WO2011029043A1 - Heteroaryl btk inhibitors - Google Patents

Heteroaryl btk inhibitors Download PDF

Info

Publication number
WO2011029043A1
WO2011029043A1 PCT/US2010/047879 US2010047879W WO2011029043A1 WO 2011029043 A1 WO2011029043 A1 WO 2011029043A1 US 2010047879 W US2010047879 W US 2010047879W WO 2011029043 A1 WO2011029043 A1 WO 2011029043A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ring
nitrogen
sulfur
oxygen
Prior art date
Application number
PCT/US2010/047879
Other languages
French (fr)
Inventor
Minna Bui
Patrick Conlon
Daniel A. Erlanson
Junfa Fan
Bing Guan
Brian T. Hopkins
Alexey Ishchenko
Tracy J. Jenkins
Gnanasambandam Kumaravel
Doug Marcotte
Noel Powell
Daniel Scott
Art Taveras
Deping Wang
Min Zhong
Original Assignee
Biogen Idec Ma Inc.
Sunesis Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogen Idec Ma Inc., Sunesis Pharmaceuticals, Inc. filed Critical Biogen Idec Ma Inc.
Priority to US13/393,191 priority Critical patent/US9029359B2/en
Priority to EP10814583A priority patent/EP2485589A4/en
Publication of WO2011029043A1 publication Critical patent/WO2011029043A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Protein kinases are a large multigene family consisting of more than 500 proteins which play a critical role in the development and treatment of a number of human diseases in oncology, neurology and immunology.
  • the Tec kinases are non-receptor tyrosine kinases which consists of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk) and Bmx (bone-marrow tyrosine kinase gene on chromosome X; also known as Etk)) and are primarily expressed in haematopoietic cells, although expression of Bmx and Tec has been detected in endothelial and liver cells.
  • Tec
  • Tec kinases (Itk, Rlk and Tec) are expressed in T cell and are all activated downstream of the T-cell receptor (TCR).
  • Btk is a downstream mediator of B cell receptor (BCR) signaling which is involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
  • PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, which then induces additional B-cell signaling.
  • IP3 inositol triphosphate
  • DAG diacylglycerol
  • Mutations that disable Btk enzymatic activity result in XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency.
  • Tec kinases are targets of interest for autoimmune disorders.
  • the present invention provides a compound of formula I:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R x , X 1 , X 2 , L, Ring A 1 , y, z, and p are as defined and described herein.
  • These compounds are inhibitors of a number of protein kinases, in particular family members such as Itk, Txk, Tec, Bmx, and Btk (Bruton's tyrosine kinase). Accordingly, provided compounds can be used in a variety of methods including in vitro screening and activity assays as well as in vivo pre-clinical, clinical, and therapeutic settings, as described in detail herein.
  • the present invention provides pharmaceutical compositions comprising provided compounds.
  • the present invention provides methods of decreasing Btk enzymatic activity. Such methods include contacting a Btk with an effective amount of a Btk inhibitor.
  • the present invention provides methods of treating a disorder responsive to Btk inhibition in a subject in need thereof. Such disorders and methods are described in detail herein.
  • the present invention provides a compound of formula I:
  • X 1 is -0-, -CR 6 R 7 - or -NR 8 -;
  • p 0-5;
  • y is 0, 1 , or 2;
  • z is 0, 1 , or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
  • each R 1 is independently halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R, -C0 2 R, -
  • two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-, or: two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or an optionally substituted group selected from C 1-6
  • each of R 2 , R 4 , and R 8 is independently R, -CN, -C(0)R, -C0 2 R, -C(0)C(0)R,
  • R 2 and R 1 are optionally taken together with their intervening atoms to form an
  • optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • R" and R are optionally taken together with their intervening atoms to form an
  • optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • R" and R are optionally taken together with their intervening atoms to form an
  • optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • R x is hydrogen or optionally substituted C 1-6 aliphatic, or:
  • R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Ring A 1 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8- 10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered
  • heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain
  • 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.
  • aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic (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).
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 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)).
  • bivalent C x _ y (e.g., C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n - In some embodiments, n is 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.
  • cycloalkylenyl refers to a bivalent cycloalkyl group of
  • halogen means F, CI, Br, or I.
  • aralkoxy 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.”
  • aryloxy refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven 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 quaternized 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 heteroaromatic 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), ⁇ (as in pyrrolidinyl), or + NR (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 used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl 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.
  • a bivalent carbocycle is “carbocycylene”
  • a bivalent aryl ring is “arylene”
  • a bivalent benzene ring is “phenylene”
  • a bivalent heterocycle is "heterocyclylene”
  • a bivalent heteroaryl ring is “heteroarylene”
  • a bivalent alkyl chain is “alkylene”
  • a bivalent alkenyl chain is “alkenylene”
  • a bivalent alkynyl chain is “alkynylene”
  • compounds of the invention may, when specified, contain
  • substituents 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 e , -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR e , -(CH 2 ) 0 2 CH(OR e ) 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0 2 C(0)R e , -(CH 2 ) 0 2 C(0)OH, -(CH 2 ) 0 2 C(0)OR e , -(CH 2 ) 0 2 SR e , -(CH 2 ) 0 2 SH, -(CH 2 ) 0 2 NH 2 , -(CH 2 )o 2 NHR", -(CH 2 ) 0 2 NR' 2 ,
  • 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.
  • Suitable substituents on the aliphatic group of R * include halogen, -R", -(haloR"),
  • each R" is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_4 aliphatic, -CH2PI1, -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.
  • 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( H)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",
  • 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(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.
  • 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.
  • the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • 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.
  • oxo means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
  • protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound.
  • Suitable 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 r edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
  • hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), t- butoxymethyl, siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, tetrahydropyranyl (THP), 4-methoxytetrahydropyranyl (MTHP), 1 -methyl- 1 -methoxyethyl, 1 - methyl- 1 -benzyloxyethyl, 2-trimethylsilylethyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, 2,6- dichlorobenzyl, p-phenylbenzy
  • the protecting groups include methylene acetal, ethylidene acetal, 1 -1-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 3,4- dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, a-methoxybenzylidene ortho ester, a-(N,N'-dimethylamino)benzyliden
  • Amino-protecting groups include methyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2,7-dibromo)fluoroenylmethyl carbamate, 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 1 -methyl- 1 -(4-biphenylyl)ethyl carbamate (Bpoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t- butyl carbamate (BOC), allyl carbamate (Alloc), 4-nitrocinnamyl carbamate ( oc), N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benz
  • a provided compound is of formula I:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R x , X 1 , X 2 , L, Ring A 1 , y, z, and p are as defined above and described in classes and subclasses herein.
  • 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.
  • y is 0. In some embodiments, y is 1. In some embodiments, y is 2.
  • z is 0. In some embodiments, z is 1. In some embodiments, z is 2.
  • each R 1 is independently halogen, -N0 2 , -CN, -OR, -
  • each R 1 is independently halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R, -C0 2 R, -C(0)C(0)R, -S(0)R, -S(0) 2 R, -C(0)N(R) 2 , -S0 2 N(R) 2 , -OC(0)R, -N(R)C(0)R, -N(R)S0 2 N(R) 2 , -N(R)S0 2 R, -OC(0)N(R) 2 , or optionally substituted Ci-6 aliphatic.
  • R 1 is optioally substituted C 1-6 aliphatic.
  • R 1 is C1-4 alkyl. In some embodiments, R 1 is halogen. In some embodiments, R 1 is halogen substituted C1-4 alkyl. In some embodiments, R 1 is -CF 3 . In some embodiments, R 1 is -CN. In some embodiments, R 1 is methyl.
  • p is at least 2, and two R 1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R 1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two R 1 groups on adjacent carbon atoms are taken together with their intervening atoms to form a bicyclic ring
  • the bicyclic ring is further substituted with one, two, or three R 1 groups.
  • p is at least 2, and two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-.
  • two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain.
  • two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge having the formula: .
  • the bridged bicyclic group is further substituted with one, two, or three R 1 groups.
  • p is at least 2, and two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused 3-7 membered saturated or partially unsaturated carbocyclic ring.
  • two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring having the formula:
  • the spiro fused ring is further substituted with one, two, or three R 1 groups.
  • each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is hydrogen.
  • R is optionally substituted C 1-6 aliphatic.
  • R is optionally substituted phenyl.
  • R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a substituent on R is selected from -CN, -CF 3 , -OH, -
  • each of R 2 , R 4 , and R 8 is independently R, -C(0)R, -
  • each of R , R , and R is hydrogen. In some embodiments, each of R , R , and R is independently R.
  • R 2 is R, -C(0)R, -C0 2 R, -C(0)C(0)R, -C(0)CH 2 C(0)R,
  • R 2 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 2 is hydrogen. In other embodiments, R 2 is optionally substituted C 1-4 alkyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 2 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R x is hydrogen. In other embodiments, R x is optionally substituted C 1-6 aliphatic.
  • R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R x and R 2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 5-6 membered saturated monocyclic heterocyclic ring having 1 nitrogen heteroatom.
  • R 1 and R 2 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen,
  • R and R are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 and R 2 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • such 5-6 membered monocyclic rings formed by R 1 and R 2 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
  • R 1 and R 2 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
  • R and R are optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 and R 2 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 and R 2 are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • such 5-6 membered monocyclic rings formed by R 2 and R 7 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
  • R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R a 7 re optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 2 and R 7 are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 8 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen,
  • R and R are optionally taken together with their intervening atoms to form an optionally substituted 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 8 are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 8 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • such 5-6 membered monocyclic rings formed by R 2 and R 8 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
  • R 2 and R 8 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
  • R and R are optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 and R 8 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
  • R and R are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each of R 3 , R 5 , R 6 , R 7 , and R 9 is independently R, halogen,
  • each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is hydrogen. In some embodiments, each of R 3 , R 5 , R 6 , R 7 , and R 9 is
  • R 3 is R, halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R,
  • R 3 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is halogen, -CN, or optionally
  • R is hydrogen. In other embodiments, R is optionally substituted C 1-4 alkyl. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 3 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 3 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is R, -C(0)R, -C0 2 R, -C(0)C(0)R, -C(0)CH 2 C(0)R,
  • R 4 is hydrogen, -C(0)R, or optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is hydrogen. In other embodiments, R 4 is optionally substituted C 1-4 alkyl. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring.
  • R 4 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 4 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole or pyrazole.
  • R 5 is R, halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R,
  • R 5 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 5 is propargyl. In some embodiments, R 5 is halogen. In some embodiments, R 5 is hydrogen, C 1-6 aliphatic, or -N(R) 2 . In some embodiments, R 5 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R 5 is hydrogen. In other embodiments, R 5 is optionally substituted C 1-4 alkyl. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring.
  • R 5 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 5 is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0067] In some embodiments, R 6 is R, halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R,
  • R 6 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 6 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R 6 is hydrogen. In other embodiments, R 6 is optionally substituted C1-4 alkyl. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 6 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 6 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7 is R, halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R,
  • R 7 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 7 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R 7 is hydrogen. In other embodiments, R 7 is optionally substituted C1-4 alkyl. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 7 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 7 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • X 1 is -CR 6 R 7 - and R 6 and R 7 are independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted C1-4 alkyl. In some embodiments, R 6 and R 7 are independently hydrogen, unsubstituted phenyl, or C1-4 unsubstituted alkyl. In some embodiments, R 6 and R 7 are hydrogen. [0070] In some embodiments, R is R, -C(0)R, -C0 2 R, -C(0)C(0)R, -C(0)CH 2 C(0)R,
  • R 8 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R is hydrogen. In other embodiments, R 8 is optionally substituted C 1-4 alkyl. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 8 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 9 is R, halogen, -N0 2 , -CN, -OR, -SR, -N(R) 2 , -C(0)R,
  • R 9 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 9 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R 9 is hydrogen. In other embodiments, R 9 is optionally substituted C 1-4 alkyl. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R 9 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 9 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 9 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • X 1 is -0-. In some embodiments, X 1 is -CR 6 R 7 -. In
  • X is -NR -. In some embodiments, when y is 0, X is -CR R - or -NR -.
  • X 1 is -CR 6 R 7 - or -NR 8 -. In some embodiments, when z is 0,
  • X 1 is -CR 6 R 7 -. In some embodiments, when z is 1 , X 1 is -CR 6 R 7 - or -NR 8 -.
  • Ring A 1 is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A 1 is bicyclic.
  • Ring A 1 is monocyclic.
  • Ring A 1 is optionally substituted phenyl.
  • Ring A 1 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Ring A 1 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A 1 is an optionally substituted 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A 1 is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, Ring A 1 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A 1 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A 1 is a substituted phenyl moiety.
  • Ring A 1 is a phenyl moiety substituted with one or more substituents independently selected from halogen, -CN, -CF 3 , -OH, -OR, -NH 2 , -NR 2 , -COOH, - SR, -S(0)R, -S(0) 2 R, or an optionally substituted group selected from C 1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl
  • substituents on Ring A 1 are selected from halogen, -CN, -CF 3 , -OH, -NH 2 , -N(R) 2 , -COOH, -SR, -S(0)R, -S(0) 2 R, -S(0)N(R) 2 , -S(0) 2 N(R) 2 , or C 1-6 aliphatic.
  • Ring A 1 is a phenyl moiety substituted with one or more -S(0)R or -S(0) 2 R groups
  • R is -CF 3 or -NR 2
  • two substituents on Ring A 1 may be taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A 1 is selected from:
  • R x H, F, Cl, Br, I, CF 3
  • R y H, F, CI, CF 3
  • Ring A 1 is in certain embodiments, each R is an optionally substituted group selected from C 1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or 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 an optionally substituted 5-6 membered saturated, partially unsaturated, or heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from piperidine or pyrrolidine.
  • L is a covalent bond.
  • L is an optionally substituted bivalent C 1-4 saturated hydrocarbon chain, wherein one methylene unit of L is replaced by -C(O)- and one methylene unit of L is replaced by -N(R)-.
  • L is an optionally substituted bivalent Ci-4 saturated hydrocarbon chain, wherein one methylene unit of L is replaced by -C(O)- and one methylene unit of L is replaced by -N(R)-, wherein R is hydrogen.
  • one methylene unit of L is replaced by -C(R) 2 -. In some embodiments, one methylene unit of L is replaced by -C(R) 2 -, and each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic or 3-7 membered saturated carbocyclic. In some embodiments, one methylene unit of L is replaced by -C(R) 2 -, and each R is hydrogen. In some embodiments, one methylene unit of L is replaced by -C(R) 2 -, and each R is hydrogen or optionally substituted C 1-6 aliphatic.
  • one methylene unit of L is replaced by -C(R) 2 -, and each R is hydrogen or optionally substituted 3-7 membered saturated carbocyclic. In some embodiments, one methylene unit of L is replaced by -C(R) 2 -, and each R is independently hydrogen, a substituted C 1-6 aliphatic, or a substituted 3-7 membered saturated carbocyclic ring, wherein a substituent on R is selected from -CF 3 or -OH.
  • L is -C 0 -. In some embodiments, L is selected
  • L is selected from:
  • one methylene unit of L is replaced by -C(R) 2 -, and each
  • R is optionally substituted with one or more groups selected from halogen, -CN, -CF 3 , -OH, -NH 2 , -COOH, or R°.
  • one methylene unit of L is replaced by -Cy-.
  • Cy is cycloalkylenyl. In certain embodiments, Cy is an optionally substituted phenylene. In certain embodiments, Cy is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclylene. In certain embodiments, Cy is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Cy is an optionally substituted 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, Cy is
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R x , L, Ring A 1 , X 1 , p, y, and z is as defined for formula I above and described in classes and subclasses herein.
  • provided compounds are of formula I-b, I-b-i, or I-b-ii:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R x , L, Ring A 1 , X 1 , p, y, and z is as defined for formula I above and described in classes and subclasses herein.
  • y is 1
  • z is 2
  • X 1 is -0-, thereby providing compounds of formula I-a-/// or I-b-///:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R x , L, Ring A 1 , and p is as defined for formula I above and described in classes and subclasses herein.
  • y is 0 and z is 2.
  • provided compounds are of formula I-a-iv, I-a-v, I-b-iv, or I-b-v:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R x , L, Ring A 1 , and p is as defined for formula I above and described in classes and subclasses herein.
  • a compound of the present invention includes particular stereoisomers of formula Il-a, Il-b, II-c, Il-d, Ill-a, Ill-b, III-c, or Ill-d:
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , R x , L, X 1 , Ring A 1 , y, z, and p is as defined for formula I above and described in classes and subclasses herein.
  • a Btk inhibitor is a racemic mixture or enriched in one or more stereoisomers. In some embodiments, a Btk inhibitor is a compound of Formula Il-a. In some embodiments, a Btk inhibitor is a compound of Formula Il-b. In some embodiments, a Btk inhibitor is a compound of Formula Ill-a. In some embodiments, a Btk inhibitor is a compound of Formula Ill-b.
  • one methylene unit of L is replaced by -C(R) 2 -.
  • a compound of the present invention is of formula IV-a, IV- b, I -c, or IV-d:
  • each of R, R 1 , R 3 , R 4 , R 5 , R 9 , X 1 , X 2 , Ring A 1 , z, y, and p is as defined for formula I above and described in classes and subclasses herein.
  • each R is independently hydrogen, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with -CF 3 or -OH, unsubstituted C 3 _ 6 cycloalkyl, or unsubstituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a compound of the present invention is of formula V, V-a,
  • R 1 , R 3 , R 4 , R 5 , R 9 , X 1 , X 2 , Ring A 1 , z, y, and p is as defined for formula I above and described in classes and subclasses herein.
  • R 2 is taken together with R x to form an optionally substituted spirocyclic heterocyclyl ring selected from a 3 to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a compound of the present invention is of formula VI, -a, Vl-b, of VI-c:
  • each of R 1 , R 3 , R 4 , R 5 , R 9 , X 1 , L, Ring A 1 , z, y, and p is as defined for formula I above and described in classes and subclasses herein, and wherein h is 0-4.
  • h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4.
  • R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted group selected from a 4 to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7 to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 3 and R 4 are taken together to form a substituted or unsubstituted pyrrole or substituted or unsubstituted pyrazole.
  • a compound of the present invention is of formula Vll-a, Vll-b, VIII-a, VIII-b, IX-a, or IX-b:
  • each of R 1 , R 2 , R 5 , R 9 , R x , X 1 , L, Ring A 1 , z, y, and p is as defined for formula I above and described in classes and subclasses herein.
  • R 2 and R 7 are taken together with their intervening atoms to form optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a provided compound is of formula X:
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , X 2 , L, Ring A 1 , z, and p is as defined for formula I above and described in classes and subclasses herein, and wherein j is 0-4.
  • j is 0. In some embodiments, j is 1. In some embodiments, ] is 2. In some embodiments, ] is 3. In some embodiments, ] is 4.
  • R 2 and R 8 are taken together with their intervening atoms to form optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • a provided compound is of formula XI:
  • R R x , X, L, Ring A , z, and p is as defined for formula I above and described in classes and subclasses herein, and wherein k is 0-4.
  • k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.
  • a provided compound is a compound depicted in Table 1 , below. I. Exemplary Synthesis
  • the heterocyclic amine can be protected using the appropriate protecting group familiar to those skilled in the art.
  • the exo-cyclic amino goup can be substituted upon treated with a base such as sodium hydride or by other bases ⁇ e.g., DIEA, Et 3 N, K 2 C0 3 , etc.) familiar to one skilled in the art and in a solvent such as DMF or other appropriate solvents to yield 1.3.
  • the protected heterocyclic amine 1.4 can be de-protected to the amine which can be reacted with the substituted heteroaromatic such as pyridinyl and pyrimidyl moieties using DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvents to yield
  • the N-amination can be accomplished utilizing Buchwald coupling (Shafir, A. Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
  • Mahwald coupling Shafir, A. Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
  • Mehrotra M. M. et. al. Bioorganic & Medicinal Chemistry Letters 2002, 12, 1 103.
  • the exo-cyclic amine protecting group can be removed upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York.
  • the amine 1.7 can be reacted with the appropriate electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401. Li, P.; Xu, J. C. J. Pept. Res.
  • electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc
  • the exo- cyclic amine 1.7 can be reacted with chloro formate or chlorothioformate or o-, p- nitrophenylchloroformate or phenylchloroformate (or their thiocarbonyl equivalents), or diphenyl cyanocarbonimidate followed by displacement with the appropriate amine can also yield the corresponding urea, thiourea or cyanoguanidine.
  • the groups “Lg”, “Lg 1 ", and “Lg 2 " in Schemes 1 -3 are suitable leaving groups, i.e. , groups that are subject to nucleophilic displacement.
