -sulfonamide (94mg, 0.25 mmol), l-methyl-5 -phenyl- lH-pyrazole-3-carboxylic acid (50 mg, 0.25 mmol) and 3- picoline (0.07 ml, 0.74 mmol) in MeCN (dry, 5ml) at 0°C. After addition, the reaction mixture was allowed to reach rt and stirred for lh. The solvent was removed under vacuum to afford a material which was purified by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to obtain 95 mg (68%) of l-methyl-5-phenyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 24.1 as a brown glassy solid.
[00389] Step 4: Synthesis of l-methyl-5-phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}- lH-pyrazole-3-carboxamide, 1-98
[00390] 4M HC1 in dioxane (5.8 ml) was added at rt to a stirred solution of l-methyl-5- phenyl-N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H- pyrazole-3-carboxamide (24.1, 95mg, 0.17 mmol) in MeOH (HPLC grade, 3ml). The mixture was stirred at rt for 15 minutes. The solvent was removed in vacuo to afford a material which was triturated from MeOH to obtain 50mg (69%) of l-methyl-5-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 1-98 as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.48 (s, 1H), 8.51 (d, J = 4.7 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.3 Hz, 2H), 7.51 (t, J = 7.1 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 3.98 (s, 3H).
[00391] Example 25. Synthesis of l-(2-methoxyethyl)-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-87
Figure imgf000106_0001
1-87
[00392] Step 1: Synthesis of methyl l-(2-methoxyethyl)-3-phenyl-lH-pyrazole-5- carboxylate and methyl l-(2-methoxyethyl)-5-phenyl-lH-pyrazole-3-carboxylate 25.1
[00393] To a solution of methyl 3 -phenyl- lH-pyrazole-5-carboxylate (300 mg, 1.48 mmol) in MeCN (35 mL) was added K2C03 (410mg, 2.97 mmol) and KI (369mg, 2.23 mmol) at rt. The reaction mixture was stirred at rt for 10 minutes, l-bromo-2-methoxyethane (309mg, 2.23 mmol) was then added and the reaction was heated to reflux with stirring for 4h. The reaction was concentrated under reduced pressure and diluted with DCM (50 ml). The organic layer was washed with water (50 mL) and brine (25 mL), dried with MgS04 and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography (heptane/EtOAc 100/0 to 40/60) to obtain 208mg (52%) of methyl l-(2-methoxyethyl)-3-phenyl- lH-pyrazole-5-carboxylate and methyl 1 -(2 -methoxyethyl)-5 -phenyl- lH-pyrazole-3-carboxylate 25.1 as a colourless oil.
[00394] Step 2: Synthesis of lithio l-(2-methoxyethyl)-3-phenyl-lH-pyrazole-5- carboxylate 25.2
[00395] Methyl 1 -(2 -methoxyethyl)-3 -phenyl- lH-pyrazole-5-carboxylate and methyl l-(2- methoxyethyl)-5 -phenyl- lH-pyrazole-3-carboxylate (25.1, 215mg, 0.83 mmol) and LiOH (59 mg, 2.48 mmol) were suspended in THF (10 mL) and water (2 mL). The reaction mixture was stirred at rt for 3h. The solvent was removed in vacuo to afford 202mg (quant.) of lithio l-(2- methoxyethyl)-3 -phenyl- lH-pyrazole-5-carboxylate 25.2 as a white residue.
[00396] Step 3: Synthesis of l-(2-methoxyethyl)-3-phenyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 25.3
[00397] Methanesulfonyl chloride (0.04 ml, 0.56 mmol) was added to a mixture of 4-amino- N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (15 lmg, 0.4 mmol), lithio 1 -(2 -methoxyethyl)-3 -phenyl- lH-pyrazole-5-carboxylate (25.2, lOOmg, 0.4 mmol) and 3-picoline (0.12ml, 1.19 mmol) in MeCN (dry, 5ml) at 0°C. After addition the reaction mixture was allowed to reach rt and stirred for 30 minutes. The reaction mixture was diluted with DCM (75ml) and water (50ml). The aqueous layer was further extracted with DCM (2 x 40ml) and the combined layers dried over Na2S04. Evaporation of the solvent afforded a material which was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 216mg (72%) of l-(2-methoxyethyl)-3-phenyl-N-{4-[(pyrimidin-2-yl)({[2-
(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 25.3 as a yellow glassy solid.
[00398] Step 4: Synthesis of l-(2-methoxyethyl)-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-87
[00399] 4M HC1 in dioxane (6 ml) was added at rt to a stirred solution of l-(2-methoxyethyl)- 3-phenyl-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide (25.3, 216 mg, 0.35 mmol) in MeOH (3ml). The mixture was stirred for 5 minutes. The solvent was removed in vacuo and the remaining solid was triturated from MeOH to afford 111 mg (62%) of l-(2-methoxyethyl)-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-87 as a light pink solid. 1H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 10.69 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 7.48 - 7.42 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 4.6 Hz, 1H), 4.71 (t, J = 5.5 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.19 (s, 3H).
[00400] Example 26. Synthesis of l-(2-hydroxyethyl)-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl] phenyl}-lH-pyrazole-5-carboxamide, 1-96
Figure imgf000108_0001
1-96
[00401] Step 5: Synthesis of l-(2-hydroxyethyl)-3-phenyl-N-{4-[(pyrimidin-2- yl)sulfamoyl] phenyl}-lH-pyrazole-5-carboxamide, 1-96
[00402] 1M BC13 in DCM (0.36 ml) was added to a stirred solution of l-(2-methoxyethyl)-3- phenyl-N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H- pyrazole-5-carboxamide (25.3, 100 mg, 0.16 mmol) in DCM (dry, 5ml) at -78°C. The reaction mixture was stirred at -78°C for lh then it was allowed to reach rt and stirred for 4h. Further 1M BCI3 in DCM (0.26 ml) was added at -78°C, stirring at -78°C was continued for lh then the mixture was allowed to warm up to rt and stirred for 15h. The reaction crude was partitioned between DCM (50ml) and water (25ml). The aqueous layer was further extracted with DCM (3 x 30ml) and the combined layers were evaporated to dryness. The remaining material was purified by prep HPLC (MeCN /Water, 0.1% formic acid) to obtain 3mg (4%) of l-(2-hydroxyethyl)-3- phenyl-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-96 as a colourless solid. 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.37 (s, 1H), 8.48 (s, 2H), 7.96 (d, J = 25.6 Hz, 4H), 7.63 (d, J = 6.8 Hz, 2H), 7.56 - 7.47 (m, 3H), 7.01 (s, 1H), 6.90 (s, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 3.87 (q, J = 5.6 Hz, 2H). [00403] Example 27. Synthesis of 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2-yl) sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-88
Figure imgf000109_0001
1-88
[00404] Step 1: Synthesis of methyl 3-phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.1
[00405] To a solution of methyl 3 -phenyl- lH-pyrazole-5-carboxylate (300 mg, 1.48 mmol) in MeCN (30 ml) was added K2C03 (410 mg, 2.97 mmol) and KI (370 mg, 2.23 mmol) at rt. 2- Bromopropane (210 μΐ, 2.24 mmol) was added and the resulting mixture was stirred at 80°C. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml). The organic layer was washed with water (2 x 10ml) and sat. aq. NaCl (10ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a material which was purified by flash column chromatography (heptane/EtOAc 95/5 to 75/25) to obtain 240mg (66%) of methyl 3- phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.1 as a white powder.
[00406] Step 2: Synthesis of lithio 3-phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.2
[00407] To a solution of methyl 3-phenyl-l-(propan-2-yl)-lH-pyrazole-5-carboxylate (27.1, 240 mg, 0.98mmol) in THF (5ml) was added LiOH (35mg, 1.50mmol) and water (1ml). The resulting mixture was stirred under air at rt for 18h. The reaction mixture was concentrated in vacuo to afford 226mg (quant) of lithio 3 -phenyl- l-(propan-2-yl)-lH-pyrazole-5-carboxylate 27.2.