  • a “suitable leaving group” is a chemical group that is readily displaced by a desired incoming chemical moiety such as an amine. Suitable leaving groups are well known in the art, e.g., see, “Advanced Organic Chemistry,” Jerry March, 5 th Ed., pp. 351 -357, John Wiley and Sons, N.Y.
  • Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties.
  • suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methoxy, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).
  • certain compounds of formula (I) can also be prepared according to Scheme 2 using commercially available substituted heterocycles such as pyrrolidine, piperidine or azepanes which can undergo N-animation with substituted heteroaromatic such as pyridinyl and pyrimidyl moities using DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvents to yield 2.3.
  • substituted heteroaromatic such as pyridinyl and pyrimidyl moities
  • DIEA substituted heteroaromatic
  • the N-amination can also be accomplished utilizing Buchwald coupling (Shafir, A. Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
  • the exo-cyclic amine protecting group can be removed upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York to give compound 2.4.
  • the amine can be substituted using the appropriate electrophile such as 2-chloroacetyl chloride in the presence of an organic base such as triethylamine or other suitable bases familiar to those skilled in the art and in a solvent such as dichloromethane or another appropriate solvent.
  • Compound 2.5 can undergo nucleophilic displacement with various nucleophiles such as primary and secondary amines to yield compounds represented by structure 2.6.
  • the amine 3.2 can be reacted with the appropriate electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401. Li, P.; Xu, J. C. J. Pept. Res.
  • electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc
  • pyrazolo e.g. pyrazolo
  • Scheme 4 using commercially available 4,6- dihydroxypyrimidine 4.1.
  • the 4,6-dihydroxyprimidine can be chlorinated and formylation under Vilsmeier conditions upon treatment with POCI 3 and DMF to afford the 5-formyl-6,3-dichloro- 5-formylpyrimidine 4.2.
  • the aldehyde 4.2 can be condensed with the hydrazine to afford the imine which can undergo intramolecular cyclization to give 4.3.
  • the 4-chloro- 1H-pyrazolo[3,4- Jjpyrimidine intermediate can be protected upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York to afford 4.4 and can then undergo N-amination upon treatment with a substituted heterocyclic amine in the presence of DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvent.
  • the final step is the removal of the protecting group using suitable conditions to afford compounds of formula VHI-a.
  • each of the steps as depicted in Schemes 1-4 above may be performed in a manner whereby no isolation of each intermediate is performed.
  • additional steps may be performed to accomplish particular protection group and/or deprotection strategies.
  • compounds of the present invention are for use in medicine.
  • compounds of the present invention are useful as kinase inhibitors.
  • compounds of the present invention are selective inhibitors of Btk. Such methods include contacting a Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides methods of inhibiting Btk enzymatic activity by contacting a Btk with a Btk inhibitor of the present invention.
  • Btk enzymatic activity refers to Btk kinase enzymatic activity.
  • the half maximal inhibitory concentration (IC 50 ) of the Btk inhibitor against Btk is less than 1 ⁇ . In some embodiments, the IC 50 of the Btk inhibitor against Btk is less than 500 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is less than 100 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is less than 10 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is less than 1 nM.
  • the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 10 ⁇ . In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 1 ⁇ . In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 100 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 10 nM.
  • Btk inhibitors are useful for the treatment of diseases and disorders that may be alleviated by inhibiting (i.e., decreasing) Btk enzymatic activity.
  • Diseases is meant diseases or disease symptoms.
  • the present invention provides methods of treating autoimmune disorders, inflammatory disorders, and cancers in a subject in need thereof. Such methods include administering to a subject a therapeutically effective amount of a Btk inhibitor.
  • autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1 , Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis.
  • ADAM acute disse
  • inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.
  • PID pelvic inflammatory disease
  • IBD inflammatory bowel disease
  • reperfusion injury rheumatoid arthritis
  • transplant rejection transplant rejection
  • vasculitis vasculitis
  • the present invention provides methods of treating rheumatoid arthritis or lupus.
  • cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g.
  • lymphoma e.g., anaplastic large-cell lymphoma
  • leukemia e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia
  • multiple myeloma malignant mesothelioma, malignant melanoma
  • colon cancer e.g. microsatellite instability-high colorectal cancer.
  • the present invention provides methods of treating leukemia or lymphoma.
  • subject refers to a mammal to whom a pharmaceutical composition is administered.
  • exemplary subjects include humans, as well as veterinary and laboratory animals such as horses, pigs, cattle, dogs, cats, rabbits, rats, mice, and aquatic mammals.
  • candidate inhibitors capable of decreasing Btk enzymatic activity may be identified in vitro.
  • the activity of the inhibitor compounds can be assayed utilizing methods known in the art and/or those methods presented herein.
  • Btk can be found in native cells, isolated in vitro, or co-expressed or expressed in a cell. Measuring the reduction in the Btk enzymatic activity in the presence of an inhibitor relative to the activity in the absence of the inhibitor may be performed using a variety of methods known in the art, such as the BTK- POLYGAT-LS ASSAY described below in the Examples. Other methods for assaying the activity of Btk are known in the art. The selection of appropriate assay methods is well within the capabilities of those of skill in the art.
  • the compounds may be further tested for their ability to selectively inhibit Btk relative to other enzymes. Inhibition by a compound of the invention is measured using standard in vitro or in vivo assays such as those well known in the art or as otherwise described herein.
  • Compounds may be further tested in cell models or animal models for their ability to cause a detectable changes in phenotype related to Btk activity.
  • animal models may be used to test Btk inhibitors for their ability to treat autoimmune disorders, inflammatory disorders, or cancer in an animal model.
  • the present invention provides pharmaceutical compositions comprising a Btk inhibitor compound of the invention or a Btk inhibitor compound in combination with a pharmaceutically acceptable excipient (e.g., carrier).
  • a pharmaceutically acceptable excipient e.g., carrier
  • the pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.
  • the pharmaceutical compositions include a compound of the present invention and citrate as a pharmaceutically acceptable salt.
  • the Btk inhibitor included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above. Alternatively, the Btk inhibitor included in the pharmaceutical composition is not covalently linked to a carrier moiety.
  • a "pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent.
  • suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • the compounds of the invention can be administered alone or can be coadministered to a subject
  • Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms.
  • the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene -block polymers, and the like. Ampoules are convenient unit dosages.
  • the compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition.
  • co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil.
  • Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
  • Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.
  • Such agents are typically employed at a level between about 0.01% and about 2% by weight.
  • compositions of the present invention may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,91 1 ,920; 5,403,841 ; 5,212,162; and 4,861 ,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
  • compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • such compositions when administered in methods to treat cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. decreasing the number of cancer cells in a subject).
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to Btk inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of decreasing Btk enzymatic activity as measured, for example, using the methods described.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring Btk inhibition and adjusting the dosage upwards or downwards, as described above.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
  • treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the dosage range is 0.001% to 10% w/v. In some embodiments, the dosage range is 0.1 % to 5% w/v.
  • Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • Examples 2-15 are prepared according to Scheme 1 and Example 1 above.
  • Example 2 The title compound of Example 2 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-(3-phenylureido)acetic acid. H NMR
  • Example 3 The title compound of Example 3 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-benzamidoacetic acid.
  • EIMS (m/z): calcd. for C20H22N6O2 (M + +l)
  • Example 4 The title compound of Example 4 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-oxo-2-(phenylamino)acetic acid.
  • Example 5 ((3R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- hydroxy-3 -phenylpropanamide) .
  • Example 5 The title compound of Example 5 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was ssuubbssttiittuutteedd ffoorr (R)-3-hydroxy-3-phenylpropanoic.
  • Example 6 The title compound of Example 6 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (S)-3-hydroxy-3-phenylpropanoic acid.
  • EIMS (m/z): calcd. for C 2 oH 23 N 5 0 2 (M + +l) 366.2, found 366.0.
  • Example 7 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- phenylpropanamide).
  • Example 7 The title compound of Example 7 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 3-phenylpropanoic acid.
  • Example 8 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- phenoxyacetamide).
  • Example 8 The title compound of Example 8 was prepared in similar manner as described in Example 1 except except 2-(phenylamino)acetic acid was substituted for 2 -phenoxy acetic acid.
  • EIMS (m/z): calcd. for Ci 9 H 2 iN 5 0 2 (M + +l) 352.2, found 352.0.
  • Example 9 ((3S)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- amino-3-phenylpropanamide).
  • Example 9 The title compound of Example 9 was prepared in similar manner as described in Example 1 except intermediate 2-(phenylamino)acetic acid was substituted for (S)-3-tert- butoxycarbonylamino-3-phenylpropionic acid.
  • the Boc protected amine was treated with 4 N HCl in 1 ,4-dioxane (mL) for 2 h at rt.
  • the reaction mixture was concentrated in vacuo to afford a solid which purified by reverse phase chromatography CI 8 column and 10% acetonitrile/water containing 0.1% TFA to afford the final product.
  • Example 10 The title compound of Example 10 was prepared in similar manner as described in Example 1 except intermediate 2-(phenylamino)acetic acid was substituted for (R)-3-tert- butoxycarbonylamino-3-phenylpropionic acid.
  • the Boc protected amine was treated with 4 N HCl in 1 ,4-dioxane (mL) for 2 h at rt.
  • the reaction mixture was concentrated in vacuo to afford a solid which purified by reverse phase chromatography CI 8 column and 10% acetonitrile/water containing 0.1% TFA to afford the final product.
  • Example 1 ((R)- -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
  • Example 1 1 The title compound of Example 1 1 was prepared in similar manner as described in Example 1 except intermediate l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for (R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine.
  • Example 12 The title compound of Example 12 was prepared in similar manner as described in Example 1 except intermediate l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for (S)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine.
  • Example 13 The title compound of Example 13 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 3-(phenylamino)propanoic acid.
  • EIMS (m/z): calcd. for C 2 oH 2 4 6 0
  • Example 14 ((R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)- l ,2,3,4-tetrahydroquinoline-2-carboxamide).
  • Example 14 The title compound of Example 14 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (R)-l ,2,3,4-tetrahydroquinoline-2- carboxylic acid.
  • Example 15 ((S)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)- l ,2,3,4-tetrahydroquinoline-2-carboxamide).
  • Example 15 The title compound of Example 15 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (S)- 1 ,2,3 ,4-tetrahy droquinoline-2- carboxylic acid.
  • Example 17 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2-ieri- butylphenylamino)acetamide).
  • Example 17 The title compound of Example 17 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-te/ -butylaniline.
  • Example 18 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-ieri- butylphenylamino)acetamide).
  • Example 18 The title compound of Example 18 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-te/ -butylaniline.
  • Example 19 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4-ieri- butylphenylamino)acetamide).
  • Example 19 The title compound of Example 19 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-te/ -butylaniline.
  • Example 20 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- chlorophenylamino)acetamide).
  • Example 20 The title compound of Example 20 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-chloroaniline.
  • EIMS m/z: calcd. for Ci 9 H 23 Cl 6 0 (M + )+i 388.4.
  • Example 21 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- chlorophenylamino)acetamide).
  • Example 21 The title compound of Example 21 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 19 H 23 CIN 6 O (M + )+l 388.4.
  • Example 22 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4- chlorophenylamino)acetamide).
  • Example 22 The title compound of Example 22 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-chloroaniline.
  • EIMS (m/z): calcd. for Ci 9 H 23 Cl 6 0 (M + )+l 388.4.
  • Example 23 The title compound of Example 23 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoroaniline.
  • 1 H NMR 400MHz, CD 3 OD
  • EIMS (m/z): calcd. for Ci 9 H 23 FN 6 0 (M + )+i 370.4.
  • Example 24 The title compound of Example 24 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-trifluoromethylaniline. 1 H NMR (400 MHz,
  • Example 25 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,2- difluorobenzo[d][ l ,3]dioxol-4-ylamino)acetamide).
  • Example 25 The title compound of Example 25 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,2-difluorobenzo[d][l ,3]dioxol-4-amine.
  • 1 H NMR 400 MHz, CD 3 OD: ⁇ 8.25 (s, 1H), 7.33 (s, 1H), 7.03 (s, 1H), 6.87 (t, 1H), 6.48 (d, 1H), 6.35 (d, 1H), 4.45 (d, 1H), 4.27 (d, 1H), 4.06 (m, 1H), 3.87 (s, 2H), 3.63 (m, 2H), 2.01 (m, 2H), 1.80 (m, 2H).
  • EIMS (m/z): calcd. for C20H22F2N6O3 (M + )+l 432.4.
  • Example 26 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- sulfamoylphenylamino)acetamide).
  • Example 26 The title compound of Example 26 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-aminobenzenesulfonamide.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.25 8.25 (s, 1H), 7.33 (s, 1H), 7.21 (t, 1H), 7.14 (d, 1H), 37.03 (s, 2H), 6.73 (d, 1H), 4.43 (d, 1H), 4.26 (d,1H), 4.06 (m, 1H), 3.64 (m, 2H), 2.01 (m, 2H).
  • Example 27 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dichlorophenylamino)acetamide) .
  • Example 27 The title compound of Example 27 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dichloroaniline.
  • 1 H NMR 400MHz, CD 3 OD
  • ⁇ 8.26 s, 1H
  • 7.35 d, 1H
  • 7.00 m, 2H
  • 6.77 d, 1H
  • 6.42 d, 1H
  • 4.35 d, 1H
  • 4.17 d, 1H
  • 3.86 (s, 2H) 3.78 (m, 2H), 3.31 (s, 2H), 2.06 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H).
  • EIMS m/z: calcd. for C19H22CI2N6O (M + )+l 420.3.
  • Example 28 The title compound of Example 28 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(methylsulfonyl)aniline.
  • 1 H NMR 400 MHz, CD 3 OD) ⁇ 6.69 (s, 1H), 5.74 (t, 2H), 5.60 (d, 1H), 5.48 (s, 2H), 5.29 (d, 1H), 2.87 (d, 1H), 2.70 (d, 1H), 2.49 (s, 1H), 2.28 (s, 2H), 2.07 (m, 2H), 1.74 (s, 5H), 1.48 (s, 3H), 0.45 (m, 2H), 0.25 (m, 2H).
  • EIMS m/z: calcd. for C20H26N6O3S (M + )+l 430.5.
  • Example 29 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- fluorophenylamino)acetamide.
  • Example 29 The title compound of Example 29 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-fluoroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.26 8.26 (s, 1H), 7.35 (d, 1H), 7.02 (m, 2H), 6.82 (d, 2H), 6.21 (d, 1H), 4.35 (d, H), 4.20 (d, 1H), 4.07 (s, 1H), 3.75 (s, 4H).
  • 2.06 (m, 1H), 1.94 (m, 1H), 1.82 (m, 2H).
  • EIMS m/z: calcd. for Ci 9 H 23 F 6 0 (M + )+l 370.4.
  • Example 30 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,6- diethylphenylamino)acetamide) .
  • Example 30 The title compound of Example 30 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,6-diethylaniline.
  • 1 H NMR 400 MHz, CD 3 OD: ⁇ 8.30 (s, 1H), 7.39 (d, 1H), 7.13 (d, 2H), 7.05 (t, 3H), 4.57 (d, 1H), 4.33 (d, 1H), 4.1 1 (s, 1H), 3.68 (m, 3H), 2.66 (m, 4H), 2.15 (m, 1H), 2.03 (s, 1H), 1.84 (t, 2H), 1.22 (m, 5H).
  • EIMS m/z: calcd. for C23H32N6O (M + )+i 408.5.
  • Example 31 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(m- tolylamino)acetamide).
  • Example 31 The title compound of Example 31 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-methylaniline.
  • 1H NMR 400MHz, CD 3 OD: ⁇ 8.25 (s, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 6.96 (t, 1H), 6.17 (t, 3H), 4.87 (d, 1H), 24.20 (d, 1H), 4.08 (s, 1H), 3.76 (m, 3H), 2.21 (s, 2H), 2.04 (s, 1H), 1.93 (m, 1H), 1.81 (m, 2H).
  • EIMS m/z: calcd. for C 2 oH 26 N 6 0 (M + )+l 366.2.
  • Example 32 The title compound of Example 32 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-methoxyaniline.
  • 1 H NMR 400 MHz, CD 3 OD: ⁇ 8.24 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.95 (t, 1H), 6.24 (d, 1H), 6.12 (m, 2H), 4.32 (d, 1H), 4.15 (d, 1H), 4.07 (s, 1H), 3.75 (m, 1H), 3.69 (s, 2H), 3.30 (s, 1H), 2.03 (m, 1H), 1.92 (m, 1H), 1.81 (m, 2H).
  • EIMS (m/z): calcd. for C 2 oH26N 6 0 2 (M + )+i 382.5.
  • Example 33 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4- fluorophenylamino)acetamide).
  • Example 33 The title compound of Example 33 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-fluoroaniline.
  • Example 34 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- cyanophenylamino)acetamide).
  • Example 34 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-aminobenzonitrile.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 2 oH 23 N 7 0 (M + )+l 377.4.
  • Example 35 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,5- dichlorophenylamino)acetamide) .
  • Example 35 The title compound of Example 35 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,5-dichloroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.24 s, 1H), 7.33 (s, 1H), 7.15 (d, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 6.48 (s, 1H), 4.37 (d, 1H), 4.18 (d, 1H), 4.07 (s, 1H), 3.82 (s, 2H), 3.75 (m, 2H), 2.06 (m, 1H), 1.98 (m, 1H), 1.83 (m, 2H).
  • EIMS m/z: calcd. for C19H22CI2N6O (M + )+i 421.3.
  • Example 36 The title compound of Example 36 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(trifluoromethoxy)aniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C20H23F3N6O2 (M + )+l 436.4.
  • Example 37 The title compound of Example 37 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-(methoxy)aniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C20H26N6O2 (M + )+l 382.5.
  • Example 38 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- isopropylphenylamino)acetamide).
  • Example 38 The title compound of Example 38 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for S-isopropylaniline H NMR (400 MHz, CD 3 OD) ⁇ 8.26 (s, 1H), 7.69 (d, 1H), 7.36 (s, 1H), 7.21 (d, 1H), 7.05 (s, 2H), 6.55 (d, 2H), 6.41 (s, 1H), 4.44 (d, 1H), 4.25 (s, 1H), 4.06 (s, 1H), 3.65 (m, 2H), 2.77 (m, 1H), 2.35 (s, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.79 (m, 2H), 1.19 (d, 5H). EIMS (m/z): calcd. for C 2 2H 3 oN 6 02 (M + )+i 394.3.
  • Example 39 The title compound of Example 39 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for biphenyl-3 -amine.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 2 5H28N 6 0 (M + )+i 428.5.
  • Example 40 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- bromophenylamino)acetamide) .
  • Example 40 The title compound of Example 40 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-bromoaniline. 1 H NMR (400 MHz, CD 3 OD) ⁇ 8.25
  • Example 41 The title compound of Example 41 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 5,6,7,8-tetrahydronaphthalen-l -amine. 1 H NMR
  • Example 42 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- phenoxyphenylamino)acetamide).
  • Example 42 The title compound of Example 42 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3 -phenoxy aniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.24 s, 1H
  • 7.33 s, 1H
  • 7.26 t, 2H
  • 7.01 m, 4H
  • 6.91 m, 2H
  • 6.29 m, 3H
  • 6.16 s, 1H
  • 4.35 d, 1H
  • 4.02 (s, 1H) 3.70 (s, 3H), 1.96 (m, 2H), 1.77 (s, 2H).
  • EIMS m/z: calcd. for C25H28N6O (M + )+l 444.5.
  • Example 43 (3-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethylamino)-N,N-dimethylbenzamide).
  • Example 43 The title compound of Example 43 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-amino- NN-dimethylbenzamide.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C22H29N7O2 (M + )+l 423.5.
  • Example 44 The title compound of Example 44 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-4-fluoroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.27 8.27 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.90 (t, 1H), 6.56 (t, 1H), 6.43 (m, 1H), 4.36 (d, 1H), 4.19 (d, 1H), 4.07 (s, 1H), 3.72 (s, 2H), 3.63 (m, 5H), 2.04 (m, 1H), 1.96 (m, 1H), 1.82 (m, 2H).
  • EIMS (m/z): calcd. for Ci 9 H 22 ClF 6 0 (M + )+l 404.9.
  • Example 45 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dihydro- 1 H-inden-4-ylamino)acetamide) .
  • Example 45 The title compound of Example 45 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dihydro-1H-inden-4-amine.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.20 8.20 (s, 1H), 7.34 (s, 1H), 7.00 (s, 1H), 6.84 (t, 1H), 6.58 (d, 1H), 6.16 (d, 1H), 4.29 (d, 1H), 4.12 (d, 2H), 3.77 (s, 4H), 2.84 (t, 2H), 2.69 (t, 2H), 2.04 (t, 3H), 1.91 (m, 1H), 1.79 (m, 2H).
  • EIMS (m/z): calcd. for C 22 H 2 8 6 0 (M + )+l 392.5.