[00408] Step 3: Synthesis of 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 27.3
[00409] To a solution of lithio 3 -phenyl- l-(propan-2-yl)-lH-pyrazole-5-carboxylate (27.2, 226mg, 0.96 mmol) in MeCN (10ml) was added 4-amino-N-(pyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (380 mg, 1 mmol) and 3-picoline (280 μΐ, 2.87 mmol). To this solution was added methanesulfonyl chloride (112 μΐ, 1.44 mmol) and the mixture was stirred at rt. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml). The organic layer was washed with water (10ml), 0.2N HCl (10ml) and sat. aq. NaCl (10ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a pale yellow oil which was purified by flash column chromatography (DCM/MeOH 100/0 to 99/1) to obtain 470mg (75%) of 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 27.3 as a yellow oil.
[00410] Step 4: Synthesis of 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2-yl) sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-88
[00411] To 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide (27.3, 470 mg, 0.75 mmol) was added 4M HCl in dioxane (5 ml) and the resulting mixture was stirred at rt for 16h. The reaction mixture was concentrated in vacuo and the remaining solid was triturated from 9: 1 MeOH water (10ml) to obtain 195mg (53%) of 3-phenyl-l-(propan-2-yl)-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-88 as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.66 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 8.9 Hz, 2H), 7.86 - 7.80 (m, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.41 (s, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 4.8 Hz, 1H), 5.36 (p, J = 6.6 Hz, 1H), 1.48 (s, 3H), 1.47 (s, 3H). Scheme XII
Figure imgf000110_0001
[00412] The compound of Example 28 was prepared according to the reaction sequence in Scheme XII
[00413] Example 28. Synthesis of 4-chloro-N-{4-[(pyrimidin-2- yl)sulfamoyl] phenyl}benzami 1-21
Figure imgf000110_0002
1-21 [00414] Triethylamine (0.20 ml, 1.40 mmol) was added at rt to a stirred solution of 4-amino- N-(pyrimidin-2-yl)benzene-l -sulfonamide (300mg, 1.20 mmol) in DCM (HPLC grade, 10ml), followed by 4-chlorobenzoyl chloride (0.11 ml, 0.90 mmol). The mixture was stirred at rt for 5 minutes. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by prep HPLC (MeCN/Water, 0.1% formic acid) to afford 17mg (4%>) of 4- chloro-N-{4-[(pyrimidin-2-yl)sulfamoyl]phenyl}benzamide 1-21 as a bright yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H), 10.62 (s, 1H), 8.48 (s, 2H), 8.04-7.87 (m, 6H), 7.67-7.60 (m, 2H), 7.01 (s, 1H).
[00415] Synthesis of 4-chloro-N- 4-(phenylsulfamoyl)phenyl] benzamide, 1-66
Figure imgf000111_0001
1-66
[00416] Purification by prep HPLC (MeCN/Water, 0.1% formic acid) afforded 20mg (13%) of 4-chloro-N-[4-(phenylsulfamoyl)phenyl]benzamide 1-66 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 10.18 (s, 1H), 7.99 - 7.93 (m, 2H), 7.92 - 7.86 (m, 2H), 7.76 - 7.70 (m, 2H), 7.64 - 7.58 (m, 2H), 7.25 - 7.18 (m, 2H), 7.09 (dd, J = 8.6, 1.0 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H).
Scheme XIII
Figure imgf000111_0002
[00417] The compound of Example 29 was prepared according to the reaction sequence in Scheme XIII. [00418]
[00419] Example 29. Synthesis of 4-chloro-N-methyl-N- {4- [(pyrimidin-2- yl)sulfamoyl] henyl} benzamide, 1-39
Figure imgf000112_0001
1-39
[00420] Step 1: Synthesis of 4-(methylamino)-N-(pyrimidin-2-yl)benzene-l-sulfonamide 29.1
[00421] Paraformaldehyde (0.60g, 20.0 mmol) was added to a stirred mixture of 4-amino-N- (pyrimidin-2-yl)benzene-l -sulfonamide (1.00 g, 4.0 mmol) in MeOH (HPLC grade, 20 ml), followed by sodium methoxide (1.08g, 20.0 mmol). The reaction mixture was heated to 65°C for
2h then cooled to 0°C with continued stirring. NaBH4 (0.76g, 20.0 mmol) was added portionwise then the mixture was heated to 65°C for lh. The mixture was evaporated to dryness then partitioned between DCM (150 ml) and sat. aq. NaCl (100 ml). The aqueous layer was neutralised with 6M HC1 and evaporated to dryness. The salts were then washed with DCM (3 x 50ml) and the combined layers were evaporated to dryness to give 0.63g (48%) of 4- (methylamino)-N-(pyrimidin-2-yl)benzene-l -sulfonamide 29.1 as a colourless solid.
[00422] Step 2: Synthesis of 4-chloro-N-methyl-N- {4- [(pyrimidin-2-yl)sulfamoyl] phenyl} benzamide, 1-39
[00423] DIPEA (129.7 μΐ, 0.74 mmol) was added to a solution of 4-(methylamino)-N- (pyrimidin-2-yl)benzene-l -sulfonamide (29.1, 150 mg, 0.57 mmol) in DCM (HPLC grade, 10 ml). The mixture was cooled to 0°C then a solution of 4-chlorobenzoyl chloride (99 mg, 0.57 mmol) in DCM (HPLC grade, 5ml) was added over 5 minutes. The resulting mixture was stirred at rt for lh. Water (20ml) was added and the mixture was extracted with DCM (2 x 20 ml). The combined layers were evaporated to dryness then purified using flash column chromatography (heptanes/EtOAc 60/40 to 0/100) to afford 17mg (7.5%) of 4-chloro-N-methyl-N- {4- [(pyrimidin-2-yl)sulfamoyl]phenyl}benzamide 1-39 as a colourless solid. IH NMR (500 MHz, Chloroform-d) δ 9.99 (s, IH), 8.53 (d, J = 4.9 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.21 - 7.17 (m, 2H), 7.15 - 7.08 (m, 4H), 7.01 (t, J = 4.9 Hz, IH), 3.51 (s, 3H). Scheme XIV
Figure imgf000113_0001
[00424] Each compound of Examples 30-32 was prepared according to the reaction sequence in Scheme XIV or an adaptation thereof
[00425] Example 30. Synthesis of 3-(2-hydroxyphenyl)-N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-63
Figure imgf000113_0002
1-63
[00426] Step 1: Synthesis of 4-Amino-N-methyl-N-(pyrimidin-2-yl)benzene-l- sulfonamide 30.1
[00427] lodomethane (0.50 ml, 8.0 mmol) was added to a mixture of 4-amino-N-(pyrimidin- 2-yl)benzene-l -sulfonamide (2.00g, 8.0 mmol) and K2C03 (1.10 g, 8.0 mmol) in DMF (HPLC grade, 35 ml) at 0°C. The reaction mixture was allowed to reach rt and stirred for lh. The mixture was diluted with water (100 ml) then extracted with DCM (3 x 100 ml). The combined organic layers were dried over Na2S04 and evaporated to dryness to afford 1.74 g (81%) of 4- amino-N-methyl-N-(pyrimidin-2-yl)benzene-l -sulfonamide 30.1 as a light yellow solid.
[00428] Step 2B: Synthesis of 3-(2-methoxyphenyl)-N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-p razole-5-carboxamide, 1-60
Figure imgf000114_0001
1-60
[00429] DIPEA (0.79 ml, 4.54 mmol) and HATU (0.86g, 2.27 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (0.33g, 1.51 mmol) in DMF (HPLC grade, 15ml), followed by 4-amino-N-methyl-N-(pyrimidin-2-yl)benzene-l- sulfonamide (30.1, 0.40g, 1.51 mmol). The mixture was stirred for 20h at rt then 23h at 60°C. The reaction mixture was diluted with water (100 ml), extracted with DCM (3 x 75ml) and the combined organics dried over Na2S04. The solvent was removed in vacuo and the crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to obtain 0.25g (36%) of 3-(2-methoxyphenyl)-N-{4-[methyl(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-5-carboxamide 1-60 as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 13.54 (s, 1H), 10.47 (s, 1H), 8.59 (d, J = 4.8 Hz, 2H), 8.00 (dd, 4H), 7.77 (s, 1H), 7.39 (t, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.12 (t, J = 4.8 Hz, 1H), 7.06 (t, 1H), 3.92 (s, 3H), 3.58 (s, 3H).