  • Example 46 The title compound of Example 46 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for naphthalen- 1 -amine.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 23 H 2 6 6 0 (M + )+l 402.5.
  • Example 47 The title compound of Example 47 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-fluoroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.24 s, 1H
  • 7.35 s, 1H
  • 6..99 s, 1H
  • 6.85 t, 1H
  • 6.66 d, 1H
  • 6.26 d, 1H
  • 4.30 d, 1H
  • 2.18 (s, 3H) 2.03 (m, 1H), 1.87 (m, 1H), 1.82 (m, 2H).
  • EIMS m/z: calcd. for C19H22CIFN6O (M + )+l 404.9.
  • Example 48 N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
  • Example 48 The title compound of Example 48 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3,5-dichloroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.28 8.28 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.57 (s, 1H), 6.45 (s, 2H), 4.36 (d, 1H), 4.21 (d, 1H), 4.07 (s, 1H), 3.76 (m, 5H), 2.01 (m, 2H), 1.83 (m, 2H).
  • Example 49 The title compound of Example 49 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-5-fluoroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.24 s, 1H
  • 7.34 s, 1H
  • 7.14 t, 1H
  • 7.03 m, 3H
  • 6.69 d, 1H
  • 4.40 d, 1H
  • 4.23 d, 1H
  • 3.80 s, 2H
  • 3.66 m, 2H
  • 2.88 s, 2H
  • 1.80 m, 1H
  • Example 50 The title compound of Example 50 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-isopropoxyaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 22 H 30 N 6 O 2 (M + )+l 410.5.
  • Example 51 The title compound of Example 51 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-6-fluoroaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.27 8.27 (s, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 6.91 (t, 1H), 6.52 (m, 2H), 4.40 (d, 1H), 4.24 (d, 1H), 4.08 (s, 1H), 3.81 (s, 2H), 3.71 (m, 2H), 2.05 (m, 2H), 1.84 (m, 2H).
  • EIMS (m/z): calcd. for C 19 H 22 CIFN 6 O (M + )+l 404.9.
  • Example 52 The title compound of Example 52 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-methylaniline.
  • 1 H NMR 400 MHz, CD 3 OD) ⁇ 8.06 (s, 1H), 7.09 (s, 1H), 6.88 (t, 1H), 6.67 (d, 1H), 6.57 (s, 1H), 6.62 (d, 1H), 4.02 (m, 3H), 3.77 (m, 4H), 2.12 (s, 3H), 1.90 (m, 1H), 1.79 (m, 2H), 1.64 (m, H), 1.29 (m, 1H).
  • EIMS (m/z): calcd. for C 2 oH 25 Cl 6 0 (M + )+l 400.9.
  • Example 53 The title compound of Example 53 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-methoxyaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 54 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l - oxoisoindolin-4-ylamino)acetamide).
  • Example 54 The title compound of Example 54 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-aminoisoindolin-l -one.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.23 8.23 (s, 1H), 7.70 (d, 1H), 7.33 (s, 1H), 7.21 (t, 2H), 7.10 (d, 1H), 6.99 (s, 1H), 6.58 (d, 1H), 4.35 (m, 1H), 4.18 (d, 1H), 3.89 (s, 2H), 3.70 (m, 2H), 2.36 (s, 1H), 2.02 (m, 2H), 1.81 (m, 1H).
  • EIMS (m/z): calcd. for C 2 iH 25 N 7 0 2 (M + )+l 407.5.
  • Example 55 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- ethynylphenylamino)acetamide) .
  • Example 55 The title compound of Example 55 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-ethynylaniline. 1 H NMR (400 MHz, DMSO-d 6 ) ⁇
  • Example 56 The title compound of Example 56 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(pyrrolidin-l -yl)aniline.
  • Example 57 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-ieri- butyl-1 -methyl- 1H-pyrazol-5-ylamino)acetamide).
  • Example 57 The title compound of Example 57 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-ieri-butyl-l -methyl- 1H-pyrazol-5-amine.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (+) MS m/z 41 1 (M+l).
  • Example 58 N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l -ieri- butyl-3-methyl-1H-pyrazol-5-ylamino)acetamide).
  • Example 58 The title compound of Example 58 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-ieri-butyl-3-methyl-1H-pyrazol-5-amine. 1 H NMR
  • Example 59 The title compound of Example 59 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for pyridin-3 -amine.
  • EIMS (+) MS m z 352 (M+l).
  • Example 60 The title compound of Example 60 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3 -(1 -methyl- 1H-pyrazol-3-yl)aniline.
  • EIMS (+) MS m z 431 (M+l).
  • Example 61 The title compound of Example 61 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for , -dimethylbenzene- 1 ,3 -diamine.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (+) MS m/z 494 (M+l).
  • Example 62 The title compound of Example 62 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3,4-difluoroaniline. 1 H NMR (400 MHz, DMSO-d 6 )
  • ES (+) EIMS m/z 437 (M+l).
  • Example 64 The title compound of Example 64 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-methyl-3-trifluoromethylaniline.
  • ES (+) MS m/z 433 (M+l).
  • Example 65 The title compound of Example 65 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-methyl-3-trifluoromethylaniline. 1 H NMR (400
  • Example 66 The title compound of Example 66 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-aminobenzonitrile.
  • ES (+) MS m/z 476 (M+l).
  • Example 67 The title compound of Example 67 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4,2-difluoroaniline. 1H NMR (400 MHz, DMSO-d 6 ) ⁇
  • Example 68 The title compound of Example 68 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted/or 3,5-difluoroaniline.
  • ES (+) MS m/z 487 (M+l).
  • Example 69 The title compound of Example 69 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoro-5-trifluoromethylaniline.
  • ES (+) MS m z 4
  • Example 70 The title compound of Example 70 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoro-3-trifluoromethylaniline.
  • Example 71 The title compound of Example 71 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-difluoroaniline.
  • MS m/z
  • Example 72 The title compound of Example 72 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for cyclopentanamine. 1 H NMR (400 MHz, CD 3 OD) ⁇
  • Example 73 The title compound of Example 73 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-amino-2-(trifluoromethyl)benzonitrile. H NMR
  • Example 74 The title compound of Example 74 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-//woro-3-trifluoromethylaniline.
  • 1 H NMR 400 MHz, CD 3 OD
  • ES (+) MS m z 437 (M+l).
  • Example 75 (2-(1H-indazol-7-ylamino)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -yl)acetamide) .
  • Example 75 The title compound of Example 75 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for iH-indazol-7-amine.
  • 1H NMR 400 MHz, CD 3 OD
  • ES (+) MS m/z 391 (M+l).
  • Example 76 (2-(1H-indazol-4-ylamino)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -yl)acetamide) .
  • Example 76 The title compound of Example 76 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 1H-indazol-4-amine.
  • 1H NMR 400 MHz, CD 3 OD
  • ES (+) MS m/z 391 (M+l).
  • Example 77 (2-(3-(1H-pyrazol-l -yl)phenylamino)-N-(l-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
  • Example 77 The title compound of Example 77 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-(1H-pyrazol- l-yl)aniline.
  • Example 78 The title compound of Example 78 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-me//zy/-1H-indazol-4-amine.
  • Example 79 The title compound of Example 79 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-phenyl-1H-pyrazol-3-amine.
  • Example 80 The title compound of Example 80 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 1 -methyl- 1H-pyrazol-3 -amine.
  • ES (+) MS m/z 355 (M+l).
  • Example 82 The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for quinolin-8-amiriQ.
  • Example 82 The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(trifluoromethylthio)aniline.
  • Example 83 The title compound of Example 83 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-morpholinoaniline.
  • 1 H NMR 400 MHz, CD3OD
  • MS m/z 436 (M+l).
  • Example 84 N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dimethylphenylamino)acetamide.
  • Example 82 The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dimethyloaniline.
  • tert-Bu yX methyl(l -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate The tert-bvAyX l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- ylcarbamate intermediate (0.28 g, 0.6 mmol) synthesized from the corresponding 4-chloro-7- tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-bvXyX piperidin-3 -ylcarbamate in a similar fashion as described in example 155 was dissolved in DMF (3 mL) was added NaH (26 mg, 0.66 mmol), and the reaction mixture was stirred at rt for 30 min.
  • N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine To a solution of l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-one (75 mg, 0.2 mmol) and benzylamine (25 ⁇ L, 0.22 mmol) in MeOH (3 mL) was added AcOH (20 ⁇ L, 0.4 mmol) and NaBH 3 CN (32 mg, 0.5 mmol).
  • N-benzyl-2-(phenylamino)-N-(l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acetamide To a solution of N-phenylglycine (29 mg, 0.2 mmol), HATU (75 mg, 0.2 mmol), Et 3 N (50 ⁇ , 0.4 mmol) in DMF (3 mL) was added N-benzyl-l -(7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (90 mg, 0.2 mmol).
  • Examples 87-89 were prepared according to Example 86 above.
  • Example 92 N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-2-chlorobenzamide).
  • N-(l-(7H-pyrrolo[2,3-d]pyrimidiii-4-yl)piperidin-3-yl)-2-aminoacetamide To a solution of 2-(ter£-butoxycarbonylamino)acetic acid (0.7 g, 4 mmol), HATU (1.5 g, 4 mmol), Et 3 N (1.1 mL, 4 mmol) in DMF (60 mL) was added N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -amine (1.8 g, 40 mmol).
  • Examples 93-99 were prepared according to the method outlined in example 92 above.
  • Example 93 The title compound of Example 93 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 3-chlorobenzoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.27 8.27 (s, 1H), 7.85 (s, 1H), 7.77(d, 2H), 7.75(d, 1H), 7.56 (d, 1H), 7.47 (m, 2H), 7.34(s, 1H), 7.10 (d, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.31 (m, 1H), 4.01 (d, 2H), 3.75-3.65(m, 2H), 2.15-2.04 (m, 2H), 1.82 (m, 2H).
  • EIMS (m/z): calcd. for C19H23CIN6O2 (M + )+l 414.4.
  • Example 94 The title compound of Example 94 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 4-chlorobenzoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS m/z: calcd. for C19H23CIN6O2 (M + )+i 414.4.
  • Example 95 The title compound of Example 95 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 4-ieri-butylbenzoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.27 8.27 (s, 1H), 7.78 (d, 2H), 7.51 (d, 2H), 7.34 (s, 1H), 7.10 (s, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.31 (m, 1H), 4.01 (d, 2H), 3.75-3.65(m, 2H), 2.15-2.04(m, 2H), 1.82 (m, 2H).
  • EIMS (m/z): calcd. for C24H30N6O2 (M + )+l 435.4.
  • Example 96 The title compound of Example 96 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 2-phenylacetic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 21 H 24 N 6 O 2 (M + )+i 394.5.
  • Example 97 The title compound of Example 97 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 1 -naphthoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 2 4H24 6 0 2 (M +1) 429.6.
  • Example 98 The title compound of Example 98 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 2-naphthoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C24H24N6O2 (M +1) 429.6.
  • Example 98 The title compound of Example 98 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for cyclohexanecarboxylic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 8.30 s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 4.51(d, 1H), 4.34 (d, 1H), 4.02 (s, 2H), 3.78 (d, 2H), 3.67-3.57 (m, 2H), 2.25-2.20 (m, 1H), 2.05- 1.89 (m, 2H), 1.82-1.79 (m, 8H), 1.71- 1.68 (m, 2H), 1.14-1.26 (m, 4H).
  • EIMS (m/z): calcd. for C20H28N6O2 (M +1) 386.5.
  • Examples 101 -132 were prepared according to the method outlined in example
  • Example 101 The title compound of Example 101 was prepared in similar manner as described in Example 100 except (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for 1 -(7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine.
  • Example 102 The title compound of Example 102 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (S)-2-aminopropanoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 364 (M+l).
  • Example 103 The title compound of Example 103 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-methyl-2-aminobutanoic acid.
  • Example 104 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- phenyl-2-(phenylamino)propanamide)
  • Example 104 The title compound of Example 104 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-phenyl-2-aminopropanoic acid.
  • 1H MR 400 MHz, CD 3 OD
  • Example 105 The title compound of Example 105 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-4-methyl-2-aminopentanoic acid.
  • Example 106 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- phenyl-2-(phenylamino)acetamide).
  • Example 106 The title compound of Example 106 was prepared in similar manner as described in Example
  • Example 107 The title compound of Example 107 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-cyclopropyl-2-aminoacetic acid.
  • Example 108 The title compound of Example 108 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3,3-dimethyl-2-aminobutanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • Example 109 The title compound of Example 109 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-cyclohexyl-2-aminoacetic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 433 (M+l).
  • Example 1 10 ((2R,3R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-hydroxy-2-(phenylamino)butanamide).
  • Example 1 10 The title compound of Example 1 10 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3R)-3-hydroxy-2-aminobutanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 395 (M+l).
  • Example 1 1 1 ((2R,3S)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-hydroxy-2-(phenylamino)butanamide).
  • Example 1 1 1 The title compound of Example 1 1 1 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3S)-3-hydroxy-2-aminobutanoic acid.
  • 'H NMR 400 MHz, CD 3 OD
  • Example 1 12 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
  • Example 1 12 The title compound of Example 1 12 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-methyl-2-aminobutanoic acid.
  • Example 1 13 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
  • Example 1 13 The title compound of Example 1 13 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3 -hydro xy-3-methyl-2- aminobutanoic acid.
  • Example 1 14 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
  • Example 1 14 The title compound of Example 1 14 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-aminobutanoic acid.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): calcd. for C 2 iH 2 6 6 0 (M+H) 379, found 379 (M+H).
  • Example 1 15 ((2R,3S)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-methyl-2-(phenylamino)pentanamide).
  • Example 1 15 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3S)-3-methyl-2-aminopentanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 407 (M+l).
  • Example 1 16 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-4-
  • Example 1 16 The title compound of Example 1 16 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-4-(methylsulfonyl)-2- aminobutanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 457 (M+
  • Example 1 17 ((2R,3R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-methyl-2-(phenylamino)pentanamide).
  • Example 1 17 The title compound of Example 1 17 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3R)-2-amino-3-methylpentanoic acid.
  • Example 1 18 The title compound of Example 1 18 was prepared in similar manner as described in Example 107 except iodobenzene was substituted for l -chloro-3-fluoro-5-iodobenzene.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 1 19 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
  • Example 1 19 The title compound of Example 1 19 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l-chloro-3-iodobenzene.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 120 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(3,5-difluorophenylamino)acetamide).
  • Example 120 The title compound of Example 120 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3,5-difluorobenzene.
  • 1 H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 426 (M+l).
  • Example 121 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(3-fluoro-5-(trifluoromethyl)phenylamino)acetamide).
  • Example 121 The title compound of Example 121 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3-fluoro-5-trifluoromethylbenzene.
  • 1H NMR 400 MHz, CD 3 OD
  • Example 122 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-5- methyl-2-(phenylamino)hexanamide).
  • Example 122 The title compound of Example 122 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for (R)-2-amino-5-methylhexanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 420 (M+l
  • Example 123 The title compound of Example 123 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 2-amino-4,4,4-trifluorobutanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 433 (M+l);
  • Example 124 The title compound of Example 124 was prepared in similar manner as described in Example 1 18 except (R)-2-amino-2-cyclopropylacetic acid that was substituted for 1 (R)-2-amino-3,3- dimethylbutanoic acid.
  • 1H NMR 400 MHz, CD 3 OD
  • EIMS (m/z): 459 (M+l
  • Example 125 The title compound of Example 125 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3,5-dichlorobenzene.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 126 The title compound of Example 126 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 1 1 - aminocyclopropanecarboxylic acid.
  • Example 126 The title compound of Example 126 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 1-aminocyclopentanecarboxylic acid.
  • EIMS (m/z): calcd. for C 23 H 2 8 6 0 (M + +l)
  • Example 128 ((R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- methyl-2-(phenylamino)propanamide).
  • Example 126 The title compound of Example 126 was prepared in similar manner as described in Example 100 except 2-amino-2-methylpropanoic acid that was substituted for 1- aminocyclopentanecarboxylic acid.
  • EIMS (m/z): calcd. for C 2 iH 2 6 6 0 (M + +l) 379.22, found 379.00.
  • Example 129 The title compound of Example 129 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3-chloro-5-fluorophenylamino)butanoic acid.
  • Example 130 The title compound of Example 130 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3,5-dichlorophenylamino)butanoic acid.
  • Example 131 The title compound of Example 131 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3-chlorophenylamino)butanoic acid.
  • Example 132 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- cyclopropyl-2-(3,5-dichlorophenylamino)propanamide).
  • Example 132 The title compound of Example 132 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-3-cyclopropyl-2-(3,5-dichlorophenylamino)propanoic acid.
  • 1 H NMR 400 MHz, DMSO-i3 ⁇ 4) ⁇ 1 1.65 (br.
  • Oxetan-3-one (7.2 g, 0.1 mol) was added to the reaction mixture at -70 °C, and the resulting reaction mixture was stirred at RT. After consumption of starting material (by TLC), the reaction mixture was diluted with EtOAc (200 mL) and filtered, and the solid residue was washed with EtOAc (2x 300 mL). The combined organic layers were washed with 1 % citric acid (2 x 300 mL) and brine solution (300 mL), dried over Na 2 SC>4, and filtered, and the solvent was removed under reduced pressure. The crude material was purified with flash chromatography (20% EtOAc/Hexane) to afford the title intermediate (10 g, 37%) as an off-white solid.
  • (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid A solution of amino acid (R)-2-amino-2-cyclopropylacetic acid (1 mmol), l -bromo-3-chloro-5-fluorobenzene (1 mmol), Cs 2 C0 3 (2 mmol), and Cul (0.04 mmol) in DMF (2 mL) can be heated at 90 °C for 12 h under an atmosphere of nitrogen. The solution can be cooled to rt, diluted with EtOAc-water (2: 1 , 15 mL), and adjusted to a pH 3-5 with 1 N C1 . The organic layer can be separated, washed with brine, dried ( a 2 S0 4 ), and concentrated in vacuo to afford the title intermediate as an oil, which can be used without further purification.
  • the solution can be stirred for 1 h with the solvent concentrated in vacuo to afford a solid, which can be used without further purification.
  • the solid can be dissolved in DMF (4 mL), treated with DIEA (6 mmol) and 4- amino-6-chloropyrimidine-5-carbonitrile (1 mmol), and heated to 100 °C for 4 h.
  • the solution can be cooled to RT, diluted with water, and extracted with EtOAc, and the organic phase can be dried ( a 2 S0 4 ), filtered, and concentrated in vacuo to afford an oil, which can be purified by reverse phase chromatography C 18 column and 10% acetonitrile/water containing 0.1 % TFA to afford the title compound.
  • Example 135 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-1-(7- oxo-5,6,7, 8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
  • Example 135 The title compound of Example 135 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-5,6- dihydropyrido[2,3-d]pyrimidin-7(8H)-one.
  • Example 136 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-l -(7- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
  • Example 136 The title compound of Example 136 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-7-methyl- 7H-pyrrolo[2,3-d]pyrimidine.
  • Example 137 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-l -(l- methyl- 1 H-pyrazolo[3 ,4-d]pyrimid -4-yl)piperidin-3-yl)acetamide).
  • Example 137 The title compound of Example 137 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro- 1 -methyl- 1H-pyrazolo[3,4-d]pyrimidine.
  • Example 138 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-1-(5- fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
  • Example 138 The title compound of Example 138 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-Chloro-5-fluoro- 7H-pyrrolo[2,3-d]pyrimidine.
  • the 4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine was synthesized as reported by Wang, X.; Seth, P. P.; Ranken, R.; Swayze, E. E; Migawa M. T. Synthesis and Biological Activity of 5-Fluorotubercidiny. Nucleosides, Nucleotides Nucleic Acids 2004, 23, 161.
  • Examples 140-146 were prepared according to Example 139 above.
  • Example 140 ((R)-N-(l-(6-amino-5-chloropyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
  • Example 140 The title compound of Example 140 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 5,6-dichloropyrimidin-4-amine.
  • Example 141 ((R)-N-(l-(6-acetamidopyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
  • Example 141 The title compound of Example 141 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for N-(6-chloropyrimidin-4-yl)acetamide.
  • Example 142 The title compound of Example 142 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-isopropylpyrimidin-4-amine.
  • Example 143 The title compound of Example 143 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-ethylpyrimidin-4-amine.
  • Example 144 The title compound of Example 144 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-methylpyrimidin-4-amine.
  • Example 145 ((R)-N-(l -(6-aminopyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
  • Example 145 The title compound of Example 145 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloropyrimidin-4-amine.
  • Example 146 ((R)-2-(3,5-dichlorophenylamino)-N-(l-(6-oxo-6,7-dihydro-5H- pyrrolo [2 ,3 -d]pyrimidin-4-yl)piperidin-3 -yl)acetamide) .
  • Example 146 The title compound of Example 146 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one.
  • tert-BvXy ⁇ 5-methylpyridin-3-ylcarbamate A solution of 5-methyl-pyridin-3- ylamine (250 mg, 2.31 mmol) and di-ieri-butyldicarbonate (505 mg, 2.31 mmol) in THF (5 mL) was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo to afford a residue, which was suspended in EtOAc and washed with aq. NaHC0 3 and water. The organic phase was collected, dried (Na 2 S0 4 ), filtered, and concentrated in vacuo to give an oil, which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to yield the title intermediate.
  • reaction mixture was concentrated in vacuo, and the residue was dissolved in CH 2 C1 2 (3 mL) and MeOH (1 mL), treated with a polymer supported carbonate resin, filtered, and concentrated in vacuo to afford a residue, which was used without further purification.
  • Example 150 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((3R,4S)-
  • Example 152 ((R)-2-cyclopropyl-2-(3,5-dichlorophenylamino)-N-((3R,4S)-4- methyl- 1 -( 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)piperidin-3 -yl)acetamide) .
  • Example 153 ((R)-2-(3,5-dichlorophenylamino)-N-((3R,4S)-4-methyl-l -(1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)pentanamide).
  • Examples 156-160 were prepared according to Example 155 above.
  • Example 156 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(3- chlorophenyl)-2-cyanoguanidine).
  • Example 156 The title compound of Example 156 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 3-chloroaniline.
  • Example 157 The title compound of Example 157 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-chloroaniline.
  • 1 H NMR (d 6 -DMSO 400 MHz): ⁇ 12.32 (br. s., 1H), 9.18 (s, 1H), 8.24 (s, 1H), 7.22 - 7.42 (m, 3H), 7.12 (d, J 9.04 Hz, 2H), 6.80 (br. s., 1H), 4.34 (br. s., 1H), 4.19 (br. s., 1H), 3.88 (br. s., 1H), 3.26 - 3.52 (m, 2H), 1.91 (d, J - 4.02 Hz, 1H), 1.77 (br. s., 1H), 1.40 - 1.71 (m, 2H).
  • Example 158 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyano-3-(3-(trifluoromethyl)phen l)guanidine .
  • Example 158 The title compound of Example 158 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 3-(trifluoromethyl)aniline.
  • Example 159 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyano-3-(4-(trifluoromethyl)phen l)guanidine).
  • Example 159 The title compound of Example 159 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-(trifluoromethyl)aniline.
  • 1 H NMR (d 6 -DMSO, 400 MHz): ⁇ 12.08 (br. s., 1H), 9.74 - 10.05 (m, 1H), 9.48 (br. s., 1H), 8.31 - 8.45 (m, 1H), 8.26 (s, 1H), 7.44 - 7.77 (m, 2H), 7.15 - 7.34 (m, 2H), 6.57 (d, J 8.28 Hz, 1H), 4.49 (br. s., 1H), 4.36 (br.
  • Example 160 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(4- ieri-butylphenyl)-2-cyanoguanidine).
  • Example 158 The title compound of Example 158 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-iert-butylaniline.
  • BTK-POL YGA T-LS ASSA Y The purpose of the BTK in vitro assay is to determine compound potency against BTK through the measurement of IC 50 . Compound inhibition is measured after monitoring the amount of phosphorylation of a fluorescein-labeled polyGAT peptide (Invitrogen PV361 1) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitor. The BTK kinase reaction was done in a black 96 well plate (costar 3694).
  • kinase buffer 10 mM Tris-HCl pH 7.5, 10 mM MgC12, 200 ⁇ Na3V04, 5 mM DTT, 0.01 % Triton X- 100, and 0.2 mg/ml Casein
  • 1 ⁇ L of a 4-fold, 40X compound titration in 100% DMSO solvent is added, followed by adding 15 xL of BTK enzyme mix in 1 X kinase buffer (with a final concentration of 0.25 nM).
  • the assay is incubated for 30 minutes before being stopped with 28 ⁇ L of a 50 mM EDTA solution.
  • Five xL of the kinase reaction is transferred to a low volume white 384 well plate (Corning 3674) and 5 ⁇ L of a 2X detection buffer (Invitrogen PV3574, with 4nM Tb-PY20 antibody, Invitrogen PV3552) is added.
  • the plate is covered and incubated for 45 minutes at room temperature.
  • Time resolved fluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nm emission; 518 nm fluorescein emission) is measured.
  • IC 50 values are calculated using a four parameter fit with 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control.
  • Protocol for human B cell stimulation Human B cells were purified from 150 ml of blood. Briefly, the blood was diluted 1/2 with PBS and centrifuged through a Ficoll density gradient. The B cells were isolated from the mononuclear cells by negative selection using the B cell isolation kit II from Milenyi (Auburn, CA). 50,000 B cells per well were then stimulated with 10 g/ml of goat F(ab') 2 anti-human IgM antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA) in a 96-well plate. Compounds were diluted in DMSO and added to the cells. Final concentration of DMSO was 0.5%. Proliferation was measured after 3 days using Pro mega CellTiter-Glo® (Madison, WI). Certain compounds of formula I were tested and found to be active.
  • Table 1 shows the activity of selected compounds of this invention in the in vitro
  • Btk kinase assay Compounds have an activity designated as "A” provided an IC 50 ⁇ 100 nM; compounds having an activity designated as “B” provided an IC 50 of 100-999 nM; compounds having an activity designated as “C” provided an IC 50 of 1000- 10,000 nM; and compounds having an activity designated as "D” provided an IC 50 of > 10,000 nM. In some instances where a compound tested has activity "D”, other structurally similar compounds beyond the measurable limits of the assay are not included in Table 1.

Abstract

The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.

Description

HETEROARYL BTK INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to United States provisional application serial number 61/240,003, filed September 4, 2009, the entirety of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Protein kinases are a large multigene family consisting of more than 500 proteins which play a critical role in the development and treatment of a number of human diseases in oncology, neurology and immunology. The Tec kinases are non-receptor tyrosine kinases which consists of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk) and Bmx (bone-marrow tyrosine kinase gene on chromosome X; also known as Etk)) and are primarily expressed in haematopoietic cells, although expression of Bmx and Tec has been detected in endothelial and liver cells. Tec kinases (Itk, Rlk and Tec) are expressed in T cell and are all activated downstream of the T-cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling which is involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, which then induces additional B-cell signaling. Mutations that disable Btk enzymatic activity result in XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency. Given the critical roles which Tec kinases play in both B-cell and T-cell signaling, Tec kinases are targets of interest for autoimmune disorders.
[0003] Consequently, there is a great need in the art for effective inhibitors of Btk. The present invention fulfills these and other needs. SUMMARY OF THE INVENTION
[0004] In certain embodiments, the present invention provides a compound of formula I:
Figure imgf000003_0001
wherein each of R1, R2, R3, R4, R5, Rx, X1, X2, L, Ring A1, y, z, and p are as defined and described herein. These compounds are inhibitors of a number of protein kinases, in particular family members such as Itk, Txk, Tec, Bmx, and Btk (Bruton's tyrosine kinase). Accordingly, provided compounds can be used in a variety of methods including in vitro screening and activity assays as well as in vivo pre-clinical, clinical, and therapeutic settings, as described in detail herein.
[0005] In certain embodiments, the present invention provides pharmaceutical compositions comprising provided compounds.
[0006] In certain embodiments, the present invention provides methods of decreasing Btk enzymatic activity. Such methods include contacting a Btk with an effective amount of a Btk inhibitor.
[0007] In certain embodiments, the present invention provides methods of treating a disorder responsive to Btk inhibition in a subject in need thereof. Such disorders and methods are described in detail herein.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0008] In certain embodiments, the present invention provides a compound of formula I:
Figure imgf000004_0001
I wherein:
X1 is -0-, -CR6R7- or -NR8-;
X2 is =CR9- or =N-;
p is 0-5;
y is 0, 1 , or 2;
z is 0, 1 , or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
each R1 is independently halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -
C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, - N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR,
-N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, -OC(0)N(R)2, or an optionally substituted group selected from C1-i2 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8- 10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-, or: two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or an optionally substituted group selected from C1-6
aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3- 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 heteroaryl ring having 1-3 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 an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R2, R4, and R8 is independently R, -CN, -C(0)R, -C02R, -C(0)C(0)R,
-C(0)CH2C(0)R, -C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2, or:
R2 and R1 are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
2 7
R" and R are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
2 8
R" and R are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R3, R5, R6, R7, and R9 is independently R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, - C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2, or:
R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx is hydrogen or optionally substituted C1-6 aliphatic, or:
Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring A1 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8- 10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is a covalent bond or an optionally substituted, bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, - C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, - C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-; and
each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered
heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Definitions
[0009] Compounds of this invention include those described generally above, 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.
[0010] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0011] 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, "cycloaliphatic" (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. [0012] 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).
[0013] The term "lower alkyl" refers to a C1-4 straight or branched alkyl group.
Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
[0014] The term "lower haloalkyl" refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
[0015] 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)).
[0016] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.
[0017] As used herein, the term "bivalent Cx_y (e.g., 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.
[0018] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n- In some embodiments, n is 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.
[0019] 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. [0020] As used term "cycloalkylenyl" refers to a bivalent cycloalkyl group of
the following structure:
Figure imgf000010_0001
.
[0021] The term "halogen" means F, CI, Br, or I.
[0022] 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."
[0023] The term "aryl" used alone or as part of a larger moiety as in "aralkyl,"
"aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven 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.
[0024] 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 quaternized 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 heteroaromatic 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.
[0025] 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), ΝΗ (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).
[0026] 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 cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. 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. [0027] 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.
[0028] As used herein and unless otherwise specified, the suffix "-ene" is used to describe a bivalent group. Thus, any of the terms above can be modified with the suffix "-ene" to describe a bivalent version of that moiety. For example, a bivalent carbocycle is "carbocycylene", a bivalent aryl ring is "arylene", a bivalent benzene ring is "phenylene", a bivalent heterocycle is "heterocyclylene", a bivalent heteroaryl ring is "heteroarylene", a bivalent alkyl chain is "alkylene", a bivalent alkenyl chain is "alkenylene", a bivalent alkynyl chain is "alkynylene", and so forth.
[0029] As described herein, compounds of the invention may, when specified, 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.
[0030] 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)o-4CH(OR0)2; -(CH2)0 4SR°; -(CH2)0 4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-1-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(R0)N(R°)C(0)OR°; -(CH2)0 4C(0)R°; -C(S)R°; -(CH2y4C(0)OR°; -(CH2)0 4C(0)SR°; -(CH2)o 4C(0)OSiR°3; -(CH2)0 4OC(0)R°; -OC(O)(CH2)0 4SR- 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( OR°)R°; -(CH2)0 4SSR°; -(CH2)0 4S(0)2R°; -(CH2y4S(0)2OR°; -(CH2y4OS(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( H)NR°2; -P(0)2R°; -P(0)R°2; -OP(0)R°2; -OP(0)(OR°)2; SiR°3; -(C 1-4 straight or branched alkylene)0-N(R°)2; or -(C1-4 straight or branched alkylene)C(0)0-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -0(CH2)o-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 O^- heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0031] 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 2Re, -(haloR*), -(CH2)0 2OH, -(CH2)0 2ORe, -(CH2)0 2CH(ORe)2; -O(haloR'), -CN, -N3, -(CH2)0 2C(0)Re, -(CH2)0 2C(0)OH, -(CH2)0 2C(0)ORe, -(CH2)0 2SRe, -(CH2)0 2SH, -(CH2)0 2NH2, -(CH2)o 2NHR", -(CH2)0 2NR'2, -N02, -SiR'3, -OSiR'3, -C(0)SRe , -(C1-4 straight or branched alkylene)C(0)ORe, 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 C1-4 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. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
[0032] 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, C 1-6 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.
[0033] 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, -CH2PI1, -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.
[0034] 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( H)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.
[0035] 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 -NO2, 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.
[0036] 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.
[0037] In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0038] 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.
[0039] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl.
[0040] One of ordinary skill in the art will appreciate that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term "protecting group," as used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is masked or blocked, permitting, if desired, a reaction to be carried out selectively at another reactive site in a multifunctional compound. Suitable 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, 3r edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. In certain embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group is preferably selectively removable by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms a separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group will preferably have a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized. By way of non-limiting example, hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), t- butoxymethyl, siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, tetrahydropyranyl (THP), 4-methoxytetrahydropyranyl (MTHP), 1 -methyl- 1 -methoxyethyl, 1 - methyl- 1 -benzyloxyethyl, 2-trimethylsilylethyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, 2,6- dichlorobenzyl, p-phenylbenzyl, 4-picolyl, diphenylmethyl, p,p '-dinitrobenzhydryl, triphenylmethyl, p-methoxyphenyldiphenylmethyl, 1 , 1 -bis(4-methoxyphenyl)- 1 ' -pyrenylmethyl, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), dimethylthexylsilyl, i-butyldimethylsilyl (TBDMS), i-butyldiphenylsilyl (TBDPS), triphenylsilyl, diphenylmethylsilyl (DPMS), i-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, pivaloate, adamantoate, crotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4- dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, o-(dibromomethyl)benzoate, 2-(methylthiomethoxy)ethyl, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (l ,1,3,3-tetramethylbutyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, o-(methoxycarbonyl)benzoate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1 ,2- or 1 ,3-diols, the protecting groups include methylene acetal, ethylidene acetal, 1 -1-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 3,4- dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, a-methoxybenzylidene ortho ester, a-(N,N'-dimethylamino)benzylidene derivative, 2-oxacyclopentylidene ortho ester, di-1-butylsilylene group (DTBS), 1 ,3-(1 , 1 ,3,3- tetraisopropyldisiloxanylidene) derivative (TIPDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate. Amino-protecting groups include methyl carbamate, 9- fluorenylmethyl carbamate (Fmoc), 9-(2,7-dibromo)fluoroenylmethyl carbamate, 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 1 -methyl- 1 -(4-biphenylyl)ethyl carbamate (Bpoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t- butyl carbamate (BOC), allyl carbamate (Alloc), 4-nitrocinnamyl carbamate ( oc), N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-nitobenzyl carbamate, p-chlorobenzyl carbamate, diphenylmethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, 2,4-dimethylthiophenyl carbamate (Bmpc), 2- triphenylphosphonioisopropyl carbamate (Ppoc), m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, N'-p- toluenesulfonylaminocarbonyl derivative, N'-phenylaminothiocarbonyl derivative, i-amyl carbamate, p-cyanobenzyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, 2-furanylmethyl carbamate, isoborynl carbamate, isobutyl carbamate, 1 -methyl- 1 -phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenoxyacetamide, acetoacetamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N- acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl- 3- oxazolin-2-one, N-phthalimide, N-2,5-dimethylpyrrole, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-benzylamine, N- triphenylmethylamine (Tr), N-2-picolylamino N'-oxide, N-l ,l-dimethylthiomethyleneamine, N- benzylideneamine, N-/ methoxybenzylideneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-/ nitrobenzylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo- 1 - cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-nitroamine, N- nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-
4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl- 4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide Exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described by Greene and Wuts (supra).
[0041] The symbol ">/w " denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0042] In some embodiments, a provided compound is of formula I:
Figure imgf000019_0001
I
wherein each of R1, R2, R3, R4, R5, Rx, X1, X2, L, Ring A1, y, z, and p are as defined above and described in classes and subclasses herein.
[0043] 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.
[0044] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.
[0045] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2.
[0046] In certain embodiments, each R1 is independently halogen, -N02, -CN, -OR, -
SR, -N(R)2, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, - C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, -OC(0)N(R)2, or optionally substituted C 1-i2 aliphatic. In some embodiments, each R1 is independently halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -C(0)C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)S02N(R)2, -N(R)S02R, -OC(0)N(R)2, or optionally substituted Ci-6 aliphatic. In some embodiments, R1 is optioally substituted C 1-6 aliphatic. In some embodiments, R1 is C1-4 alkyl. In some embodiments, R1 is halogen. In some embodiments, R1 is halogen substituted C1-4 alkyl. In some embodiments, R1 is -CF3. In some embodiments, R1 is -CN. In some embodiments, R1 is methyl.
[0047] In some embodiments, p is at least 2, and two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form a bicyclic ring
having the formula:
Figure imgf000020_0001
. in certain embodiments, the bicyclic ring is further substituted with one, two, or three R1 groups.
[0048] In some embodiments, p is at least 2, and two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-. In certain embodiments, two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain. In some embodiments, two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge having the formula:
Figure imgf000021_0001
. In certain embodiments, the bridged bicyclic group is further substituted with one, two, or three R1 groups.
[0049] In some embodiments, p is at least 2, and two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring having the formula:
Figure imgf000021_0002
in certain embodiments, the spiro fused ring is further substituted with one, two, or three R1 groups.
[0050] In some embodiments, each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0051] In certain embodiments, a substituent on R is selected from -CN, -CF3, -OH, -
NH2, or -C02H.
[0052] In some embodiments, each of R2, R4, and R8 is independently R, -C(0)R, -
C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2. In some
2 4 8 2 4 8 embodiments, each of R , R , and R is hydrogen. In some embodiments, each of R , R , and R is independently R.
[0053] In some embodiments, R2 is R, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R,
-C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2. In some embodiments, R2 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R2 is hydrogen. In other embodiments, R2 is optionally substituted C 1-4 alkyl. In some embodiments, R2 is optionally substituted phenyl. In some embodiments, R2 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R2 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0054] In some embodiments, Rx is hydrogen. In other embodiments, Rx is optionally substituted C 1-6 aliphatic.
[0055] In some embodiments, Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 5-6 membered saturated monocyclic heterocyclic ring having 1 nitrogen heteroatom.
[0056] In some embodiments, R1 and R2 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen,
1 2 ·
or sulfur. In some embodiments, R and R are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1 and R2 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, such 5-6 membered monocyclic rings formed by R1 and R2 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
[0057] In some embodiments, R1 and R2 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
1 2 ·
nitrogen, oxygen, or sulfur. In some embodiments, R and R are optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1 and R2 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1 and R2 are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0058] In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, such 5-6 membered monocyclic rings formed by R2 and R7 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
[0059] In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R a7re optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R7 are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0060] In some embodiments, R2 and R8 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen,
2 8 ·
or sulfur. In some embodiments, R and R are optionally taken together with their intervening atoms to form an optionally substituted 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R8 are optionally taken together with their intervening atoms to form an optionally substituted five-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R8 are optionally taken together with their intervening atoms to form an optionally substituted six-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, such 5-6 membered monocyclic rings formed by R2 and R8 are substituted, and the substituents are taken together to form a seven- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, thereby forming a 6,5- or 6,6-fused bicyclic ring.
[0061] In some embodiments, R2 and R8 are optionally taken together with their intervening atoms to form an optionally substituted seven-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
2 8 ·
nitrogen, oxygen, or sulfur. In some embodiments, R and R are optionally taken together with their intervening atoms to form an optionally substituted eight-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 and R8 are optionally taken together with their intervening atoms to form an optionally substituted nine-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from
2 8 ·
nitrogen, oxygen, or sulfur. In some embodiments, R and R are optionally taken together with their intervening atoms to form an optionally substituted ten-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0062] In some embodiments, each of R3, R5, R6, R7, and R9 is independently R, halogen,
-N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, - S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, each of R3, R5, R6, R7, and R9 is hydrogen. In some embodiments, each of R3, R5, R6, R7, and R9 is independently R.
[0063] In some embodiments, R3 is R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R,
-C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, R3 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R3 is halogen, -CN, or optionally
3 3 substituted C 1-6 alkyl. In some embodiments, R is hydrogen. In other embodiments, R is optionally substituted C 1-4 alkyl. In some embodiments, R3 is optionally substituted phenyl. In some embodiments, R3 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R3 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0064] In some embodiments, R4 is R, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R,
-C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2. In some embodiments, R4 is hydrogen, -C(0)R, or optionally substituted C 1-6 aliphatic. In some embodiments, R4 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R4 is hydrogen. In other embodiments, R4 is optionally substituted C 1-4 alkyl. In some embodiments, R4 is optionally substituted phenyl. In some embodiments, R4 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R4 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0065] In some embodiments, R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole or pyrazole.