[00430] Step 3: Synthesis of 3-(2-hydroxyphenyl)-N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide, 1-63
[00431] 3-(2-methoxyphenyl)-N-{4-[methyl(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole- 5-carboxamide (1-60, 200mg, 0.42 mmol) in DCM (dry, 10ml) was cooled to -78°C. 1M BBr3 in DCM (0.92 ml) was added and the mixture stirred at -78°C for lh then rt for 60h. The reaction mixture was diluted with water (25ml). The aqueous layer was extracted with DCM (5 x 15ml). The solid which was present in both layers was filtered off and washed with 2.5 ml of DMSO:MeCN:water (2:4: 1) to afford 36mg (18%) of 3-(2-hydroxyphenyl)-N-{4- [methyl(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-63 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.53 (s, 1H), 10.48 (s, 1H), 8.60 (d, J = 4.8 Hz, 2H), 8.01 (dd, 4H), 7.72 (d, J = 7.0 Hz, 1H), 7.22 (t, 2H), 7.13 (t, J = 4.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.92 (t, 1H), 3.60 (s, 3H).
[00432] Example 31. Step 2 A: Synthesis of 4-chloro-N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}benzamide, 1-48
Figure imgf000115_0001
1-48
[00433] Triethylamine (0.09 ml, 0.68 mmol) was added at rt to a stirred solution of 4-amino- N-methyl-N-(pyrimidin-2-yl)benzene-l -sulfonamide (30.1 150mg, 0.57 mmol) in DCM (HPLC grade, 7ml), followed by 4-chlorobenzoyl chloride (0.07 ml, 0.57 mmol). The mixture was stirred for 14h at rt. The reaction mixture was diluted with water (75 ml) then extracted with DCM (3 x 50ml) and the combined organics dried over Na2S04. The solvent was removed in vacuo and the crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to afford 104mg (44%) of 4-chloro-N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}benzamide 1-48 as a cream solid. 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.58 (d, J = 4.8 Hz, 2H), 8.11 - 7.82 (m, 6H), 7.62 (d, J = 8.6 Hz, 2H), 7.12 (t, 1H), 3.58 (s, 3H).
[00434] Example 32. Step 2B: Synthesis of N-{4-[methyl(pyrimidin-2- yl)sulfamoyl]phenyl}-3-phenyl-lH-pyrazole-5-carboxamide, 1-47
Figure imgf000115_0002
[00435] DIPEA (0.42 ml, 2.39 mmol) and HATU (460m g, 1.2 mmol) were added at rt to a stirred solution of 5 -phenyl- lH-pyrazole-3-carboxylic acid (150mg, 0.8 mmol) in DMF (HPLC grade, 7ml), followed by 4-amino-N-methyl-N-(pyrimidin-2-yl)benzene-l -sulfonamide (30.1, 210mg, 0.8 mmol). The mixture was stirred for 15h at rt. The reaction mixture was diluted with sat. aq. NaHC03 (100ml) then extracted with DCM (3 x 50ml) and the combined organic layers dried over Na2S04. The solvent was removed in vacuo, the crude material was washed with DMSO:MeCN (1 :2, 4ml), MeOH (5ml) then purified by prep HPLC (MeCN/Water, 0.1% formic acid) to afford 13mg (4%) of N-{4-[methyl(pyrimidin-2-yl)sulfamoyl]phenyl}-3-phenyl-lH- pyrazole-5-carboxamide 1-47 as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.91 (s, 1H), 10.54 (s, 1H), 8.60 (d, J = 4.8 Hz, 2H), 8.02 (q, J = 9.0 Hz, 4H), 7.85 (d, J = 7.3 Hz, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.13 (t, J = 4.8 Hz, 1H), 3.60 (s, 3H).
Scheme XV
Figure imgf000116_0001
[00436] Each compound of Examples 33-37 was prepared according to the reaction sequence in Scheme XV or an adaptation thereof
[00437] Example 33. Synthesis of 4-chloro-N-{3-[(pyrimidin-2- yl)sulfamoyl]phenyl}benzamide, 1-64
Figure imgf000117_0001
1-64
[00438] Step 1: Synthesis of 3-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzene-l-sulfonamide 33.1
[00439] DIPEA (0.35 ml, 2 mmol) and DMAP (20mg, 0.20 mmol) were added to a stirred solution of 3-amino-N-(pyrimidin-2-yl)benzenesulfonamide (500mg, 2.0 mmol) in DCM (HPLC grade, 5 ml) at 0°C, followed by SEMC1 (0.35 ml, 2.0 mmol). The mixture was stirred at rt for 62h. The reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined organics were dried over Na2S04 and evaporated to dryness. The crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to afford 360mg (47%) of 3-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l- sulfonamide 33.1 as a yellow-brown solid.
[00440] Step 2A: Synthesis of 4-chloro-N-{3-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl}) sulfamoyl]phenyl}benzamide 33.2
[00441] DIPEA (0.25 ml, 1.4 mmol) and HATU (270mg, 0.71 mmol) were added at rt to a stirred solution of 4-chlorobenzoic acid (70mg, 0.47 mmol) in DCM (HPLC grade, 10ml) followed by 3 -amino-N-(pyrimidin-2-yl)-N- { [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 - sulfonamide (33.1, 180mg, 0.47 mmol). The mixture was stirred for 21h at rt, then re-treated with 4-chlorobenzoic acid (40mg, 0.26 mmol), DIPEA (0.32 ml, 1.84 mmol) and HATU (360mg, 0.95 mmol) and stirred for 24h at rt. The reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined layers were dried over Na2S04 and evaporated to dryness. The crude product was purified by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to afford 82mg (33%) of 4-chloro-N-{3-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}benzamide 33.2 as a light brown solid.
[00442] Step 3A: Synthesis of 4-chloro-N-{3-[(pyrimidin-2-yl)sulfamoyl]phenyl} benzamide, 1-64
[00443] 4M HC1 in dioxane (5.44 ml) was added at rt to 4-chloro-N-{3-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}benzamide (33.2, 80mg, 0.16 mmol). The mixture was stirred for 15 minutes then the solvent removed in vacuo. The crude material was suspended in MeOH and filtered off to afford 32mg (51%) of 4-chloro-N-{3-[(pyrimidin-2- yl)sulfamoyl]phenyl}benzamide 1-64 as an off-white solid.
[00444] 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.61 (s, 1H), 8.50 (s, 3H), 8.02 (dt, 3H), 7.71 (d, J = 8.2 Hz, 1H), 7.63 (dt, 2H), 7.55 (t, J = 8.2 Hz, 1H), 7.03 (s, 1H).
[00445] Example 34. Synthesis of l-[5-(2-Hydroxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide 1-77
Figure imgf000118_0001
1-77
[00446] Step 1: Synthesis of N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3- dihydro-lH-indole-5-sulfonamide 34.1
[00447] DIPEA (0.32 ml, 1.81 mmol) and DMAP (20mg, 0.18 mmol) were added to a stirred solution of N-(pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide (500mg, 1.81 mmol) in DCM (HPLC grade, 15 ml) at 0°C followed by SEMC1 (0.32 ml, 1.81 mmol). The mixture was stirred at rt for 90h. The reaction mixture was diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined layers were dried over Na2S04 and evaporated to dryness. The crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 0/100) to afford 243mg (32%) of N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro- lH-indole-5 -sulfonamide 34.1 as a light yellow oil.
[00448] Step 2B: Synthesis of l-[5-(2-Methoxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH-indole-5-sulfonamide 34.2
[00449] DIPEA (0.21 ml, 1.23 mmol) and HATU (230mg, 0.62 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (90mg, 0.41 mmol) in DMF (7.5ml), followed by N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3- dihydro-lH-indole-5 -sulfonamide (34.1, 170mg, 0.41 mmol). The mixture was stirred for 65h at rt then further DIPEA (0.21 ml, 1.23 mmol), HATU (230mg, 0.62 mmol) and 3-(2- methoxyphenyl)-lH-pyrazole-5-carboxylic acid (90mg, 0.41 mmol) were added and stirring at rt was continued for 3h. The solvent was removed in vacuo and the remaining material was purified by prep HPLC (MeCN/water, 2mM ammonium bicarbonate) to afford 46mg (18%) of l-[5-(2-methoxyphenyl)-lH-pyrazole-3-carbonyl]-N-(pyrimidin-2-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH-indole-5-sulfonamide 34.2 as of a brown glassy solid.