[0066] In some embodiments, R5 is R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R,
-C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, R5 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R5 is propargyl. In some embodiments, R5 is halogen. In some embodiments, R5 is hydrogen, C 1-6 aliphatic, or -N(R)2. In some embodiments, R5 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R5 is hydrogen. In other embodiments, R5 is optionally substituted C 1-4 alkyl. In some embodiments, R5 is optionally substituted phenyl. In some embodiments, R5 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R5 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0067] In some embodiments, R6 is R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R,
-C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, R6 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R6 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R6 is hydrogen. In other embodiments, R6 is optionally substituted C1-4 alkyl. In some embodiments, R6 is optionally substituted phenyl. In some embodiments, R6 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R6 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R6 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0068] In some embodiments, R7 is R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R,
-C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, R7 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R7 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R7 is hydrogen. In other embodiments, R7 is optionally substituted C1-4 alkyl. In some embodiments, R7 is optionally substituted phenyl. In some embodiments, R7 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R7 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0069] In certain embodiments, X1 is -CR6R7- and R6 and R7 are independently hydrogen, substituted or unsubstituted phenyl, or substituted or unsubstituted C1-4 alkyl. In some embodiments, R6 and R7 are independently hydrogen, unsubstituted phenyl, or C1-4 unsubstituted alkyl. In some embodiments, R6 and R7 are hydrogen. [0070] In some embodiments, R is R, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R,
-C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2. In some embodiments, R8 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R is hydrogen. In other embodiments, R8 is optionally substituted C 1-4 alkyl. In some embodiments, R8 is optionally substituted phenyl. In some embodiments, R8 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R8 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0071] In some embodiments, R9 is R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R,
-C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2. In some embodiments, R9 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R9 is halogen, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R9 is hydrogen. In other embodiments, R9 is optionally substituted C 1-4 alkyl. In some embodiments, R9 is optionally substituted phenyl. In some embodiments, R9 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R9 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R9 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0072] In certain embodiments, X1 is -0-. In some embodiments, X1 is -CR6R7-. In
1 8 1 6 7 8 some embodiments, X is -NR -. In some embodiments, when y is 0, X is -CR R - or -NR -.
In some embodiments, when z is 0, X1 is -CR6R7- or -NR8-. In some embodiments, when z is 0,
X1 is -CR6R7-. In some embodiments, when z is 1 , X1 is -CR6R7- or -NR8-.
[0073] In some embodiments, X2 is =CR9-. In other embodiments, X2 is =N-.
[0074] In some embodiments, Ring A1 is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A1 is bicyclic. In some embodiments, Ring A1 is monocyclic. In some embodiments, Ring A1 is optionally substituted phenyl. In some embodiments, Ring A1 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A1 is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A1 is an optionally substituted 7- 10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A1 is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, Ring A1 is an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A1 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0075] In some embodiments, Ring A1 is a substituted phenyl moiety. In certain embodiments, Ring A1 is a phenyl moiety substituted with one or more substituents independently selected from halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, - C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, - N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR, -N(R)C(0)N(R)2, - N(R)S02N(R)2, -N(R)S02R, -OC(0)N(R)2, or an optionally substituted group selected from C1- i2 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0076] In certain embodiments, Ring A1 is a phenyl moiety substituted with one or more substituents independently selected from halogen, -CN, -CF3, -OH, -OR, -NH2, -NR2, -COOH, - SR, -S(0)R, -S(0)2R, or an optionally substituted group selected from C1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, substituents on Ring A1 are selected from halogen, -CN, -CF3, -OH, -NH2, -N(R)2, -COOH, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or C 1-6 aliphatic.
[0077] In some embodiments, when Ring A1 is a phenyl moiety substituted with one or more -S(0)R or -S(0)2R groups, R is -CF3 or -NR2,
[0078] In some embodiments, two substituents on Ring A1 may be taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0079] In some embodiments, Ring A1 is selected from:
Rx = H, F, Cl, Br, I, CF3 Ry = H, F, CI, CF3
ryl,
Figure imgf000032_0001
[0080] In some embodiments, Ring A1 is
Figure imgf000032_0002
In certain embodiments, each R is an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 5-6 membered saturated, partially unsaturated, or heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, wherein two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from piperidine or pyrrolidine.
[0081] In certain embodiments, L is a covalent bond. In other embodiments, L is an optionally substituted, bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-. In some embodiments, L is an optionally substituted, bivalent C1-4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-. In some embodiments, L is an optionally substituted, bivalent C 1-4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one methylene unit of L is replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-. In some embodiments, L is an optionally substituted, bivalent C 1-4 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein two methylene units of L are independently replaced by - Cy-, -C(R)2-, -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-.
[0082] In certain embodiments, L is an optionally substituted bivalent C 1-4 saturated hydrocarbon chain, wherein one methylene unit of L is replaced by -C(O)- and one methylene unit of L is replaced by -N(R)-. In certain embodiments, L is an optionally substituted bivalent Ci-4 saturated hydrocarbon chain, wherein one methylene unit of L is replaced by -C(O)- and one methylene unit of L is replaced by -N(R)-, wherein R is hydrogen.
[0083] In some embodiments, one methylene unit of L is replaced by -C(R)2-. In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic or 3-7 membered saturated carbocyclic. In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each R is hydrogen. In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each R is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each R is hydrogen or optionally substituted 3-7 membered saturated carbocyclic. In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each R is independently hydrogen, a substituted C1-6 aliphatic, or a substituted 3-7 membered saturated carbocyclic ring, wherein a substituent on R is selected from -CF3 or -OH.
[0084] In some embodiments, L is -C 0 -. In some embodiments, L is selected
Figure imgf000034_0001
In some embodiments, L is selected from:
Figure imgf000034_0002
[0086] In some embodiments, one methylene unit of L is replaced by -C(R)2-, and each
R is optionally substituted with one or more groups selected from halogen, -CN, -CF3, -OH, -NH2, -COOH, or R°.
[0087] In some embodiments, one methylene unit of L is replaced by -Cy-.
[0088] In certain embodiments, Cy is cycloalkylenyl. In certain embodiments, Cy is an optionally substituted phenylene. In certain embodiments, Cy is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclylene. In certain embodiments, Cy is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Cy is an optionally substituted 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, Cy is
Figure imgf000035_0001
Figure imgf000035_0002
wherein each of R1, R2, R3, R4, R5, R6, R7, R8, Rx, L, Ring A1, X1, p, y, and z is as defined for formula I above and described in classes and subclasses herein.
[0090] In certain embodiments, X2 is =CR9-. In some embodiments, provided compounds are of formula I-b, I-b-i, or I-b-ii:
Figure imgf000036_0001
Figure imgf000036_0002
I-b-//
wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, Rx, L, Ring A1, X1, p, y, and z is as defined for formula I above and described in classes and subclasses herein.
[0091] In certain embodiments, y is 1 , z is 2, and X1 is -0-, thereby providing compounds of formula I-a-/// or I-b-///:
I-b-///
Figure imgf000036_0003
wherein each of R1, R2, R3, R4, R5, R9, Rx, L, Ring A1, and p is as defined for formula I above and described in classes and subclasses herein.
[0092] In certain embodiments, y is 0 and z is 2. In some embodiments, provided compounds are of formula I-a-iv, I-a-v, I-b-iv, or I-b-v:
I-b-v
Figure imgf000037_0001
wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, Rx, L, Ring A1, and p is as defined for formula I above and described in classes and subclasses herein.
[0093] In some embodiments, a compound of the present invention includes particular stereoisomers of formula Il-a, Il-b, II-c, Il-d, Ill-a, Ill-b, III-c, or Ill-d:
Figure imgf000038_0001
Figure imgf000039_0001
Ill-d
wherein each of R1, R2, R3, R4, R5, R9, Rx, L, X1, Ring A1, y, z, and p is as defined for formula I above and described in classes and subclasses herein.
[0094] In some embodiments, a Btk inhibitor is a racemic mixture or enriched in one or more stereoisomers. In some embodiments, a Btk inhibitor is a compound of Formula Il-a. In some embodiments, a Btk inhibitor is a compound of Formula Il-b. In some embodiments, a Btk inhibitor is a compound of Formula Ill-a. In some embodiments, a Btk inhibitor is a compound of Formula Ill-b.
[0095] As discussed above, in some embodiments, one methylene unit of L is replaced by -C(R)2-. In some embodiments, a compound of the present invention is of formula IV-a, IV- b, I -c, or IV-d:
IV-b
Figure imgf000039_0002
Figure imgf000040_0001
IV-d
wherein each of R, R1, R3, R4, R5, R9, X1, X2, Ring A1, z, y, and p is as defined for formula I above and described in classes and subclasses herein.
[0096] In certain embodiments of formula IV-a, IV-b, IV-c, or IV-d, each R is independently hydrogen, unsubstituted C 1-6 alkyl, C1-6 alkyl substituted with -CF3 or -OH, unsubstituted C3_6 cycloalkyl, or unsubstituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0097] In some embodiments, a compound of the present invention is of formula V, V-a,
V-b -c:
Figure imgf000040_0002
V-a
Figure imgf000041_0001
wherein each of R1, R3, R4, R5, R9, X1, X2, Ring A1, z, y, and p is as defined for formula I above and described in classes and subclasses herein.
[0098] In some embodiments, R2 is taken together with Rx to form an optionally substituted spirocyclic heterocyclyl ring selected from a 3 to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, a compound of the present invention is of formula VI, -a, Vl-b, of VI-c:
Figure imgf000041_0002
Figure imgf000042_0001
wherein each of R1, R3, R4, R5, R9, X1, L, Ring A1, z, y, and p is as defined for formula I above and described in classes and subclasses herein, and wherein h is 0-4.
[0099] In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, h is 2. In some embodiments, h is 3. In some embodiments, h is 4.
[0100] In certain embodiments, R3 and R4 are taken together with their intervening atoms to form an optionally substituted group selected from a 4 to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7 to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3 and R4 are taken together to form a substituted or unsubstituted pyrrole or substituted or unsubstituted pyrazole. In some embodiments, a compound of the present invention is of formula Vll-a, Vll-b, VIII-a, VIII-b, IX-a, or IX-b:
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000043_0002
wherein each of R1, R2, R5, R9, Rx, X1, L, Ring A1, z, y, and p is as defined for formula I above and described in classes and subclasses herein.
[0101] In certain embodiments, R2 and R7 are taken together with their intervening atoms to form optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, a provided compound is of formula X:
Figure imgf000044_0001
X
wherein each of R1, R2, R3, R4, R5, R6, Rx, X2, L, Ring A1, z, and p is as defined for formula I above and described in classes and subclasses herein, and wherein j is 0-4.
[0102] In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, ] is 2. In some embodiments, ] is 3. In some embodiments, ] is 4.
[0103] In certain embodiments, R2 and R8 are taken together with their intervening atoms to form optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, a provided compound is of formula XI:
Figure imgf000044_0002
R1, R2, R3, R4, R5, 2 1
wherein each of R Rx, X, L, Ring A , z, and p is as defined for formula I above and described in classes and subclasses herein, and wherein k is 0-4.
[0104] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.
[0105] In certain embodiments, a provided compound is a compound depicted in Table 1 , below. I. Exemplary Synthesis
[0106] Compounds of the invention are synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention.
[0107] Compounds of formula (I) can be prepared according to Scheme 1 using commercially available or synthesized substituted amine protected heterocycles such as 3-(tert- Butoxycarbonylamino pyrrolidine, 3-(iert-Butoxycarbonylamino)piperidine or 3-itert- Butoxycarbonylamino)azepane (Huang, P.; Wang, S, Zheng, H,; Fei, X. Tetrahedron Lett. 1997, 38, 271. Hu, X. E.; Kim, N. K.; Ledoussal, B. Org. Lett. 2002, 4, 4499. Kitas, E. A.; Galley, G.; Jakob-Roetne, R.; Flohr, A.; Wostl, A.; Mauser, H.; Alker, A. M.; Czech, C; Ozmen, L.; David- Pierson, P.; Reinhardt, D. Jacobsen, H. Bioorg. Med. Chem. Lett. 2008, 18, 304. Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Deng, Z. J.; Williams, T. M.; Vacca, J. P.; Selnick,
H. G.; Potteiger, C. M. PCT Int. Appl. (2006), 292 pp. WO 2006044504). The heterocyclic amine can be protected using the appropriate protecting group familiar to those skilled in the art. The exo-cyclic amino goup can be substituted upon treated with a base such as sodium hydride or by other bases {e.g., DIEA, Et3N, K2C03, etc.) familiar to one skilled in the art and in a solvent such as DMF or other appropriate solvents to yield 1.3. The protected heterocyclic amine 1.4 can be de-protected to the amine which can be reacted with the substituted heteroaromatic such as pyridinyl and pyrimidyl moieties using DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvents to yield
I.6. Alternatively, the N-amination can be accomplished utilizing Buchwald coupling (Shafir, A. Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. Mehrotra, M. M. et. al. Bioorganic & Medicinal Chemistry Letters 2002, 12, 1 103). The exo-cyclic amine protecting group can be removed upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York. The amine 1.7 can be reacted with the appropriate electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401. Li, P.; Xu, J. C. J. Pept. Res. 2001 , 58, 129.) in the presence of a base such as DIEA or other bases familiar to one skilled in the art and in an appropriate solvent to yield 1.8. Alternatively and/or addtionally, the exo- cyclic amine 1.7 can be reacted with chloro formate or chlorothioformate or o-, p- nitrophenylchloroformate or phenylchloroformate (or their thiocarbonyl equivalents), or diphenyl cyanocarbonimidate followed by displacement with the appropriate amine can also yield the corresponding urea, thiourea or cyanoguanidine. When synthesizing compounds containing the 1H-pyrazolo[3,4-d]pyrimidine moiety or other compounds reported within this invention which contain functional groups that are not compatible with electrophilic substitution, it will be necessary to do an additional step to remove the protecting group to afford compound I.
[0108] The groups "Lg", "Lg1", and "Lg2" in Schemes 1 -3 are suitable leaving groups, i.e. , groups that are subject to nucleophilic displacement. A "suitable leaving group" is a chemical group that is readily displaced by a desired incoming chemical moiety such as an amine. Suitable leaving groups are well known in the art, e.g., see, "Advanced Organic Chemistry," Jerry March, 5th Ed., pp. 351 -357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, acetoxy, methoxy, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).
1 2
[0109] The groups "Pg", "Pg ", and "Pg " in Schemes 1 -4 are suitable protecting groups, as defined above and described herein. One of ordinary skill will be familiar with a variety of protecting group and protecting group strategies that many be employed in the Schemes depicted below. Scheme 1
1.7
Figure imgf000047_0001
[0110] Alternatively and/or additionally, certain compounds of formula (I) can also be prepared according to Scheme 2 using commercially available substituted heterocycles such as pyrrolidine, piperidine or azepanes which can undergo N-animation with substituted heteroaromatic such as pyridinyl and pyrimidyl moities using DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvents to yield 2.3. The N-amination can also be accomplished utilizing Buchwald coupling (Shafir, A. Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742. Mehrotra, M. M. et. ah Bioorganic & Medicinal Chemistry Letters 2002, 12, 1 103) to afford 2.3. The exo-cyclic amine protecting group can be removed upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York to give compound 2.4. The amine can be substituted using the appropriate electrophile such as 2-chloroacetyl chloride in the presence of an organic base such as triethylamine or other suitable bases familiar to those skilled in the art and in a solvent such as dichloromethane or another appropriate solvent. Compound 2.5 can undergo nucleophilic displacement with various nucleophiles such as primary and secondary amines to yield compounds represented by structure 2.6. When synthesizing compounds containing the 1H-pyrazolo[3,4-d]pyrimidine moiety or other compounds reported within this invention which contain functional groups that are not compatible with electrophilic substitution it may be necessary to do an additional step to remove the protecting group to afford compound of formula V.
Scheme 2
Figure imgf000049_0001
[0111] Compounds of formula (I) can be prepared via intermediates 2.4 which can be reacted with the appropriate electrophile such as a substituted or unsubstituted glycyl carboxamide as shown in Scheme 3. The protected amine compound 3.1 can be de -protected upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in
Organic Synthesis, 3rd edition, John Wiley & Sons, New York. The amine 3.2 can be reacted with the appropriate electrophile such as a substituted acid chloride, sulfonyl chloride, alkyl halide or carboxylic acid which can be activated using standard peptide coupling reagents such as EDCI/HOBt, PyBOP, HATU or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401. Li, P.; Xu, J. C. J. Pept. Res. 2001, 58, 129.) in the presence of an organic base such as DIEA or other bases familiar to one skilled in the art and in an appropriate solvent to yield 3.3. When synthesizing compounds containing the 1H-pyrazolo[3,4-d]pyrimidine moiety or other compounds reported herein containing functional groups that are not compatible with electrophilic substitution it will be necessary to do an additional step to remove the protecting group to afford compound IV-d.
Scheme 3
Figure imgf000050_0001
[0112] Compounds of formula (I) wherein R3 and R4 join together to form a heteroaryl
(e.g. pyrazolo) can be prepared according to Scheme 4 using commercially available 4,6- dihydroxypyrimidine 4.1. The 4,6-dihydroxyprimidine can be chlorinated and formylation under Vilsmeier conditions upon treatment with POCI3 and DMF to afford the 5-formyl-6,3-dichloro- 5-formylpyrimidine 4.2. The aldehyde 4.2 can be condensed with the hydrazine to afford the imine which can undergo intramolecular cyclization to give 4.3. The 4-chloro- 1H-pyrazolo[3,4- Jjpyrimidine intermediate can be protected upon treatment with suitable conditions as described in Greene and Wuts, Protective Group in Organic Synthesis, 3rd edition, John Wiley & Sons, New York to afford 4.4 and can then undergo N-amination upon treatment with a substituted heterocyclic amine in the presence of DIEA or by other bases familiar to one skilled in the art and in a solvent such as DMF or another appropriate solvent. The final step is the removal of the protecting group using suitable conditions to afford compounds of formula VHI-a.
Scheme 4
Figure imgf000051_0001
[0113] In certain embodiments, each of the aforementioned synthetic steps of Schemes 1-
4 may be performed sequentially with isolation of each intermediate performed after each step. Alternatively, each of the steps as depicted in Schemes 1-4 above, may be performed in a manner whereby no isolation of each intermediate is performed. Furthermore, it will be readily apparent to the skilled artisan that additional steps may be performed to accomplish particular protection group and/or deprotection strategies.
Methods of Use
[0114] In certain embodiments, compounds of the present invention are for use in medicine. In some embodiments, compounds of the present invention are useful as kinase inhibitors. In certain embodiments, compounds of the present invention are selective inhibitors of Btk. Such methods include contacting a Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides methods of inhibiting Btk enzymatic activity by contacting a Btk with a Btk inhibitor of the present invention.
[0115] Btk enzymatic activity, as used herein, refers to Btk kinase enzymatic activity.
For example, where Btk enzymatic activity is decreased, PIP3 binding and/or phosphorylation of PLCy is decreased. In some embodiments, the half maximal inhibitory concentration (IC50) of the Btk inhibitor against Btk is less than 1 μΜ. In some embodiments, the IC50 of the Btk inhibitor against Btk is less than 500 nM. In some embodiments, the IC50 of the Btk inhibitor against Btk is less than 100 nM. In some embodiments, the IC50 of the Btk inhibitor against Btk is less than 10 nM. In some embodiments, the IC50 of the Btk inhibitor against Btk is less than 1 nM. In some embodiments, the IC50 of the Btk inhibitor against Btk is from 0.1 nM to 10 μΜ. In some embodiments, the IC50 of the Btk inhibitor against Btk is from 0.1 nM to 1 μΜ. In some embodiments, the IC50 of the Btk inhibitor against Btk is from 0.1 nM to 100 nM. In some embodiments, the IC50 of the Btk inhibitor against Btk is from 0.1 nM to 10 nM.
[0116] In certain embodiments, Btk inhibitors are useful for the treatment of diseases and disorders that may be alleviated by inhibiting (i.e., decreasing) Btk enzymatic activity. By "diseases" is meant diseases or disease symptoms. Thus, the present invention provides methods of treating autoimmune disorders, inflammatory disorders, and cancers in a subject in need thereof. Such methods include administering to a subject a therapeutically effective amount of a Btk inhibitor. The term "autoimmune disorders" includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1 , Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis. The term "inflammatory disorders" includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present invention provides methods of treating rheumatoid arthritis or lupus. The term "cancer" includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g. small-cell lung carcinoma, non-small-cell lung carcinoma), gastric carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g. microsatellite instability-high colorectal cancer). In certain embodiments, the present invention provides methods of treating leukemia or lymphoma.
[0117] The term "subject," as used herein, refers to a mammal to whom a pharmaceutical composition is administered. Exemplary subjects include humans, as well as veterinary and laboratory animals such as horses, pigs, cattle, dogs, cats, rabbits, rats, mice, and aquatic mammals.
Assays
[0118] To develop useful Btk inhibitors, candidate inhibitors capable of decreasing Btk enzymatic activity may be identified in vitro. The activity of the inhibitor compounds can be assayed utilizing methods known in the art and/or those methods presented herein.