[00450] Step 3B: Synthesis of l-[5-(2-Hydroxyphenyl)-lH-pyrazole-3-carbonyl]-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide, 1-77
[00451] 1M BBr3 in DCM (0.19 ml) was added to a stirred solution of l-[5-(2- methoxyphenyl)- 1 H-pyrazole-3 -carbonyl] -N-(pyrimidin-2-yl)-N- { [2-
(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH-indole-5-sulfonamide (34.2, 46mg, 0.08 mmol) in DCM (3ml) at -78°C. The reaction mixture was allowed to reach rt and stirred for 20h. Further 1M BBr3 in DCM (0.08ml) was added at -78°C, the reaction was allowed to reach rt and stirred for 20h. The crude was partitioned between DCM (25ml) and water (25ml). The aqueous layer was extracted further with DCM (2 x 15ml), the combined layers were dried over Na2S04 and evaporated to dryness to afford a material which was purified by prep HPLC (MeCN/water, 0.1% formic acid) to obtain 16mg (45% yield) of 1- [5 -(2-hydroxyphenyl)-l H-pyrazole-3 - carbonyl]-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide 1-77 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.44 (s, 1H), 11.72 (s, 1H), 10.33 (s, 1H), 8.47 (d, 2H), 8.19 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.69 (s, 1H), 7.21 (dt, 2H), 6.98 (d, J = 7.8 Hz, 2H), 6.90 (td, 1H), 4.62 (s, 2H), 3.31 (t, 2H).
[00452] Example 35. Synthesis of 5-phenyl-N-{3-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-3-carboxamide, 1-
Figure imgf000119_0001
1-61
[00453] Step 2B: Synthesis of 5-phenyl-N-{3-[(pyrimidin-2-yl)({2- [(trimethylsilyl)oxy] ethyl}) sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 35.1
[00454] DIPEA (0.35 ml, 2 mmol) and HATU (380mg, 1.0 mmol) were added at rt to a stirred solution of 5 -phenyl- 1 H-pyrazole-3 -carboxylic acid (130mg, 0.67 mmol) in DMF (HPLC grade, 10ml), followed by 3-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene- 1-sulfonamide (33.1, 250mg, 0.67 mmol). The mixture was stirred for 20h at rt and then filtered, diluted with water (75 ml) and extracted into DCM (3 x 50 ml). The combined layers were dried over Na2S04 and evaporated to dryness. The crude product was purified by flash column chromatography (heptane/EtOAc 100/0 to 50/50) then by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to afford 146mg (40%) of 5-phenyl-N-{3-[(pyrimidin-2-yl)({2- [(trimethylsilyl)oxy]ethyl})sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 35.1 as an off white solid.
[00455] Step 3C: Synthesis of 5-phenyl-N-{3-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-3-carboxamide, 1-61
[00456] 4M HC1 in dioxane (9.13 ml) was added at rt to a stirred solution of 4-phenyl-N-{3- [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H-pyrazole-3- carboxamide (35.1, 150mg, 0.27 mmol) in MeOH (HPLC grade, 5ml). The mixture was stirred at rt for lh then the solvent removed in vacuo. The crude material was suspended in MeOH and filtered off to afford 73mg (66%) of 5-phenyl-N-{3-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH- pyrazole-3-carboxamide 1-61 as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.85 (d, J = 16.9 Hz, 1H), 11.89 (s, 1H), 10.51 (s, 1H), 8.62 (s, 1H), 8.50 (d, J = 4.7 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.68 (d, 1H), 7.60 - 7.45 (m, 3H), 7.42 (dt, J = 7.4 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.04 (s, 1H).
[00457] Example 36. Synthesis of 5-(2-hydroxyphenyl)-N-{3-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide, 1-81
Figure imgf000120_0001
1-81
[00458] Step 2B: Synthesis of 4-(2-methoxyphenyl)-N-{3-[(pyrimidin-2-yl)({[2- trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-pyrazole-3-carboxamide 36.1
[00459] DIPEA (0.21 ml, 1.23 mmol) and HATU (230mg, 0.62 mmol) were added at rt to a stirred solution of 3-(2-methoxyphenyl)-lH-pyrazole-5-carboxylic acid (90mg, 0.41 mmol) in DMF (7.5ml), followed by 3-amino-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzene- 1-sulfonamide (33.1, 160mg, 0.41 mmol). The mixture was stirred for 65h. The solvent was removed in vacuo to afford a material that was purified by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to obtain 56mg (24%) of 4-(2-methoxyphenyl)-N- {3 - [(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl } - 1 H-pyrazole-3 - carboxamide 36.1 as a white solid.
[00460] Step 3B: Synthesis of 5-(2-hydroxyphenyl)-N-{3-[(pyrimidin-2-yl)sulfamoyl] phenyl}- lH-pyrazole-3-carboxamide, 1-81
[00461] 1M BBr3 in DCM (0.24 ml) was added to a stirred solution of 4-(2-methoxyphenyl)- N-{3-[(pyrimidin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-pyrazole-3- carboxamide (36.1 , 56mg, 0.10 mmol) in DCM (dry, 3.5ml) at -78°C. The reaction mixture was allowed to reach rt and stirred for 3h. Further 1M BBr3 in DCM (0.10ml) was added at -78°C, the reaction mixture was allowed to reach rt, stirred for 17h and then heated to 40°C for 5h. The DCM solvent was flushed off under a stream of nitrogen and DCM (dry, 5ml) was added. Further 1M BBr3 in DCM (0.10ml) was added and the resulting mixture was heated to 60°C for lh. The reaction crude was partitioned between DCM (25ml) and water (25ml). The aqueous layer was further extracted with DCM (3 x 25ml) and the combined layers dried over Na2S04. The solvent was removed in vacuo to afford 64mg (quant.) of 4-(2-methoxyphenyl)-N-{3- [(pyrimidin-2-yl)( { [2-trimethylsilyl)ethoxy]methyl } )sulfamoyl]phenyl} - 1 H-pyrazole-3 - carboxamide 36.2 as an off-white solid. A portion (44 mg, 0.10 mmol) of this material was dissolved in DCM (dry, 3ml) and the resulting solution was cooled to -78°C. 1M BC13 in DCM (0.10ml) was added at -78°C, the reaction mixture was allowed to reach 0°C and stirred for 14h. The mixture was then cooled down to -78°C and further 1M BC13 in DCM (0.10ml) was added. The reaction mixture was allowed to reach rt and stirred for 19h. The reaction crude was partitioned between DCM (25ml) and water (25ml). The aqueous layer was further extracted with DCM (2x 25ml). The combined layers were dried over Na2S04 and evaporated to dryness to afford a solid that was purified by prep HPLC (MeCN/water, 0.1% formic acid) to obtain 15mg (34%>) of 5-(2-hydroxyphenyl)-N-{3-[(pyrimidin-2-yl)sulfamoyl]phenyl}-lH-pyrazole-3- carboxamide 1-81 as an off white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.42 (s, 1H), 11.85 (s, 1H) 10.27 (s, 2H), 8.47 (d, 3H), 7.99 (s, 1H), 7.69 (s, 2H), 7.52 (s, 1H), 7.22 (s, 2H), 6.96 (d, J = 45.2 Hz, 3H).