[0119] Compounds that decrease Btk enzymatic activity may be identified and tested using biologically active Btk, either recombinant or naturally occurring. Btk can be found in native cells, isolated in vitro, or co-expressed or expressed in a cell. Measuring the reduction in the Btk enzymatic activity in the presence of an inhibitor relative to the activity in the absence of the inhibitor may be performed using a variety of methods known in the art, such as the BTK- POLYGAT-LS ASSAY described below in the Examples. Other methods for assaying the activity of Btk are known in the art. The selection of appropriate assay methods is well within the capabilities of those of skill in the art. [0120] Once compounds are identified that are capable of reducing Btk enzymatic activity, the compounds may be further tested for their ability to selectively inhibit Btk relative to other enzymes. Inhibition by a compound of the invention is measured using standard in vitro or in vivo assays such as those well known in the art or as otherwise described herein.
[0121] Compounds may be further tested in cell models or animal models for their ability to cause a detectable changes in phenotype related to Btk activity. In addition to cell cultures, animal models may be used to test Btk inhibitors for their ability to treat autoimmune disorders, inflammatory disorders, or cancer in an animal model.
Pharmaceutical Compositions
[0122] In another aspect, the present invention provides pharmaceutical compositions comprising a Btk inhibitor compound of the invention or a Btk inhibitor compound in combination with a pharmaceutically acceptable excipient (e.g., carrier).
[0123] The pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein. For example, in some embodiments, the pharmaceutical compositions include a compound of the present invention and citrate as a pharmaceutically acceptable salt. The Btk inhibitor included in the pharmaceutical composition may be covalently attached to a carrier moiety, as described above. Alternatively, the Btk inhibitor included in the pharmaceutical composition is not covalently linked to a carrier moiety.
[0124] A "pharmaceutically acceptable carrier," as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. [0125] The compounds of the invention can be administered alone or can be coadministered to a subject. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).
Formulations
[0126] Compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.
[0127] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
[0128] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[0129] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0130] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[0131] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[0132] When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene -block polymers, and the like. Ampoules are convenient unit dosages. The compounds of the invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
[0133] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
[0134] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
[0135] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
[0136] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
[0137] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
[0138] Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.
[0139] The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,91 1 ,920; 5,403,841 ; 5,212,162; and 4,861 ,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
Effective Dosages
[0140] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g. decreasing the number of cancer cells in a subject).
[0141] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to Btk inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
[0142] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of decreasing Btk enzymatic activity as measured, for example, using the methods described.
[0143] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring Btk inhibition and adjusting the dosage upwards or downwards, as described above.
[0144] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. In some embodiments, the dosage range is 0.001% to 10% w/v. In some embodiments, the dosage range is 0.1 % to 5% w/v.
[0145] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
Examples
[0146] The examples below are meant to illustrate certain embodiments of the invention, and not to limit the scope of the invention. Abbreviations: AcCN = acetonitrile; BuOH = butanol; DCM = dichloromethane; DIEA, DIPEA = Ν,Ν-diisopropylethylamine; DMA = N,N- dimethylacetamide; DMAP = Ν,Ν-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; EtOAc = Ethyl Acetate; HOBt = 1 -hydro xybenzotriazole; HPLC = high pressure liquid chromatography; MS = mass-spectrometry; MsCl = methanesulfonylchloride; NMR = nuclear magnetic resonance; TFA = trifluoroacetic acid; THF = tetrahydrofuran; RT = room temperature; LC/MS = liquid chromatography mass spectroscopy; NCS = N-chlorosuccinimde; TMSI = trimethylsilylimidazole; NMM = N-methylmaleimide; IBCF = isobutylchloroformate; LDA = lithium diisopropylamide; Tf = triflate (trifluoromethanesulfonate); CDI = carbonyldiimidazole; DPPA = diphenylphosphoryl azide; HATU = 2-(7-Aza-1H-benzotriazole- l -yl)-l ,l ,3,3-tetramethyluronium hexafluorophosphate; DME = dimethyl ether; Boc = tert- butoxycarbonyl; NBS = N-bromosuccinimide; EDCI = l -ethyl-3-(3-dimethylaminopropyl) carbodiimide; dppf = l ,l '-bis(diphenylphosphino)ferrocene; SEM: 2-(trimethylsilyl) ethoxymethyl.
[0147] Starting materials for syntheses described herein are commercially available or can be synthesized by methods known in the art and/or described herein. [0148] It will be appreciated that for compound preparations described herein, when reverse phase HPLC is used to purify a compound, a compound may exist as a mono-, di-, or tri- trifluroacetic acid salt.
Example 1
[0149] Compounds useful in the methods and compositions described herein may be synthesized by a variety of routes, including the general synthetic routes described above in Schemes 1-4
[0150] Example 1. (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)acetamide) .
Figure imgf000060_0001
l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. To a solution of tert-butyl piperidin- 3-ylcarbamatecompound (5.0 g, 25 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.75 g, 25 mmol) in DMF (50 mL) was added DIEA (4.2 mL, 3.1 g, 25 mmol) and the solution was stirred at 100 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give tert-butyl l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- ylcarbamate. To a solution of tert-butyl l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- ylcarbamate (6.3 g, 20 mmol) in dioxane (50 ml) was added 4.0 N C1 (50 mL, 200 mmol) and stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give compound 33.
Figure imgf000060_0002
(N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(phenylamino)acetamide. To a solution of 2-(phenylamino)acetic acid (37 mg, 0.25 mmol), EDCI (53 mg, 0.275 mmol), and HOBt (37 mg, 0.275 mmol) in DMF (1 mL) was DIEA (1.7 mL, 1.3 mg, 1.0 mmol) and 1 -(711- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (54 mg, 0.25 mmol). The solution was stirred at rt for several hours, diluted with water and EtOAc (1 : 1 , 10 mL). The organic phase was separated, washed with brine, dried ( a2S04) and concentrated in vacuo to afford a residue which was purified by reverse phase chromatography C 18 column and 10% acetonitrile/water containing 0.1% TFA to afford example 2 . 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.35 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.44 (s, 1H), 7.03-7.70 (m, 3H), 6.52-6.58 (m, 3H), 4.37 (d, J = 12.7 Hz, 1H), 4.25 (d, J = 12.2 Hz, 1H), 3.84 (s, 1H), 3.60 (m, 2H), 3.46 (m, 1H), 3.36 (m 1H), 1.87 (m, 2H), 1.61 (m, 2H). EIMS (m/z): calcd. for C19H22N6O (M++l) 351.2, found 351.2.
[0151] Examples 2-15 are prepared according to Scheme 1 and Example 1 above.
[0152] Example 2. (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- phenylureido)acetamide).
Figure imgf000061_0001
The title compound of Example 2 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-(3-phenylureido)acetic acid. H NMR
(400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.78 (m, 1H), 8.32 (s, 1H), 8.15 (d, J = 6.4 Hz, 1H), 7.37 (d, J = 8.3Hz, 1H), 7.21 (t, J = 7.3 Hz, 2H), 7.02 (s, 1H), 6.89 (t, J = 7.1 Hz, 1H), 6.36 (m, 1H), 4.48 (d, J = 13.2 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.84 (m, 1H), 3.73 (m, 2H), 3.42 (m, 1H), 3.28 (m, 1H), 1.88-1.95 (m, 2H), 1.63 (m, 2H). EIMS (m/z): calcd. for C20H23N7O2 (M++l) 394.1 , found 394.3.
[0153] Example 3. (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)benzamide).
Figure imgf000061_0002
The title compound of Example 3 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-benzamidoacetic acid. 1H NMR (400 MHz, DMSO-d6) 12.50 (s, 1H), 8.71 (m, 1H), 8.32 (s, 1H), 8.1 1 (d, J = 6.4 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.45-7.56 (m, 3H), 7.40 (s, 1H), 7.01 (s, 1H), 4.48 (d, J =1 1.7 Hz, 1H), 4.32 (d, J = 1 1.7 Hz, 1H), 3.82-3.93 (m, 3H), 3.41 (m, 1H), 3.25-3.33 (m, 1H), 1.90-1.94 (m, 2H), 1.64 (m, 2H). EIMS (m/z): calcd. for C20H22N6O2 (M++l) 379.2, found 379.3.
[0154] Example 4. (Nl-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N2- phenyloxalamide).
Figure imgf000062_0001
The title compound of Example 4 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 2-oxo-2-(phenylamino)acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.70 (s, 1H), 9.05 (d, J = 7.3 Hz, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.33-7.37 (m, 3H), 7.13 (m, 1H), 6.897 (s, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.48 (d, J = 10.8 Hz, 1H), 8.34 (s, 1H), 7.99 (m, 1H), 7.45 (m, 1H), 7.32 (m, 4H), 7.22 (m, 1H), 7.02 (d, J = 13.7 Hz, 1H), 3.90 (m, 1H), 3.30 (t, J = 1 1.5 Hz, 1H), 3.21 (t, J = 1 1.0 Hz, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.63 (m, 1H). EIMS (m/z): calcd. for C19H20N6O2 (M++l) 365.2, found 365.2.
[0155] Example 5. ((3R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- hydroxy-3 -phenylpropanamide) .
Figure imgf000062_0002
The title compound of Example 5 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was ssuubbssttiittuutteedd ffoorr (R)-3-hydroxy-3-phenylpropanoic. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.34 (s, 1H), 7.99 (m, 1H), 7.45 (m, 1H), 7.32 (m, 4H), 7.22 (m, 1H), 7.02 (d, J = 13.7 Hz, 1H), 4.95 (m, 1H), 4.30-4.48 (m, 2H), 3.79 (m, 1H), 3.38 (m, 1H), 3.09-3.24 (m, 1H), 2.35 (m 1H), 1.83-1.90 (m, 2H), 1.54-1.60 (m, 2H). EIMS (m/z): calcd. for C20H23N5O2 (M++l) 366.2, found 366.0.
[0156] Example 6. ((3S)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- hydroxy-3-phenylpropanamide).
Figure imgf000063_0001
The title compound of Example 6 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (S)-3-hydroxy-3-phenylpropanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.32 (s, 1H), 7.98 (m, 1H), 7.43 (m, 1H), 7.32 (m, 4H), 7.22 (m, 1H), 7.01 (d, J = 13.7 Hz, 1H), 4.95 (m, 1H), 4.30-4.51 (m, 2H), 3.78 (m, 1H), 3.36 (m, 1H), 3.07-3.22 (m, 1H), 2.34 (m 1H), 1.83-1.90 (m, 2H), 1.54-1.60 (m, 2H) ppm. EIMS (m/z): calcd. for C2oH23N502 (M++l) 366.2, found 366.0.
[0157] Example 7. (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- phenylpropanamide).
Figure imgf000063_0002
The title compound of Example 7 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 3-phenylpropanoic acid. 1H NMR (400
MHz, DMSO-i¼) δ 12.49 (s, 1H), 8.32 (s, 1H), 7.99 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 7.23-7.26
(m, 2H), 7.13-7.18 (m, 3H), 6.99 (s, 1H), 4.39 (d, J = 13.9 Hz, 1H), 4.26 (d, J = 12.2 Hz, 1H),
3.79 (m, 1H), 3.41 (t, J = 10.5 Hz, 1H), 3.22 (t, J = 1 1.0 Hz, 1H), 2.78 (m, 2H), 2.37 (m, 2H), 1.88 (m, 2H), 1.54-1.62 (m, 2H) ppm. EIMS (m/z): calcd. for C2oH23 502 (M++l) 351.2, found 351.0.
[0158] Example 8. (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- phenoxyacetamide).
Figure imgf000064_0001
The title compound of Example 8 was prepared in similar manner as described in Example 1 except except 2-(phenylamino)acetic acid was substituted for 2 -phenoxy acetic acid. 1H NMR (400MHz, DMSO-i¼) δ 12.48 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 6.8 Hz, 1H), 7.40 (s, 1H), 7.28 (t, J= 7.60 Hz, 2H), 6.91 -6.96 (m, 3H), 4.49 (d, J = 5.4 Hz, 2H), 4.45 (m, 1H), 4.32 (d, J= 13.2 Hz, 1H), 3.90 (m, 1H), 3.37 (m, 2H), 1.73-1.91 (m, 2H), 1.61-1.70 (m, 2H) ppm. EIMS (m/z): calcd. for Ci9H2iN502 (M++l) 352.2, found 352.0.
[0159] Example 9. ((3S)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- amino-3-phenylpropanamide).
Figure imgf000064_0002
The title compound of Example 9 was prepared in similar manner as described in Example 1 except intermediate 2-(phenylamino)acetic acid was substituted for (S)-3-tert- butoxycarbonylamino-3-phenylpropionic acid. The Boc protected amine was treated with 4 N HCl in 1 ,4-dioxane (mL) for 2 h at rt. The reaction mixture was concentrated in vacuo to afford a solid which purified by reverse phase chromatography CI 8 column and 10% acetonitrile/water containing 0.1% TFA to afford the final product. EIMS (m/z): calcd. for C20H24N6O (M++l) 365.2, found 365.4.
Figure imgf000065_0001
The title compound of Example 10 was prepared in similar manner as described in Example 1 except intermediate 2-(phenylamino)acetic acid was substituted for (R)-3-tert- butoxycarbonylamino-3-phenylpropionic acid. The Boc protected amine was treated with 4 N HCl in 1 ,4-dioxane (mL) for 2 h at rt. The reaction mixture was concentrated in vacuo to afford a solid which purified by reverse phase chromatography CI 8 column and 10% acetonitrile/water containing 0.1% TFA to afford the final product. EIMS (m/z): calcd. for C2oH24 60 (M++l) 365.2, found 365.4.
[0161] Example 1 1. ((R)- -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)acetamide).
Figure imgf000065_0002
The title compound of Example 1 1 was prepared in similar manner as described in Example 1 except intermediate l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for (R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.33 (s, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.42 (s, 1H), 7.05 (t, J = 7.6 Hz, 2H), 6.98 (s, 1H), 6.51-6.57 (m, 3H), 4.40 (d, J = 12.7 Hz, 1H), 4.26 (d, J = 12.2 Hz, 1H), 3.87 (s, 1H), 3.64 (m, 2H), 3.45 (m, 1H), 3.33 (m 1H), 1.90 (m, 2H), 1.64 (m, 2H) ppm. EIMS (m/z): calcd. for C19H22N6O (M++l) 351.2, found 351.2.
[0162] Example 12. ((S)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)acetamide).
Figure imgf000066_0001
The title compound of Example 12 was prepared in similar manner as described in Example 1 except intermediate l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for (S)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. 1H NMR (400 MHz, OMSO-d6) δ 12.63 (s, 1H), 8.34 (s, 1H), 8.06 (d, J =6.8 Hz, 1H), 7.43 (s, 1H), 7.00-7.06 (m, 3H), 6.51-6.57 (m, 3H), 4.40 (d, J =12.7 Hz, 1H), 4.25 (d, J =12.2 Hz, 1H), 3.87 (s, 1H), 3.64 (m, 2H), 3.45 (m, 1H), 3.35 (m 1H), 1.90 (m, 2H), 1.65 (m, 2H) ppm. EIMS (m/z): calcd. for
Figure imgf000066_0002
(M++l) 351.2, found 351.2.
[0163] Example 13. ( -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-
(phenylamino)propanamide) .
Figure imgf000066_0003
The title compound of Example 13 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for 3-(phenylamino)propanoic acid. 1H NMR (400 MHz, DMSO-ί ί) δ 12.65 (s, 1H), 8.35 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 7.45 (s, 1H), 7.05-7.12 (m, 3H), 6.60-6.62 (m, 3H), 4.39 (d, J = 12.2 Hz, 1H), 4.20 (d, J = 12.7 Hz, 1H), 3.83 (s, 1H), 3.53 (m, 1H), 3.39 (m, 1H), 3.14-3.27 (m, 2H), 2.33-2.37 (m, 2H), 1.91 (m, 2H), 1.59-1.63 (m, 2H) ppm. EIMS (m/z): calcd. for C2oH24 60 (M++l) 365.2, found 365.0.
[0164] Example 14. ((R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)- l ,2,3,4-tetrahydroquinoline-2-carboxamide).
Figure imgf000067_0001
The title compound of Example 14 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (R)-l ,2,3,4-tetrahydroquinoline-2- carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.31 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.43 (s, 1H), 6.98 (s, 1H), 6.86 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.54 (d, J =7.8 Hz, 1H), 6.44 (t, J =7.1 Hz, 1H), 4.39 (d, J = 123.2 Hz, 1H), 4.25 (d, J =12.7 Hz, 1H), 3.81-3.87 (m, 2H), 3.34-3.46 (m, 2H), 2.56 (m, 1H), 2.44 (m, 1H), 1.63-1.95 (m, 7H) ppm. EIMS (m/z): calcd. for C2iH24 60 (M++l) 377.2, found 377.2.
[0165] Example 15. ((S)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)- l ,2,3,4-tetrahydroquinoline-2-carboxamide).
Figure imgf000067_0002
The title compound of Example 15 was prepared in similar manner as described in Example 1 except 2-(phenylamino)acetic acid was substituted for (S)- 1 ,2,3 ,4-tetrahy droquinoline-2- carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 6.99 (s, 1H), 6.87 (t, J = 7.1 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H), 6.53 (d, J = 6.8 Hz, 1H), 6.45 (t, J = 7.1 Hz, 1H), 4.38 (d, J = 13.2 Hz, 1H), 4.23 (d, J=13.2 Hz, 1H), 3.83 (m, 2H), 3.46 (m, 2H), 2.56 (m, 1H), 2.44 (m, 1H), 1.65-1.88 (m, 7H) ppm. EIMS (m/z): calcd. for C21H24N6O (M++l) 377.2, found 377.2.
[0166] Example 16 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(methyl(phenyl)amino)acetamide).
Figure imgf000068_0001
tert-Butyl l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate. To a mixture of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1 1.7 g, 25 mmol) and tert-bu yl piperidin-3- ylcarbamate (5.0, 25 mmol) in DMF (50 mL) was added DIEA (3.2 g, 4.3 mL, 25 mmol) and the solution stirred was at 80 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography to give compound 16.2.
[0167] l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. A solution of Boc protected amine (9.4 g, 20 mmol) in 4.0 N C1 in dioxane (50 ml) was stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give 16.3 which used without any further purification.
[0168] 2-chloro-N-( 1 -(7-tosyl-7H-pyrrolo [2,3 -d]pyrimidin-4-yl)piperidin-3 - yl)acetamide. To a solution of compound 16.3 (7.4 g, 20 mmol), Et3N (12.1 g, 16.8 mL, 120 mmol) in CH2CI2 (200 mL) was added with a-chloroacetyl chloride 16.4 (2.4 g, 22 mmol) at 0 °C. After stirring at rt for 1 h, the reaction mixture was diluted with CH2CI2 (300 mL) and washed with sat. aq. NH4CI, sat. aq. NaHC03, and brine, and the organic layer was dried ( a2S04) and concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, 50% EtOAc in hexane) to afford compound 16.5.
[0169] 2-(methyl(phenyl)amino)-N-(l -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acetamide. A mixture of 16.6 (223 mg, 0.5 mmol), alkyl chloride 16.6 (107 mg, 1.0 mmol), LiBr (85 mg, 1.0 mmol), and K2C03 (0.34, 2.5 mmol) in DMF (2.5 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, 50% EtOAc in hexane) to give the desided product 16.7.
[0170] N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(methyl(phenyl)amino)acetamide. A mixture of 16.7 (73 mg, 0.2 mmol) and K2C03 (0.138 mg, 1.0 mmol) in MeOH (2 mL) and water (0.5 mL) was stirred at 65 °C for 5 h. The solvent was removed in vacuo and the residue diluted with water. The precipitate was isolated by filtration and purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1 % TFA to afford example 16.8. 1H NMR (400 MHz, DMSO-c¼) δ 12.48 (s, 1H), 8.31 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.39 (s, 1H), 7.12 (t, J = 7.1 Hz, 2H), 6.91 (s, 1H), 6.59-6.63 (m, 3H), 4.36 (d, J = 12.7 Hz, 1H), 4.23 (d, J = 12.7 Hz, 1H), 3.83-3.94 (m, 3H), 3.46 (m, 1H), 3.36 (m, 1H), 2.95 (s, 3H), 1.89 (m, 2H), 1.64 (m, 2H) ppm. EIMS (m/z): calcd. for C2oH24 60 (M++l) 365.2, found 365.0.
[0171] Examples 17-84 were prepared according to Scheme 2 and Example 16 above.
[0172] Example 17 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2-ieri- butylphenylamino)acetamide).
Figure imgf000069_0001
The title compound of Example 17 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-te/ -butylaniline. 1H NMR (400 MHz, CD3OD) δ
1.27 (s, 9 H), 1.78 (m, 2 H), 1.94 (m, 1 H), 2.04 (d, J = 14.18 Hz, 1 H), 3.60 (m, 2 H), 3.60 (m, 2 H), 3.90 (s, 2 H), 4.29 (d, J = 12.72 Hz, 1 H), 4.48 (d, J = 13.69 Hz, 1 H), 6.92 (d, J = 7.83 Hz, 1 H), 6.90 (s, 1 H), 7.09 (m, 2 H), 7.17 (m, 2H), 7.26 (s, 1H), 7.34 (d, 1 H), 7.52 (s, 1 H), 8.15 (s, 1 H).