[00462] Example 37. Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indole-5-sulfonamide, 1-65
Figure imgf000122_0001
1-65
[00463] Step 2B: Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2-yl)- N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH-indole-5-sulfonamide 37.1
[00464] DIPEA (0.16 ml, 0.89 mmol) and HATU (170mg, 0.45 mmol) were added at rt to a stirred solution of 5 -phenyl- lH-pyrazole-3-carboxylic acid (60mg, 0.30 mmol) in DMF (HPLC grade, 10ml) followed by N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro- lH-indole-5 -sulfonamide (34.1, 120mg, 0.30 mmol). The mixture was stirred for 27h at rt then re-treated with 5 -phenyl- lH-pyrazole-3-carboxylic acid (30mg, 0.15 mmol), DIPEA (0.20 ml, 1.1 mmol) and HATU (220mg, 0.58 mmol) and stirred for 74h at rt. The solvent was removed in vacuo and the crude product purified by prep HPLC (MeCN/Water, 2mM ammonium bicarbonate) to afford 46mg (27%) of 1 -(5 -phenyl- lH-pyrazole-3 -carbonyl)-N-(pyrimidin-2-yl)- N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH-indole-5-sulfonamide 37.1 as an off-white solid.
[00465] Step 3C: Synthesis of l-(5-phenyl-lH-pyrazole-3-carbonyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indole-5-sulfonamide, 1-65
[00466] 4M HC1 in dioxane (2.75 ml) was added at rt to a stirred solution of 1 -(5 -phenyl- 1 H- pyrazole-3-carbonyl)-N-(pyrimidin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-lH- indole-5 -sulfonamide (37.1, 50mg, 0.08 mmol) in MeOH (HPLC grade, 5ml). The mixture was stirred for 10 minutes then the solvent removed in vacuo. The crude material was suspended in MeOH and filtered off to afford 14mg (39%) of 1 -(5 -phenyl- lH-pyrazole-3 -carbonyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indole-5-sulfonamide 1-65 as a yellow-grey solid. 1H NMR (500 MHz, DMSO-d6) δ 13.85 (d, J = 19.5 Hz, 1H), 11.67 (s, 1H), 8.50 (d, J = 4.7 Hz, 2H), 8.26 (s, 1H), 7.97 - 7.77 (m, 4H), 7.49 (t, J = 7.7 Hz, 1H), 7.46 - 7.31 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.03 (s, 1H), 4.60 (dt, 2H), 3.25 (t, J = 8.5 Hz, 2H). Scheme XVI
Figure imgf000123_0001
/ \ (step 2)
Figure imgf000123_0002
[00467] The compound of Example 38 was prepared according to the reaction sequence in Scheme XVI.
[00468] Example 38. Synthesis of l-methyl-3-phenyl-N-[4-(phenylformamido) sulfonylphenyl] -lH-pyrazole-5-carboxamide, 1-94
Figure imgf000123_0003
1-94
[00469] Step 1: Synthesis of N-(4-aminobenzenesulfonyl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzamide 38.1
[00470] DIPEA (0.47 ml, 2.7 mmol) and DMAP (22mg, 0.18 mmol) were added to a solution of N-(4-aminobenzenesulfonyl)benzamide (500mg, 1.81 mmol) in DCM (HPLC grade, 10 ml), followed by SEMCl (0.35 ml, 2.0 mmol). The mixture was stirred at rt for 2.5h. Water (20ml) was added and the mixture extracted with DCM (2 x 20 ml). The solvent was removed in vacuo and the crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 50/50) to afford 615mg (75%) of N-(4-aminobenzenesulfonyl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzamide 38.1 as a colourless solid.
[00471] Step 2: Synthesis of l-methyl-3-phenyl-N-{4-[(l-phenyl-N-{[2- (trimethylsilyl)ethoxy] methyl} formamido)sulfonyl]phenyl}-lH-pyrazole-5-carboxamide 38.2
[00472] 3-picoline (0.14 ml, 1.5 mmol) was added to a stirred solution of N-(4- aminobenzenesulfonyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzamide (38.1, 200mg, 0.49 mmol) and l-methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (99mg, 0.49 mmol) in MeCN (dry,
5 ml). The mixture was cooled to 0°C and methanesulfonyl chloride (0.04 ml, 0.52 mmol) added. The resulting mixture was stirred at rt for 1.5h, then re-treated with methanesulfonyl chloride (0.019 ml, 0.25 mmol) and stirred for a further lh. The mixture was diluted with water (20ml) and concentrated in vacuo. The crude was extracted with DCM (2 x 20 ml) and the combined layers were evaporated to dryness. The crude material was purified by flash column chromatography (heptane/EtOAc 100/0 to 50/50) to afford 228mg (78%) of l-methyl-3 -phenyl- N- {4-[( 1 -phenyl-N- { [2-(trimethylsilyl)ethoxy]methyl} formamido)sulfonyl]phenyl} - 1 H- pyrazole-5-carboxamide 38.2 as a colourless solid.
[00473] Step 3: Synthesis of l-methyl-3-phenyl-N-[4-(phenylformamido)sulfonylphenyl]- lH-pyrazole-5-carboxamide, 1-94
[00474] 4M HC1 in dioxane (8ml) was added to l-methyl-3 -phenyl-N- [4-(l -phenyl-N- {[2- (trimethylsilyl)ethoxy]methyl}methanesulfonyl)phenyl]-lH-pyrazole- 5-carboxamide (38.2, 220mg, 372 mmol) and the resulting mixture was stirred at rt for 16h and then at 50°C for 20h. The solvent was removed in vacuo and the crude product was purified by prep HPLC (MeCN/Water, 0.1% formic acid) to afford 36mg (20%) of 1 -methyl-3 -phenyl-N- [4- (phenylformamido)sulfonylphenyl]-lH-pyrazole-5-carboxamide 1-94 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.48 (br s, 1H), 10.70 (s, 1H), 8.07 - 7.94 (m, 4H), 7.87 (d, J = 7.3 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.53 - 7.43 (m, 5H), 7.35 (t, J = 7.4 Hz, 1H), 4.14 (s, 3H).
Figure imgf000125_0001
Figure imgf000125_0002
[00475] Each compound of Examples 39-40 was prepared according to the reaction sequence in Scheme XVII or an adaptation thereof
[00476] Example 39. Synthesis of 3-(2-hydroxyphenyl)-N-[4-(phenylsulfamoyl)phenyl]- lH-pyrazole-5-carboxamide 1-37
Figure imgf000125_0003
1-37
[00477] Step 1: Synthesis of 3-(2-hydroxyphenyl)-lH-pyrazole-5-carbonyl chloride 39.1
[00478] A mixture of 3-(2-hydroxyphenyl)-lH-pyrazole-5-carboxylic acid (200mg, 0.98 mmol) and thionyl chloride (2 ml, 27.54 mmol) was refluxed for 3h. The reaction mixture was allowed to cool and concentrated in vacuo to afford 218mg (99%) of 3-(2-hydroxyphenyl)-lH- pyrazole-5-carbonyl chloride 39.1 as an orange solid.
[00479] Step 2: Synthesis of 3-(2-hydroxyphenyl)-N-[4-(phenylsulfamoyl)phenyl]-lH- pyrazole-5-carboxamide, 1-37 [00480] To a solution of 4-amino-N-(pyridin-2-yl)benzene-l -sulfonamide (245mg, 0.98 mmol) in DCM (5 ml) was added DIPEA (256 μΐ, 1.47 mmol) at rt. The resulting solution was cooled down to 0°C and 3-(2-hydroxyphenyl)-lH-pyrazole-5-carbonyl chloride (39.1, 218mg, 0.98 mmol) in DCM (10ml) was added. The mixture was allowed to reach rt and stirred for 16h. The reaction mixture was concentrated in vacuo and the remaining material was purified by flash column chromatography (DCM/MeOH 100/0 to 95/5) and prep HPLC (MeCN/water, 0.1% formic acid) to obtain 5mg (1%) of 3-(2-hydroxyphenyl)-N-{4-[(pyridin-2- yl)sulfamoyl]phenyl}-lH-pyrazole-5-carboxamide 1-37 as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.02 (d, J = 4.5 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.30 (d, J = 1.5 Hz, 1H), 7.23 - 7.18 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.85 (t, J = 5.5 Hz, 1H).