[0173] Example 18 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-ieri- butylphenylamino)acetamide).
Figure imgf000070_0001
The title compound of Example 18 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-te/ -butylaniline. 1H NMR (MeOH, 400MHz): δ 1.27 (s, 9 H), 1.78 (m, 2 H), 1.94 (m, 1 H), 2.04 (d, J = 14.18 Hz, 1 H), 3.60 (m, 2 H), 3.60 (m, 2 H), 3.90 (s, 2 H), 4.29 (d, J = 12.72 Hz, 1 H), 4.48 (d, J = 13.69 Hz, 1 H), 6.70 (d, J = 7.83 Hz, 1 H), 6.99 (s, 1 H), 7.06 (m, 3 H), 7.06 (s, 3 H), 7.17 (t, J = 7.83 Hz, 1 H), 7.34 (s, 1 H), 8.26 (s, 1 H).
[0174] Example 19 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4-ieri- butylphenylamino)acetamide).
Figure imgf000070_0002
The title compound of Example 19 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-te/ -butylaniline. 1H NMR (MeOH, 400MHz): δ 1.26 (s, 9 H), 1.78 (m, J = 8.07, 8.07 Hz, 2 H), 1.95 (m, 1 H), 2.05 (m, J = 12.23 Hz, 1 H), 3.65 (m, 2 H), 3.89 (s, 2 H), 4.06 (m, 1 H), 4.28 (d, J = 12.72 Hz, 1 H), 4.46 (d, J = 13.21 Hz, 1 H), 6.85 (d, J = 8.31 Hz, 2 H), 7.08 (s, 1 H), 7.30 (d, J = 7.83 Hz, 2 H), 7.36 (s, 1 H), 8.27 (s, 1 H).
[0175] Example 20 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- chlorophenylamino)acetamide).
Figure imgf000071_0001
The title compound of Example 20 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-chloroaniline. 1H NMR (400 MHz) δ 8.25 (s, 1H), 7.35 (d, 1H), 7.03 (s, 1H), 6.84-6.95 (m, 2H), 6.62 (m, 1H), 6.49 (t, 1H), 4.87 (d, 1H), 4.21 (d, 1H), 1.95 (m, 1H), 1.82 (m, 2H) ppm. EIMS (m/z): calcd. for Ci9H23Cl 60 (M+)+i 388.4.
[0176] Example 21 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- chlorophenylamino)acetamide).
Figure imgf000071_0002
The title compound of Example 21 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloroaniline. 1H NMR (400 MHz, CD3OD) δ 1.82 (m, 2 H), 1.95 (m, 1 H), 2.03 (m, 1 H), 3.74 (m, 3 H), 4.07 (m, 1 H), 4.18 (m, J = 13.69 Hz, 1 H), 4.34 (d, J =13.21 Hz, 1 H), 6.42 (d, J = 8.31 Hz, 1 H), 6.50 (s, 1 H), 6.57 (d, J = 7.83 Hz, 1 H), 6.99 (m, 3 H), 7.34 (s, 1 H), 8.25 (s, 1 H) ppm. EIMS (m/z): calcd. for C19H23CIN6O (M+)+l 388.4.
[0177] Example 22 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4- chlorophenylamino)acetamide).
Figure imgf000071_0003
The title compound of Example 22 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-chloroaniline. 1H NMR (400 MHz, CD3OD): 1.80 (m, 2 H), 1.93 (m, 1 H), 2.02 (m, 1 H), 3.77 (m, J = 8.80 Hz, 1 H), 4.05 (m, 1 H), 4.16 (m, 1 H), 4.30 (d, J = 13.21 Hz, 1 H), 6.45 (d, J = 7.83 Hz, 2 H), 6.97 (d, J = 8.80 Hz, 3 H), 6.97 (d, J = 8.80 Hz, 2 H), 7.34 (s, 1 H), 8.24 (s, 1 H) ppm. EIMS (m/z): calcd. for Ci9H23Cl 60 (M+)+l 388.4.
[0178] Example 23 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- fluorophenylamino)acetamide).
Figure imgf000072_0001
The title compound of Example 23 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoroaniline. 1H NMR (400MHz, CD3OD) δ 8.25 (s, 1H), 7.35 (d, 1H), 7.03 (s, 1H), 6.84-6.95 (m, 2H), 6.62 (m, 1H), 6.49 (t, 1H), 4.87 (d, 1H), 4.21 (d, 1H), .06 (s, 1H), 3.98 (s, 1H), 3.73 (m, 3H), 3.63 (s, 1H), 2.35 (s, 1H), 2.01 (m, 1H), 1.95 (m, 1H), 1.82 (m, 2H) ppm. EIMS (m/z): calcd. for Ci9H23FN60 (M+)+i 370.4.
[0179] Example 24 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(trifluoromethyl)phenylamino)acetamide).
Figure imgf000072_0002
The title compound of Example 24 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-trifluoromethylaniline. 1H NMR (400 MHz,
CD3OD) δ 8.26 (s, 1H), 7.34 (s, 1H), 7.22 (t, 1H), 7.03 (s, 1H), 6.89 (d, 1H), 6.79 (s, 1H), 6.74
(d, 1H), 4.45 (d, 1H), 4.28 (d, 1H), 4.06 (s, 1H), 3.81 (s, 2H), 3.62 (m, 2H), 2.05 (s, 1H), 1.97
(m, 1H), 1.80 (m, 12H). EIMS (m/z): calcd. for C^H^NeO (M+)+i 420.4.
[0180] Example 25 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,2- difluorobenzo[d][ l ,3]dioxol-4-ylamino)acetamide).
Figure imgf000073_0001
The title compound of Example 25 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,2-difluorobenzo[d][l ,3]dioxol-4-amine. 1H NMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.33 (s, 1H), 7.03 (s, 1H), 6.87 (t, 1H), 6.48 (d, 1H), 6.35 (d, 1H), 4.45 (d, 1H), 4.27 (d, 1H), 4.06 (m, 1H), 3.87 (s, 2H), 3.63 (m, 2H), 2.01 (m, 2H), 1.80 (m, 2H). EIMS (m/z): calcd. for C20H22F2N6O3 (M+)+l 432.4.
[0181] Example 26 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- sulfamoylphenylamino)acetamide).
Figure imgf000073_0002
The title compound of Example 26 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-aminobenzenesulfonamide. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.33 (s, 1H), 7.21 (t, 1H), 7.14 (d, 1H), 37.03 (s, 2H), 6.73 (d, 1H), 4.43 (d, 1H), 4.26 (d,1H), 4.06 (m, 1H), 3.64 (m, 2H), 2.01 (m, 2H). EIMS (m/z): calcd. for Ci9H25N703S (M+)+l 431.5.
[0182] Example 27 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dichlorophenylamino)acetamide) .
Figure imgf000073_0003
The title compound of Example 27 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dichloroaniline. 1H NMR (400MHz, CD3OD) δ 8.26 (s, 1H), 7.35 (d, 1H), 7.00 (m, 2H), 6.77 (d, 1H), 6.42 (d, 1H), 4.35 (d, 1H), 4.17 (d, 1H), 4.08 (s, 1H), 3.86 (s, 2H), 3.78 (m, 2H), 3.31 (s, 2H), 2.06 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H). EIMS (m/z): calcd. for C19H22CI2N6O (M+)+l 420.3.
[0183] Example 28 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(methylsulfonyl)phenylamino)acetamide).
Figure imgf000074_0001
The title compound of Example 28 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(methylsulfonyl)aniline. 1H NMR (400 MHz, CD3OD) δ 6.69 (s, 1H), 5.74 (t, 2H), 5.60 (d, 1H), 5.48 (s, 2H), 5.29 (d, 1H), 2.87 (d, 1H), 2.70 (d, 1H), 2.49 (s, 1H), 2.28 (s, 2H), 2.07 (m, 2H), 1.74 (s, 5H), 1.48 (s, 3H), 0.45 (m, 2H), 0.25 (m, 2H). EIMS (m/z): calcd. for C20H26N6O3S (M+)+l 430.5.
[0184] Example 29 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- fluorophenylamino)acetamide).
Figure imgf000074_0002
The title compound of Example 29 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-fluoroaniline. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.35 (d, 1H), 7.02 (m, 2H), 6.82 (d, 2H), 6.21 (d, 1H), 4.35 (d, H), 4.20 (d, 1H), 4.07 (s, 1H), 3.75 (s, 4H). 2.06 (m, 1H), 1.94 (m, 1H), 1.82 (m, 2H). EIMS (m/z): calcd. for Ci9H23F 60 (M+)+l 370.4.
[0185] Example 30 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,6- diethylphenylamino)acetamide) .
Figure imgf000075_0001
The title compound of Example 30 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,6-diethylaniline. 1H NMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 7.39 (d, 1H), 7.13 (d, 2H), 7.05 (t, 3H), 4.57 (d, 1H), 4.33 (d, 1H), 4.1 1 (s, 1H), 3.68 (m, 3H), 2.66 (m, 4H), 2.15 (m, 1H), 2.03 (s, 1H), 1.84 (t, 2H), 1.22 (m, 5H). EIMS (m/z): calcd. for C23H32N6O (M+)+i 408.5.
[0186] Example 31 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(m- tolylamino)acetamide).
Figure imgf000075_0002
The title compound of Example 31 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-methylaniline. 1H NMR (400MHz, CD3OD): δ 8.25 (s, 1H), 7.36 (s, 1H), 7.03 (s, 1H), 6.96 (t, 1H), 6.17 (t, 3H), 4.87 (d, 1H), 24.20 (d, 1H), 4.08 (s, 1H), 3.76 (m, 3H), 2.21 (s, 2H), 2.04 (s, 1H), 1.93 (m, 1H), 1.81 (m, 2H). EIMS (m/z): calcd. for C2oH26N60 (M+)+l 366.2.
[0187] Example 32 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- methoxyphenylamino)acetamide).
Figure imgf000075_0003
The title compound of Example 32 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-methoxyaniline. 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 6.95 (t, 1H), 6.24 (d, 1H), 6.12 (m, 2H), 4.32 (d, 1H), 4.15 (d, 1H), 4.07 (s, 1H), 3.75 (m, 1H), 3.69 (s, 2H), 3.30 (s, 1H), 2.03 (m, 1H), 1.92 (m, 1H), 1.81 (m, 2H). EIMS (m/z): calcd. for C2oH26N602 (M+)+i 382.5.
[0188] Example 33 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4- fluorophenylamino)acetamide).
Figure imgf000076_0001
The title compound of Example 33 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-fluoroaniline. 1H NMR (CD3OD, 400 MHz): δ 8.25 (s, 1H), 7.35 (s, 1H), 7.02 (s, 1H), 6.8 (t, 2H), 6.54 (m, 2H), 4.85 (d, 1H), 4.20 (d, 1H), 4.06 (s, 1H), 3.72 (m, 3H), 2.02 (m, 1H), 1.93 (m, 1H), 1.81 (m, 2H). EIMS (m/z): calcd. for C19H23FN6O2 (M+)+l 370.4.
[0189] Example 34 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- cyanophenylamino)acetamide).
Figure imgf000076_0002
The title compound of Example 34 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-aminobenzonitrile. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.32 (d, 1H), 7.20 (t, 1H), 7.01 (s, 1H), 6.91 (d, 1H), 6.81 (d, 1H), 6,76 (s, 1H), 4.41 (d, 1H), 4.23 (d, 1H), 4.05 (s, 1H), 3.78 (s, 2H), 3.67 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.79 (m, 2H). EIMS (m/z): calcd. for C2oH23N70 (M+)+l 377.4.
[0190] Example 35 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,5- dichlorophenylamino)acetamide) .
Figure imgf000076_0003
The title compound of Example 35 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,5-dichloroaniline. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.33 (s, 1H), 7.15 (d, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 6.48 (s, 1H), 4.37 (d, 1H), 4.18 (d, 1H), 4.07 (s, 1H), 3.82 (s, 2H), 3.75 (m, 2H), 2.06 (m, 1H), 1.98 (m, 1H), 1.83 (m, 2H). EIMS (m/z): calcd. for C19H22CI2N6O (M+)+i 421.3.
[0191] Example 36 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(trifluoromethoxy)phenylamino)acetamide).
Figure imgf000077_0001
The title compound of Example 36 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(trifluoromethoxy)aniline. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.35 (s, 1H), 7.12 (t, 1H), 7.05 (s, 1H), 6.50 (d, 2H), 6.41 (s, 1H), 4.45 (d, 1H), 4.28 (d, 1H), 4.06 (s, 1H), 3.77 (s, 2H), 3.62 (m, 2H), 2.05 (m, 1H), 1.97 (m, 1H), 1.81 (m, 2H). EIMS (m/z): calcd. for C20H23F3N6O2 (M+)+l 436.4.
[0192] Example 37 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- methoxyphenylamino)acetamide).
Figure imgf000077_0002
The title compound of Example 37 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-(methoxy)aniline. 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.80 (s, 1H), 6.67 (s, 2H), 6.37 (s, 1H), 4.32 (d, 1H), 4.18 (d, 1H), 4.06 (s, 1H), 3.83 (s, 3H), 3.74 (m, 3H), 2.02 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H). EIMS (m/z): calcd. for C20H26N6O2 (M+)+l 382.5.
[0193] Example 38 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- isopropylphenylamino)acetamide).
Figure imgf000078_0001
The title compound of Example 38 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for S-isopropylaniline H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.69 (d, 1H), 7.36 (s, 1H), 7.21 (d, 1H), 7.05 (s, 2H), 6.55 (d, 2H), 6.41 (s, 1H), 4.44 (d, 1H), 4.25 (s, 1H), 4.06 (s, 1H), 3.65 (m, 2H), 2.77 (m, 1H), 2.35 (s, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.79 (m, 2H), 1.19 (d, 5H). EIMS (m/z): calcd. for C22H3oN602 (M+)+i 394.3.
[0194] Example 39 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(biphenyl-
3-ylamino)acetamide).
Figure imgf000078_0002
The title compound of Example 39 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for biphenyl-3 -amine. 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.52 (d, 2H), 7.38 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 6.93 (m, 2H), 6.81 (s, 1H), 6.53 (d, 1H), 4.35 (d, 1H), 4.20 (d, 1H), 4.08 (s, 1H), 3.85 (s, 2H), 3.66 (t, 2H), 2.02 (m, 1H), 1.92 (m, 1H), 1.80 (m, 2H). EIMS (m/z): calcd. for C25H28N60 (M+)+i 428.5.
[0195] Example 40 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- bromophenylamino)acetamide) .
Figure imgf000078_0003
The title compound of Example 40 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-bromoaniline. 1H NMR (400 MHz, CD3OD) δ 8.25
(s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.92 (t, 1H), 6.71 (d, 1H), 6.71 (d, 1H), 6.66 (s, 1H), 6.45 (d,
1H), 4.35 (d, 1H), 4.20 (d, 1H), 4.06 (s, 1H), 3.71 (s, 4H), 2.03 (m, 1H), 1.95 (m, 1H), 1.82 (m,
2H). EIMS (m/z): calcd. for Ci9H23BrN60 (M+)+i 431.3. [0196] Example 41 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(5,6,7,8- tetrahydronaphthalen- 1 -ylamino)acetamide).
Figure imgf000079_0001
The title compound of Example 41 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 5,6,7,8-tetrahydronaphthalen-l -amine. 1H NMR
(400MHz, CD3OD): δ 8.21 (s, 1H), 7.34 (s, 1H), 7.00 (s, 1H), 6.82 (t, 1H), 6.41 (d, 1H), 6.14 (d,
1H), 4.30 (d, 1H), 4.09 (m, 2H), 3.76 (m, 4H), 2.66 (m, 2H), 2.43 (s, 2H), 2.02 (m, 1H), 1.85 (m,
5H), 1.71 (s, 3H). EIMS (m/z): calcd. for C23H30N6O (M+)+i 406.5.
[0197] Example 42 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- phenoxyphenylamino)acetamide).
Figure imgf000079_0002
The title compound of Example 42 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3 -phenoxy aniline. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.33 (s, 1H), 7.26 (t, 2H), 7.01 (m, 4H), 6.91 (m, 2H), 6.29 (m, 3H), 6.16 (s, 1H), 4.35 (d, 1H), 4.23 (d, 1H), 4.02 (s, 1H), 3.70 (s, 3H), 1.96 (m, 2H), 1.77 (s, 2H). EIMS (m/z): calcd. for C25H28N6O (M+)+l 444.5.
[0198] Example 43 (3-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethylamino)-N,N-dimethylbenzamide).
Figure imgf000079_0003
The title compound of Example 43 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-amino- NN-dimethylbenzamide. 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.35 (s, 1H), 7.12 (t, 1H), 7.04 (s, 1H), 6.66 (d, 1H), 6.59 (d, 1H), 6.55 (s, 1H), 4.40 (d, 1H), 4.25 (d, 1H), 4.05 (m, 1H), 3.76 (s, 2H), 3.63 (m, 2H), 3.06 (s, 3H), 2.96 (s, 3H), 2.03 (m, 1H), 1.94 (m, 1H), 1.79 (m, 2H) ppm. EIMS (m/z): calcd. for C22H29N7O2 (M+)+l 423.5.
[0199] Example 44 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-
4-fluorophenylamino)acetamide).
Figure imgf000080_0001
The title compound of Example 44 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-4-fluoroaniline. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.90 (t, 1H), 6.56 (t, 1H), 6.43 (m, 1H), 4.36 (d, 1H), 4.19 (d, 1H), 4.07 (s, 1H), 3.72 (s, 2H), 3.63 (m, 5H), 2.04 (m, 1H), 1.96 (m, 1H), 1.82 (m, 2H). EIMS (m/z): calcd. for Ci9H22ClF 60 (M+)+l 404.9.
[0200] Example 45 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dihydro- 1 H-inden-4-ylamino)acetamide) .
Figure imgf000080_0002
The title compound of Example 45 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dihydro-1H-inden-4-amine. 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.34 (s, 1H), 7.00 (s, 1H), 6.84 (t, 1H), 6.58 (d, 1H), 6.16 (d, 1H), 4.29 (d, 1H), 4.12 (d, 2H), 3.77 (s, 4H), 2.84 (t, 2H), 2.69 (t, 2H), 2.04 (t, 3H), 1.91 (m, 1H), 1.79 (m, 2H). EIMS (m/z): calcd. for C22H28 60 (M+)+l 392.5.
[0201] Example 46 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(naphthalen- 1 -ylamino)acetamide).
Figure imgf000081_0001
The title compound of Example 46 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for naphthalen- 1 -amine. 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.43 (m, 2H), 7.27 (s, 1H), 7.13 (s, 2H), 6.89 (s, 1H), 6.33 (s, 1H), 4.16 (m, 2H), 3.95 (m, 4H), 3.84 (m, 2H), 2.02 (m, 1H), 1.88 (m, 2H), 1.77 (m, 1H). EIMS (m/z): calcd. for C23H26 60 (M+)+l 402.5.
[0202] Example 47 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-
2-fluorophenylamino)acetamide).
Figure imgf000081_0002
The title compound of Example 47 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-fluoroaniline. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 6.85 (t, 1H), 6.66 (d, 1H), 6.26 (d, 1H), 4.30 (d, 1H), 4.09 (m, 2H), 3.80 (m, 2H), 2.18 (s, 3H), 2.03 (m, 1H), 1.87 (m, 1H), 1.82 (m, 2H). EIMS (m/z): calcd. for C19H22CIFN6O (M+)+l 404.9.
[0203]Example 48 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
Figure imgf000081_0003
The title compound of Example 48 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3,5-dichloroaniline.1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 6.57 (s, 1H), 6.45 (s, 2H), 4.36 (d, 1H), 4.21 (d, 1H), 4.07 (s, 1H), 3.76 (m, 5H), 2.01 (m, 2H), 1.83 (m, 2H). EIMS (m/z): calcd. for C19H22CI2N6O (M+)+l 421.3.
[0204] Example 49 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-
5-fluorophenylamino)acetamide).
Figure imgf000082_0001
The title compound of Example 49 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-5-fluoroaniline.1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.34 (s, 1H), 7.14 (t, 1H), 7.03 (m, 3H), 6.69 (d, 1H), 4.40 (d, 1H), 4.23 (d, 1H), 4.07 (s, 1H), 3.80 (s, 2H), 3.66 (m, 2H), 2.88 (s, 2H), 1.80 (m, 1H). EIMS (m/z): calcd. for C19H22CIFN6O (M+)+l 404.9.