[00481] Example 40. Synthesis of 4-chloro-N-{4-[(pyridin-2- yl)sulfamoyl]phenyl}benzamide 1-62
Figure imgf000126_0001
1-62
[00482] Step 3: Synthesis of 4-Amino-N-(pyridin-2-yl)-N-{[2-
(trimethylsilyl)ethoxy] methyl} benzene-l-sulfonamide 40.1
[00483] To a solution of 4-amino-N-(pyridin-2-yl)benzenesulfonamide (l .OOg, 4.01 mmol) in DCM (100 ml) was added DIPEA (700 μΐ, 4.02 mmol). To this solution was added SEMC1 (710 μΐ, 4.01 mmol) at rt and the mixture was stirred at rt for 6h. The reaction mixture was partitioned between DCM (200ml) and water (20ml). The organic layer was washed further with sat. aq. NaCl (10ml), dried over Na2S04 and evaporated to dryness. The remaining material was purified by flash column chromatography (heptane/EtOAc 50/50 to 0/100) to obtain 0.80g (42%) of 4- amino-N-(pyridin-2-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide 40.1 as a colourless oil.
[00484] Step 4: Synthesis of 4-chloro-N-{4-[(pyridin-2-yl)({[2-(trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}benzamide 40.2 [00485] To a solution of 4-amino-N-(pyridin-2-yl)-N-{[2-(trimethylsilyl)ethoxy] methyl}benzene-l -sulfonamide (40.1, lOOmg, 0.26 mmol) in DCM (2 ml) was added DIPEA (50 μΐ, 0.29 mmol). To this solution was added 4-chlorobenzoyl chloride (30 μΐ, 0.23 mmol) and the mixture was stirred at rt for 2h. The reaction mixture was partitioned between DCM (100ml) and water (20ml). The organic layer was washed further with sat. aq. NaCl (10ml), dried over Na2S04 and evaporated to dryness. The remaining material was purified by flash column chromatography (heptane/EtOAc 90/10 to 20/80) to afford 200mg (19%) of 4-chloro-N- {4- [(pyridin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl} benzamide 40.2 as a white powder.
[00486] Step 5: Synthesis of 4-chloro-N-{4-[(pyridin-2-yl)sulfamoyl]phenyl}benzamide, I- 62
[00487] To 4-chloro-N-{4-[(pyridin-2-yl)({[2-(trimethylsilyl)ethoxy]methyl}) sulfamoyl] phenyl} benzamide (40.2, 100 mg, 0.19 mmol) was added 4M HC1 in dioxane (5 ml) and the resulting mixture was stirred at rt for 2h. The reaction mixture was filtered through filter paper and the resulting solid was washed with MeCN (10ml) and allowed to air dry to afford 24mg (31.7%) of 4-chloro-N- {4-[(pyridin-2-yl)sulfamoyl]phenyl}benzamide 1-62 as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.02 (s, 1H), 7.99 - 7.95 (m, 2H), 7.93 - 7.84 (m, 4H), 7.73 - 7.68 (m, 1H), 7.64 - 7.60 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H).
Scheme XVIII
Figure imgf000127_0001
[00488] The compound of Example 41 was prepared according to the reaction sequence in Scheme XVIII.
[00489] Example 41. Synthesis of 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoic acid, 1-86
Figure imgf000128_0001
1-86
[00490] Step 1: Synthesis of methyl 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoate 41.1
[00491] Methanesulfonyl chloride (0.05 ml, 0.69 mmol) was added to a mixture of methyl 4- aminobenzoate (75mg, 0.49 mmol), l-methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (100 mg, 0.49 mmol) and 3-picoline (0.14 ml, 1.48 mmol) in MeCN (dry, 5ml) at 0°C. After addition, the reaction mixture was allowed to reach rt and stirred for 17h. The reaction mixture was diluted with DCM (50ml) and water (50ml). The aqueous layer was further extracted with DCM (2 x 30ml) and the combined layers dried over Na2S04. Evaporation of the solvent afforded a material which was triturated from DMSO:MeCN (1 :2) to afford 134mg (77%) of methyl 4-(l- methyl-3 -phenyl- lH-pyrazole-5-amido)benzoate 41.1 as a white solid.
[00492] Step 2: Synthesis of 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoic acid, I- 86
[00493] LiOH (28.71 mg, 1.2 mmol) was added at rt to a stirred solution of methyl 4-(l- methyl-3 -phenyl- lH-pyrazole-5-amido)benzoate (41.1, 134 mg, 0.4 mmol) in THF (HPLC grade, 7.5ml) and water (1.5ml). The mixture was stirred at rt for 16h then heated at 50°C for 2.5h. The solvent was removed in vacuo and the resulting material was purified by prep HPLC (MeCN/water, 0.1% formic acid) to afford 27mg (20%) of 4-( l-methyl-3 -phenyl- lH-pyrazole-5- amido)benzoic acid 1-86 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 7.52 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 4.15 (s, 3H).
Scheme XIX
Figure imgf000129_0001
[00494] The compound of Example 42 was prepared according to the reaction sequence in Scheme XIX.
[00495] Example 42. Synthesis of 3-phenyl-N-{l-[(pyrimidin-2-yl)sulfamoyl] piperidin-4- yl}- lH-pyrazole-5-carboxamide 1-91
Figure imgf000129_0002
1-91
[00496] Step 1: Synthesis of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate 42.1
[00497] To a solution of benzyl piperidin-4-ylcarbamate (l .OOg, 4.27 mmol) in 1,2- dimethoxyethane (20 ml) was added sulfuric diamide (0.46g, 4.79 mmol) and the resulting mixture was stirred at 100°C for 72 hours. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml) and MeOH (10ml). This was washed with IN aqueous HC1 (10ml). DCM (100ml) and MeOH (10ml) were added to the organic layer. The organic layer was again washed with IN aqueous HC1 (2 x 10ml), dried over Na2S04 and concentrated in vacuo to afford as 1.05g (78%) of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate 42.1 as a white powder.
[00498] Step 2: Synthesis of benzyl N-{l-[(pyrimidin-2-yl)sulfamoyl]piperidin-4- yl}carbamate 42.2
[00499] To a solution of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate (42.1, 1.05g, 3.35 mmol) and 2-chloropyrimidine (0.40g, 3.46 mmol) in dioxane (1.5ml) was added CS2CO3 (1.50g, 4.6 mmol) at rt. To this mixture was added Brettphos Pd Gl (60 mg, 0.08 mmol) and Brettphos (80 mg, 0.15 mmol) and the mixture was stirred at 90°C for 8h. The reaction mixture was concentrated in vacuo and taken up in DCM (400ml). The organic layer was washed with IN aq. HC1 (20ml), followed by sat. aq. NaHC03 (20ml) and sat. aq. NaCl (20ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a material that was purified by flash column chromatography (DCM/MeOH 99/1 to 95/5) to obtain 0.1 Og (7%) of benzyl N- {l-[(pyrimidin-2-yl)sulfamoyl]piperidin-4-yl} carbamate 42.2 as a white powder.
[00500] Step 3: Synthesis of 4-amino-N-(pyrimidin-2-yl)piperidine-l-sulfonamide hydrochloride 42.3
[00501] To a solution of benzyl N-{l-[(pyrimidin-2-yl)sulfamoyl]piperidin-4-yl} carbamate (42.2, lOOmg, 0.26 mmol) in DCM (5ml) was added 1M BBr3 in DCM (260 μΐ) and the resulting mixture was stirred at for 24h. Further 1M BBr3 in DCM (260 μΐ) was added and stirring was continued for 24h. The reaction mixture was concentrated in vacuo to afford 120mg (96%) of 4-amino-N-(pyrimidin-2-yl)piperidine-l -sulfonamide hydrochloride 42.3 as a yellow powder.
[00502] Step 4: Synthesis of 3-phenyl-N-{l-[(pyrimidin-2-yl)sulfamoyl] piperidin-4-yl}- lH-pyrazole-5-carboxamide, 1-91
[00503] To a solution of 4-amino-N-(pyrimidin-2-yl)piperidine-l -sulfonamide hydrochloride (42.3, 50mg, 0.17 mmol) in DMF (1 ml) was added DIPEA (90 μΐ, 0.52 mmol) followed by 5- phenyl-lH-pyrazole-3-carboxylic acid (42mg, 0.22 mmol). To this solution was added EDC (43mg, 0.22 mmol) and the mixture was stirred at rt for 4h. The reaction mixture was concentrated in vacuo and taken up in DCM (50ml). The organic layer was washed with IN aq. HC1 (5ml), followed by sat. aq. NaHC03 (5ml), water (5ml) and sat. aq. NaCl (5ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford a material that was purified by flash column chromatography (DCM/MeOH 99/1) and prep HPLC (MeCN/water, 0.1% formic acid) to obtain 5mg (6%) of 3-phenyl-N-{l-[(pyrimidin-2-yl)sulfamoyl]piperidin-4- yl}-lH-pyrazole-5-carboxamide 1-91 as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.55 (s, 1H), 8.54 (s, 1H), 8.39 - 7.98 (m, 1H), 7.79 (s, 1H), 7.78 (s, 1H), 7.45 (s, 2H), 7.35 (s, 1H), 7.03 (t, J = 4.5 Hz, 2H), 3.91 - 3.80 (m, 1H), 3.75 (d, J = 12.2 Hz, 2H), 2.98 (t, J = 11.6 Hz, 2H), 1.84 (s, 2H), 1.61 (s, 2H).
Scheme XX
Figure imgf000131_0001
[00504] The compound of Example 43 was prepared according to the reaction sequence in Scheme XX.
[00505] Example 43. Synthesis of 5-chloro-l-methyl-N-(4-(N-(pyrimidin-2- yl)sulfamoyl)phenyl)-lH-indole-2-carboxamide 1-102
Figure imgf000131_0002
1-102
[00506] Step 1: Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylate 43.1
[00507] To a solution of 5-chloro-lH-indole-2-carboxylic acid (200mg, 1.02 mmol) in DMF (2 ml) was added at rt K2CO3 (1.23g, 8.79 mmol). To this solution was added iodomethane (950 μΐ, 15.26 mmol) and the mixture was stirred under nitrogen at rt in a sealed tube. After 20h the reaction mixture was concentrated in vacuo and partitioned between DCM (100ml) and water (10ml). The two layers were separated and the organic layer was extracted further with water (2 x 10ml) and saturated aqueous sodium chloride (10ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was azeotroped from heptane to afford 224 mg (98%) of methyl 5 -chloro-1 -methyl- lH-indole-2-carboxylate 43.1 as a pale yellow solid.
[00508] Step 2: Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylic acid 43.2
[00509] To a solution of methyl 5 -chloro-1 -methyl- lH-indole-2-carboxylate (43.1, 224 mg, 1.0 mmol) in THF (10ml) was added LiOH (36 mg, 1.5 mmol) in water (2ml) and the resulting mixture was stirred under air at rt. After 2h the solvent was removed under reduced pressure and the residue was taken up in IN aqueous hydrochloric acid (10ml). The resulting suspension was allowed to stand for ten minutes, then was filtered through filter paper and the solid was collected and dried under vacuum to afford 163 mg (77.6%) of 43.2 5 -chloro-1 -methyl- 1H- indole-2-carboxylic acid as a beige powder.
[00510] Step 3: Synthesis of 5-chloro-l-methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy] methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide 43.3
[00511] To a solution of 5-chloro-l-methyl-lH-indole-2-carboxylic acid (43.2, 81 mg, 0.39 mmol) in MeCN (dry, 5ml) was added 4-amino-N-phenyl-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (150 mg, 0.4 mmol) and 3-picoline (57 μΐ, 0.58 mmol). To this solution was added methanesulfonyl chloride (36 μΐ, 0.46 mmol) and the mixture was stirred under nitrogen at rt. After 60h the solvent was removed in vacuo and the crude material purified by flash column chromatography (heptane/EtOAc 80/20 to 60/40) to obtain 97 mg (43%) of 5-chloro-l-methyl-N-{4-[(pyrimidin-2-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}-lH-indole-2-carboxamide 43.3 as a white powder.
[00512] Step 4: Synthesis of 5-chloro-l-methyl-N-{4-[(pyrimidin-2-yl)sulfamoyl] phenyl}- lH-indole-2-carboxamide 1-102
[00513] 4M HC1 in dioxane (2 ml) was added at rt to a stirred solution of 5-chloro-l-methyl- N- {4-[(pyrimidin-2-yl)( { [2-(trimethylsilyl)ethoxy]methyl} )sulfamoyl]phenyl} - 1 H-indole-2- carboxamide (43.3, 97 mg, 0.17 mmol) and the resulting mixture was stirred under nitrogen at rt for 20h. The solvent was removed in vacuo and the residue was taken up in MeCN (5ml). The resulting suspension was filtered through filter paper to afford a white powder which was suspended in MeOH (3ml) and sonicated. The resulting suspension was filtered through filter paper under vacuum to afford 23 mg (28%) of 5-chloro-l-methyl-N-{4-[(pyrimidin-2- yl)sulfamoyl]phenyl}-lH-indole-2-carboxamide 1-102 as a white powder. 1H NMR (500 MHz, DMSO- 6) δ 11.67 (s, 1H), 10.71 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.97 (s, 4H), 7.80 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.05 (t, J = 4.6 Hz, 1H), 4.00 (s, 3H).
[00514] Example 44: Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase coupled assay
[00515] PHGDH activity was determined by detecting the NADH produced during the reaction. Diaphorase was used to catalyze the oxidation of NADH with the concomitant reduction of resazurin to the fluorescent product resorufin. Resorufm fluorescence quantitatively reflected the production of NADH by the PHGDH reaction. To drive the forward reaction, two enzymes in serine synthesis pathway subsequent to PHGDH, phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH), were also added to the reaction.
[00516] Briefly, serial dilution of compounds were incubated in a volume of 20ml in 384 well plates with the assay mixture containing 10 nM PHGDH, 500 nM PSAT1, 500 nM PSPH, 20mM NAD+, 80uM 3-phosphoglycerate, ImM glutamate, 57uM resazurin and 0.2 mg/ml diaphorase in assay buffer containing 50mM trisethanoloamine (TEA) pH8.0, 10 mM MgCl2, 0.01% Tween- 20 and 0.05% Bovine Serum Albumin (BSA). The plate was then incubated at 30°C for 60 minutes and resorufin fluorescence was measured at emission wavelength 598nM following excitation at 525nM. The positive control consisted of the complete reaction mixture with 4% DMSO and was set to 0% inhibition and negative control consisted of the reaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition. Percent inhibition with the compounds was then calculated by normalizing the fluorescence observed at a given compound concentration to the positive and negative controls. The IC50 was calculated by plotting the % inhibition versus concentration and using hyperbolic fit to determine compound concentration corresponding to 50% inhibition.
[00517] Table 2 shows the activity of selected compounds of this invention in the full-length PHGDH activity inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided an IC50 < 50 μΜ; compounds having an activity designated as "B" provided an IC50 of 50-100 μΜ; and compounds having an activity designated as "C" provided an IC50 of > 100 μΜ. "NA" stands for "not assayed." Table 2. Full length (FL) PHGDH Activity Inhibition Data
Compound PHGDH Compound PHGDH ID# ICso ID# ICso
1-1 A 1-42 C
1-2 C 1-43 C
1-3 C 1-44 C
1-4 A 1-45 C
1-5 C 1-46 C
1-6 A 1-47 C
1-7 A 1-48 C
1-8 C 1-49 C
1-9 A 1-50 C
1-10 C 1-51 C
1-11 C 1-52 C
1-12 C 1-53 C
1-13 C 1-54 C
1-14 C 1-55 C
1-15 C 1-56 C
1-16 C 1-57 C
1-17 NA 1-58 C
1-18 C 1-59 C
1-19 C 1-60 C
1-20 C 1-61 A
1-21 A 1-62 C
1-22 C 1-63 C
1-23 C 1-64 C
1-24 NA 1-65 C
1-25 C 1-66 C
1-26 C 1-67 C
1-27 C 1-68 C
1-28 C 1-69 B
1-29 C 1-70 C
1-30 C 1-71 C
1-31 B 1-72 C
1-32 A 1-73 A
1-33 C 1-74 C
1-34 C 1-75 A
1-35 A 1-76 A
1-36 A 1-77 C
1-37 C 1-78 A
1-38 B 1-79 C
1-39 B 1-80 C
1-40 C 1-81 A
1-41 B 1-82 B Compound PHGDH Compound PHGDH ID# ICso ID# ICso
1-83 C 1-84 A
[00518] Example 45: Truncated (TR) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase coupled assay
[00519] To assay the activity of inhibitors on the catalytic domain of PHGDH, truncated protein containing residues 3-315 of PHGDH ( Genbank NP 006614.2) was generated. PHGDH activity was determined by detecting the NADH produced during the reaction. Diaphorase was used to catalyze the oxidation of NADH with the concomitant reduction of resazurin to the fluorescent product resorufin. Resorufm fluorescence quantitatively reflected the production of NADH by the PHGDH reaction. To drive the forward reaction, two enzymes in serine synthesis pathway subsequent to PHGDH, phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH), were also added to the reaction.
[00520] Briefly, serial dilution of compounds were incubated in a volume of 20ml in 384 well plates with the assay mixture containing 40 nM truncated PHGDH, 500 nM PSAT1, 500 nM PSPH, 20mM NAD+, 80uM 3-phosphoglycerate, lmM glutamate, 57uM resazurin and 0.2 mg/ml diaphorase in assay buffer containing 50mM trisethanoloamine (TEA) pH8.0, 10 mM MgCl2, 0.01% Tween-20 and 0.05% Bovine Serum Albumin (BSA). The plate was then incubated at 30°C for 60 minutes and resorufin fluorescence was measured at emission wavelength 598nM following excitation at 525nM. The positive control consisted of the complete reaction mixture with 4% DMSO and was set to 0% inhibition and negative control consisted of the reaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition. Percent inhibition with the compounds was then calculated by normalizing the fluorescence observed at a given compound concentration to the positive and negative controls. The IC5o was calculated by plotting the % inhibition versus concentration and using hyperbolic fit to determine compound concentration corresponding to 50% inhibition.
[00521] Table 3 shows the activity of selected compounds of this invention in the PHGDH activity inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided an IC5o < 50 μΜ; compounds having an activity designated as "B" provided an IC50 of 50-100 μΜ; and compounds having an activity designated as "C" provided an IC50 of > 100 μΜ. Table 3. Truncated (TR) PHGDH Activity Inhibition Data
Figure imgf000136_0002
Figure imgf000136_0001
[00522] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

We claim:
1. A compound of formula I:
Figure imgf000137_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 6 membered monocyclic heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring C is phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6 membered saturated monocyclic carbocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring D is phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered saturated monocyclic carbocyclic ring;
each of m and q is independently 0, 1, 2, 3, 4, or 5; each of n and p is independently 0, 1, 2, 3, or 4;
r is 0 or 1 ;
s is 0 or 1 ;
each of R1, R2, R3, and R4 is independently halogen, R, -OR, -SR, -N(R)2, -C(0)R, -C(0)N(R)2, - N(R)C(0)R, -N02, -CN, -S02N(R)2, -N(R)S02R, or -C(0)N(R)C(0)R;
each R is independently hydrogen, or an optionally substituted group selected from Ci_6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
L1 is a covalent bond, or a bivalent Ci_4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)NR-, -N(R)C(0)-, - N(R)C(0)NR-, -NR-, -N(R)S02-,
-S02N(R)-, -C(O)-, -OC(O)-, -C(0)0-, -0-, -S-, -SO-, or -S02-;
L2 is -C(0)NR-, -NRC(O)-, -CH2N(R)-, -N(R)C(0)NR-; or
L and a substituent on Ring C are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
L is a bivalent Ci_6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by - S02NR-; -N(R)S02-,-S02-, -S02N(R)C(0)-; -C(0)N(R)S02-, -C(0)NR-, -N(R)C(0)-, or
- N(R)C(0)NR-, or L is a bivalent tetrazolylene ring;
with the provision that the compound is not 3-(2-hydroxy-3,4-dimethylphenyl)-N-(4-(N- (pyrimidin-2-yl)sulfamoyl)phenyl)-lH-pyrazole-5-carboxamide.
2. The compound of claim 1 of formula II:
Figure imgf000139_0001
or a pharmaceutically acceptable salt thereof.
The compound of claim 2 of formula III
Figure imgf000139_0002
a pharmaceutically acceptable salt thereof.
The compound of claim 3 of formula IV:
Figure imgf000139_0003
a pharmaceutically acceptable salt thereof. The compound of claim 4 of formula V:
Figure imgf000139_0004
V
or a pharmaceutically acceptable salt thereof, wherein: R5 is hydrogen or an optionally substituted Ci_6 aliphatic.
6. The compound of claim 5 of formula VI:
Figure imgf000140_0001
a pharmaceutically acceptable salt thereof.
The compound of claim 1 of formula VII
Figure imgf000140_0002
VII
or a pharmaceutically acceptable salt thereof, wherein: R5 is hydrogen or an optionally substituted Ci_6 aliphatic.
8. The compound of claim 6 of formula VIII:
Figure imgf000140_0003
VIII
a pharmaceutically acceptable salt thereof. The compoun f claim 8 of formula IX:
Figure imgf000140_0004
IX
or a pharmaceutically acceptable salt thereof.
10. The compoun f claim 7 of formula X:
Figure imgf000141_0001
X
or a pharmaceutically acceptable salt thereof. 11. The compound of claim 9 of formula XI:
Figure imgf000141_0002
XI
or a pharmaceutically acceptable salt thereof. 12. The compound of claim 11 of formula XII:
Figure imgf000141_0003
harmaceutically acceptable salt thereof.
13. The compound of claim 10 of formula XIII:
Figure imgf000142_0001
XIII
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 12 of formula XIV:
Figure imgf000142_0002
XIV
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 2 of formula XV:
Figure imgf000143_0001
XV
or a pharmaceutically acceptable salt thereof, wherein: R5 is hydrogen or an optionally substituted Ci_6 aliphatic.
16. The compound of claim 1 of formula XVI:
Figure imgf000143_0002
XVI
or a pharmaceutically acceptable salt thereof, wherein:
R5 is hydrogen or an optionally substituted Ci_6 aliphatic, and
R11 is an acidic moiety.
17. The compound of claim 1 of formula XVII:
Figure imgf000143_0003
XVII
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 of formula XVIII:
Figure imgf000144_0001
XVIII
or a pharmaceutically acceptable salt thereof, wherein:
R6 is hydrogen or an optionally substituted Ci_6 aliphatic.
19. The compound of claim 1 of formula XIX:
Figure imgf000144_0002
or a pharmaceutically acceptable salt thereof, wherein:
R6 is hydrogen or an optionally substituted Ci_6 aliphatic.
20. The compound of any one of claims 1-14 and 16, wherein m is 1, 2 or 3 and each R1 is independently selected from -OH, -CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -C02H, NH2, -CI, -Br, - F, and -I.
2
21. The compound of any one of claims 1-20, wherein wherein n is 1, 2 or 3 and each R is independently selected from -OH, -CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -CH2CH2OCH3, - CH2CH2N(CH3)2, -C02H, NH2, -CI, -Br, and -F.
22. The compound of any one of claims 1-21, wherein p is 0.
23. The compound of any one of claims 1-21, wherein p is 1, 2 or 3 and each R is independently selected from-CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -CI, -Br, and -F.
24. The compound of any one of claims 1-15 and 17-19, wherein q is 0.
25. The compound of any one of claims 1-15 and 17-19, wherein q is 1, 2 or 3 and each R4 is independently selected from-CF3, -OCi_4-alkyl, -OCF3, -OCHF2, -CI, -Br, and -F. In some embodiments, q is 1 and R4 is -CH3. In some embodiments, q is 2 and both R4 groups are -CH3.
26. A pharmaceutical composition comprising a compound according to any one of claims 1 through 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
27. A method for treating a PHGDH-mediated disorder in a patient in need thereof, comprising administering to said patient the compound of claim 1 or pharmaceutical composition thereof.
28. A method for treating cancer in a patient in need thereof, comprising administering to said patient the compound of claim 1.
29. The method of claim 28, wherein the cancer is melanoma or breast cancer.
30. A method for treating a tumor in a patient in need thereof, comprising administering to said patient the compound of claim 1.
31. The method of claim 30, wherein the tumor comprises a melanoma, breast, or lung cancer.
32. The method of claim 30, wherein the tumor comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).
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