[0205] Example 50 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- isopropoxyphenylamino)acetamid
Figure imgf000082_0002
The title compound of Example 50 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-isopropoxyaniline.1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.36 (s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.26 (s, 1H), 6.14 (d, 2H), 4.49 (m, 1H), 4.40 (d, 1H), 4.23 (d, 1H), 4.07 (s, 1H), 3.71 (m, 3H), 2.01 (m, 2H), 1.80 (m, 2H), 1.26 (s, 6H). EIMS (m/z): calcd. for C22H30N6O2 (M+)+l 410.5.
[0206] Example 51 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(5-chloro-
2-fluorophenylamino)acetamide).
Figure imgf000083_0001
The title compound of Example 51 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-6-fluoroaniline.1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 6.91 (t, 1H), 6.52 (m, 2H), 4.40 (d, 1H), 4.24 (d, 1H), 4.08 (s, 1H), 3.81 (s, 2H), 3.71 (m, 2H), 2.05 (m, 2H), 1.84 (m, 2H). EIMS (m/z): calcd. for C19H22CIFN6O (M+)+l 404.9.
[0207] Example 52 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-
2-methylphenylamino)acetamide).
Figure imgf000083_0002
The title compound of Example 52 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-methylaniline.1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.09 (s, 1H), 6.88 (t, 1H), 6.67 (d, 1H), 6.57 (s, 1H), 6.62 (d, 1H), 4.02 (m, 3H), 3.77 (m, 4H), 2.12 (s, 3H), 1.90 (m, 1H), 1.79 (m, 2H), 1.64 (m, H), 1.29 (m, 1H). EIMS (m/z): calcd. for C2oH25Cl 60 (M+)+l 400.9.
[0208] Example 53 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-
2-methoxyphenylamino)acetamide).
Figure imgf000083_0003
The title compound of Example 53 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-chloro-2-methoxyaniline.1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.08 (s, 1H), 6.79 (m, 1H), 6.61 (m, 2H), 6.33 (m, 1H), 4.08 (m, 3H), 3.76 (m, 5H), 3.68 (s, 4H), 1.96 (m, 1H), 1.77 (s, 2H), 1.66 (s, 2H). EIMS (m/z): calcd. for C2oH25Cl 602 (M+)+l 416.9.
[0209] Example 54 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l - oxoisoindolin-4-ylamino)acetamide).
Figure imgf000084_0001
The title compound of Example 54 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-aminoisoindolin-l -one. 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.70 (d, 1H), 7.33 (s, 1H), 7.21 (t, 2H), 7.10 (d, 1H), 6.99 (s, 1H), 6.58 (d, 1H), 4.35 (m, 1H), 4.18 (d, 1H), 3.89 (s, 2H), 3.70 (m, 2H), 2.36 (s, 1H), 2.02 (m, 2H), 1.81 (m, 1H). EIMS (m/z): calcd. for C2iH25N702 (M+)+l 407.5.
[0210] Example 55 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- ethynylphenylamino)acetamide) .
Figure imgf000084_0002
The title compound of Example 55 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-ethynylaniline. 1H NMR (400 MHz, DMSO-d6) δ
1.4- 1.6 (m, 2H), 1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 3.03 (t, J = 10 Hz, 1H), 3.13 (t, J = 1 1 Hz, 1H), 3.61 (s, 2H), 3.72 (s, 1H), 4.35 (d, J = 13 Hz, 1H), 4.42 (d, J = 13 Hz, 1H), 6.08 (s, 1H),
6.5- 6.6 (m, 4H), 7.02 (t, J = 8 Hz, 1H), 7.1 1 (s, 1H), 7.96 (d, J = 7 Hz, 1H), 8.06 (s, 1H), 1 1.64 (s, 1H). EIMS (+) MS m/z = 375 (M+l).
[0211] Example 56 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(pyrrolidin- 1 -yl)phenylamino)acetamide) .
Figure imgf000085_0001
The title compound of Example 56 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(pyrrolidin-l -yl)aniline. 1H NMR (400 MHz, DMSO-i/6) δ 1.5-1.7 (m, 2H), 1.7- 1.9 (m, 6H), 3.0-3.2 (m, 5H), 3.3-3.5 (m, 1H), 3.4-3.5 (m, 1H), 3.68 (d, J = 9 Hz, 1H), 3.88 (m, 1H), 4.18 (d, J = 12 Hz, 1H), 4.34 (d, J = 12 Hz, 1H), 6.39 (d, J = 8 Hz, 1H), 6.60 (t, J = 7 Hz, 1H), 6.8-6.9 (m, 2H), 7.0-7.1 (m, 1H), 7.3-7.5 (m, 1H), 8.1 1 (d, J = 7 Hz, 1H), 8.31 (s, 1H), 12.57 (s, 1H). EIMS (+) MS m/z = 420 (M+l).
[0212] Example 57 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-ieri- butyl-1 -methyl- 1H-pyrazol-5-ylamino)acetamide).
Figure imgf000085_0002
The title compound of Example 57 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-ieri-butyl-l -methyl- 1H-pyrazol-5-amine. 1H NMR (400 MHz, CD3OD) δ 1.18 (s, 9H), 1.6-1.7 (m, 1H), 1.7-1.8 (m, 2H), 1.9-2.0 (m, 1H), 3.31 (s, 2H), 3.47 (s, 3H), 3.6-3.7 (m, 2H), 3.9-4.1 (m, 1H), 4.1 -4.2 (m, 1H), 4.22 (d, J = 14 Hz, 1H), 5.22 (s, 1H), 6.64 (s, 1H), 7.1 1 (s, 1H), 8.1 1 (s, 1H). EIMS (+) MS m/z = 41 1 (M+l).
[0213] Example 58 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l -ieri- butyl-3-methyl-1H-pyrazol-5-ylamino)acetamide).
Figure imgf000085_0003
The title compound of Example 58 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-ieri-butyl-3-methyl-1H-pyrazol-5-amine. 1H NMR
(400 MHz, CD3OD) δ 1.43 (s, 9H), 1.4-1.5 (m, 2H), 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 1.91 (s, 2H), 2.24 (s, 2H), 3.1 -3.2 (m, 1H), 3.49 (t, J = 5 Hz, 2H), 3.6-3.8 (m, 1H), 4.23 (d, J = 12 Hz, 1H), 4.36 (d, J = 12 Hz, 1H), 5.72 (s, 1H), 6.57 (s, 1H), 7.06 (d, J = 8 Hz, 1H), 7.43 (d, J = 8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 8.07 (s, 1H), 1 1.63 (s, 1H). EIMS (+) MS m/z = 41 1 (M+l).
[0214] Example 59 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(pyridin-3- ylamino)acetamide).
Figure imgf000086_0001
The title compound of Example 59 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for pyridin-3 -amine. 1H NMR (400 MHz, DMSO-d6) δ 1.8-2.0 (m, 2H), 3.33 (t, J = 9 Hz, 1H), 3.49 (s, 1H), 3.80 (s, 1H), 4.25 (d, J = 12 Hz, 2H), 4.43 (d, J = 12 Hz, 2H), 4.84 (d, J = 16 Hz, 2H), 6.78 (d, J = 6 Hz, 2H), 6.87 (s, 1H), 7.37 (s, 1H), 7.98 (d, J = 6 Hz, 2H), 8.32 (s, 1H), 12.55 (s, 1H). EIMS (+) MS m z = 352 (M+l).
[0215] Example 60 (N-(l -( -(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(1 -methyl- 1H-pyrazol-3-yl)phenylamino)acetamide).
Figure imgf000086_0002
The title compound of Example 60 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3 -(1 -methyl- 1H-pyrazol-3-yl)aniline. 1H NMR (400 MHz, DMSO-i ) δ 1.5-1.6 (m, 2H), 1.8-1.9 (m, 2H), 3.1-3.6 (m, 5H), 3.65 (s, 2H), 3.80 (s, 3H), 4.23 (d, J = 12 Hz, 1H), 4.36 (d, J = 12 Hz, 1H), 6.44 (s, 1H), 6.60 (s, 1H), 6.97 (s, 2H), 7.03 (s, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 8.08 (s, 1H), 8.27 (s, 1H), 12.48 (s, 1H). EIMS (+) MS m z = 431 (M+l).
[0216] Example 61 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(dimethylamino)phenylamino)acetamide).
Figure imgf000087_0001
The title compound of Example 61 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for , -dimethylbenzene- 1 ,3 -diamine. 1H NMR (400 MHz, CD3OD) δ 0.8-1.0 (m, 2H), 1.1-1.3 (m, 2H), 2.36 (s, 6H), 2.6-2.8 (m, 2H), 2.98 (d, J = 6 Hz, 1H), 3.1-3.3 (m, 1H), 3.49 (d, J = 12 Hz, 1H), 3.69 (d, J = 12 Hz, 1H), 5.92 (s, 1H), 6.13 (s, 1H), 6.35 (d, J = 8 Hz, 1H), 6.41 (s, 1H), 6.49 (s, 1H), 6.83 (d, J = 8 Hz, 1H), 7.42 (s, 1H). EIMS (+) MS m/z = 494 (M+l).
[0217] Example 62 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,4- difluorophenylamino)acetamide).
Figure imgf000087_0002
The title compound of Example 62 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3,4-difluoroaniline.1H NMR (400 MHz, DMSO-d6)
51.6-1.7 (m, 2H), 1.8-1.9 (m, 2H), 3.3-3.5 (m, 2H), 3.59 (d, J = 6 Hz, 2H), 3.8-3.9 (m, 1H), 4.20 (d, J = 13 Hz, 1H), 4.35 (d, J = 13 Hz, 1H), 6.24 (s, 1H), 6.43 (s, 1H), 6.93 (s, 1H), 7.05 (s, 1H), 7.37 (s, 1H), 8.06 (s, 1H), 8.29 (s, 1H), 12.53 (s, 1H). EIMS (+) MS m z = 487 (M+l).
[0218] Example 63 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-fluoro-
5-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000087_0003
The title compound of Example 63 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for S-fluoro-S-trifluoromethylaniline^H NMR (400 MHz, DMSO-ί/ί) δ 1.5-1.6 (m, 2H), 1.8-2.0 (m, 2H), 3.2-3.6 (m, 5H), 4.26 (d, J = 13 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 6.53 (d, J = 12 Hz, 1H), 6.61 (d, J = 12 Hz, 1H), 6.67 (s, 1H), 6.88 (s, 1H), 7.32 (s, 1H), 8.16 (s, 1H), 8.27 (s, 1H), 12.39 (s, 1H). ES (+) EIMS m/z = 437 (M+l).
[0219] Example 64 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2-methyl-
3-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000088_0001
The title compound of Example 64 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-methyl-3-trifluoromethylaniline.1H NMR (400 MHz, DMSO-i¼) δ 1.5-1.6 (m, 2H), 1.8-2.0 (m, 2H), 2.15 (s, 3H), 3.2-3.6 (m, 5H), 4.26 (d, J = 13 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.90 (s, 1H), 7.09 (t, J = 8 Hz, 1H), 7.36 (s, 1H), 8.06 (s, 1H), 8.27 (s, 1H), 12.47 (s, 1H) ppm. ES (+) MS m/z = 433 (M+l).
[0220] Example 65 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4-methyl-
3-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000088_0002
The title compound of Example 65 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-methyl-3-trifluoromethylaniline. 1H NMR (400
MHz, DMSO-ί/ί) δ 1.5-1.7 (m, 2H), 1.8-1.9 (m, 2H), 2.21 (s, 3H), 3.3-3.4 (m, 2H), 3.5-3.8 (m, 3H), 4.26 (d, J = 13 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.79 (s, 1H), 6.91 (s, 1H), 7.03 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 8.09 (s, 1H), 8.30 (s, 1H), 12.51 (s, 1H). ES (+) MS m/z = 433 (M+l).
[0221] Example 66 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- cyanophenylamino)acetamide).
Figure imgf000089_0001
The title compound of Example 66 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-aminobenzonitrile. 1H NMR (400 MHz, DMSO-i¾) δ 1.5-1.7 (m, 2H), 1.8-1.9 (m, 2H), 3.3-3.8 (m, 5H), 4.26 (d, J = 13 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 6.17 (s, 1H), 6.49 (d, J = 8 Hz, 1H), 6.63 (t, J = 7 Hz, 1H), 6.85 (s, 1H), 7.3-7.4 (m, 2H), 7.44 (d, J = 7 Hz, 1H), 8.15 (d, J = 7 Hz, 1H), 8.24 (s, 1H), 12.37 (s, 1H). ES (+) MS m/z = 476 (M+l).
[0222] Example 67 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,4- difluorophenylamino)acetamide).
Figure imgf000089_0002
The title compound of Example 67 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4,2-difluoroaniline. 1H NMR (400 MHz, DMSO-d6) δ
1.5-1.7 (m, 2H), 1.7-2.0 (m, 2H), 3.31 (t, J = 10 Hz, 1H), 3.43 (t, J = 10 Hz, 1H), 3.69 (d, J = 6 Hz, 2H), 3.7-3.9 (m, 1H), 4.23 (d, J = 13 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 6.2-6.3 (m, 1H), 6.8- 7.0 (m, 2H), 7.37 (s, 1H), 6.13 (d, J = 6 Hz, 1H), 8.30 (s, 1H), 12.55 (s, 1H). ES (+) MS m/z =
487 (M+l).
[0223] Example 68 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5- difluorophenylamino)acetamide).
Figure imgf000089_0003
The title compound of Example 68 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted/or 3,5-difluoroaniline. 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.7 (m, 2H), 1.7-2.0 (m, 2H), 3.29 (t, J = 10 Hz, 1H), 3.41 (t, J = 1 1 Hz, 1H), 3.65 (d, J = 8 Hz, 2H), 3.7-3.8 (m, 1H), 4.23 (d, J = 12 Hz, 1H), 4.37 (d, J = 12 Hz, 1H), 6.14 (d, J = 1 1 Hz, 1H), 6.19 (t, J = 9 Hz, 1H), 6.90 (s, 1H), 7.34 (s, 1H), 8.13 (d, J = 6 Hz, 1H), 8.27 (s, 1H), 12.43 (s, 1H). ES (+) MS m/z = 487 (M+l).
[0224] Example 69 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2-fluoro-
5-(trifluoromethyl)phenylamino)acetamide .
Figure imgf000090_0001
The title compound of Example 69 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoro-5-trifluoromethylaniline. 1H NMR (400 MHz, DMSO-ί ί) δ 1.5-1.7 (m, 2H), 1.8-1.9 (m, 2H), 3.28 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.77 (d, J = 8 Hz, 2H), 3.8-3.9 (m, 1H), 4.26 (d, J = 12 Hz, 1H), 4.38 (d, J = 12 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 6.8-6.9 (m, 1H), 7.20 (d, J = 9 Hz, 1H), 7.36 (s, 1H), 8.20 (d, J = 7 Hz, 1H), 8.31 (s, 1H), 12.55 (s, 1H). ES (+) MS m z = 437 (M+l).
[0225] Example 70 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2-fluoro-
3-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000090_0002
The title compound of Example 70 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-fluoro-3-trifluoromethylaniline. 1H NMR (400 MHz, DMSO-d-6) 5 1.5-1.7 (m, 2H), 1.8-1.9 (m, 2H), 3.29 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.77 (d, J = 6 Hz, 2H), 3.8-3.9 (m, 1H), 4.26 (d, J = 12 Hz, 1H), 4.38 (d, J = 13 Hz, 1H), 6.7-6.8 (m, 3H), 6.90 (s, 1H), 7.07 (t, J = 8 Hz, 1H), 7.37 (s, 1H), 8.13 (d, J = 7 Hz, 1H), 8.29 (s, 1H), 12.47 (s, 1H). ES (+) MS m/z = 437 (M+l). [0226] Example 71 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- difluorophenylamino)acetamide).
Figure imgf000091_0001
The title compound of Example 71 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-difluoroaniline. 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.7 (m, 2H), 1.8-1.9 (m, 2H), 3.29 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.69 (d, J = 5 Hz, 2H), 3.81 (s, 1H), 4.22 (d, J = 13 Hz, 1H), 4.35 (d, J = 13 Hz, 1H), 6.29 (t, J = 8 Hz, 1H), 6.50 (q, J = 9 Hz, 1H), 6.85 (q, J = 7 Hz, 1H), 6.89 (s, 1H), 7.36 (s, 1H), 8.08 (d, J = 7 Hz, 1H), 8.27 (s, 1H), 12.46 (s, 1H). ES (+) MS m/z = 387 (M+l).
[0227] Example 72 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(cyclopentylamino)acetamide).
Figure imgf000091_0002
The title compound of Example 72 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for cyclopentanamine. 1H NMR (400 MHz, CD3OD) δ
1.1 -15 (m, 2H), 1.4-1.5 (m, 2H), 1.5-1.7 (m, 6H), 1.7-1.9 (m, 1H), 2.0-2.2 (m, 1H), 2.87 (t, J = 6
Hz, 1H), 3.16 (s, 2H), 3.7-3.8 (m, 2H), 3.9-4.1 (m, 2H), 4.20 (d, J = 13 Hz, 2H), 6.70 (d, J = 3
Hz, 1H), 7.12 (d, J = 2 Hz, 1H), 8.20 (S, 1H). ES (+) MS m/z = 443 (M+l).
[0228] Example 73 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4-cyano-
3-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000091_0003
The title compound of Example 73 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-amino-2-(trifluoromethyl)benzonitrile. H NMR
(400 MHz, CD3OD) δ 1.6-1.8 (m, 2H), 2.0-2.2 (m, 2H), 3.44 (s, 1H), 3.5-3.7 (m, 1H), 3.9 (s, 1H), 4.0-4.1 (m, 1H), 4.3-4.6 (m, 3H), 6.77 (d, J = 9 Hz, 1H), 6.99 (s, 1H), 7.06 (s, 1H), 7.34 (s, 1H), 7.58 (d, J = 9 Hz, 2H), 8.29 (d, J = 6 Hz, 1H). ES (+) MS m/z = 444 (M+l).
[0229] Example 74 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(4-fluoro-
3-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000092_0001
The title compound of Example 74 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 4-//woro-3-trifluoromethylaniline. 1H NMR (400 MHz, CD3OD) δ 1.6-1.9 (m, 2H), 2.0-2.1 (m, 2H), 3.4-3.7 (m, 2H), 3.78 (s, 1H), 4.06 (s, 1H), 4.29 (d, J = 13 Hz, 1H), 4.47 (d, J = 13 Hz, 1H ), 6.7-6.8 (m, 1H), 7.0-7.1 (m, 1H), 7.1 -7.2 (m, 2H), 7.34 (s, 1H), 8.26 (s, 1H). ES (+) MS m z = 437 (M+l).
[0230] Example 75 (2-(1H-indazol-7-ylamino)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -yl)acetamide) .
Figure imgf000092_0002
The title compound of Example 75 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for iH-indazol-7-amine. 1H NMR (400 MHz, CD3OD) δ 1.5-1.97(m, 3H), 1.8-2.0 (m, 1H), 3.5-3.6 (m, 2H), 3.90 (s, 2H), 4.0-4.1 (m, 2H), 4.17 (d, J = 13 Hz, 1H), 5.95 (d, J= 7 Hz, 1H), 6.57 (s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.0-7.1 (m, 2H), 8.03 (d, J = 4 Hz, 1H). ES (+) MS m/z = 391 (M+l).
[0231] Example 76 (2-(1H-indazol-4-ylamino)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -yl)acetamide) .
Figure imgf000093_0001
The title compound of Example 76 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 1H-indazol-4-amine. 1H NMR (400 MHz, CD3OD) δ 1.5-1.97(m, 3H), 1.8-2.0 (m, 1H), 3.5-3.6 (m, 2H), 3.93 (s, 2H), 4.0-4.1 (m, 2H), 4.25 (d, J = 13 Hz, 1H), 6.30 (s, 1H), 6.59 (s, 1H), 6.90 (t, J = 8 Hz, 1H), 7.04 (s, 1H), 7.09 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 8.02 (s, 1H). ES (+) MS m/z = 391 (M+l).
[0232] Example 77 (2-(3-(1H-pyrazol-l -yl)phenylamino)-N-(l-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000093_0002
The title compound of Example 77 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2-(1H-pyrazol- l-yl)aniline. 1H NMR (400 MHz, DMSO-i¼) δ 1.5-1.7 (m, 2H), 1.9-2.0 (m, 2H), 3.30 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.69 (d, J = 6 Hz, 2H), 3.8-3.9 (m, 1H), 4.23 (d, J = 14 Hz, 1H), 4.39 (d, J = 14 Hz, 1H), 6.45 (s, 2H), 6.9-7.0 (m, 2H), 7.00 (s, 1H), 7.1 1 (d, J = 8 Hz, 1H), 7.37 (s, 1H), 7.63 (s, 1H), 8.12 (d, J = 7 Hz, 1H), 8.80 (s, 2H), 12.57 (s, 1H). ES (+) MS m z = 417 (M+l).
[0233] Example 78 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l -methyl-
1 H-indazol-4-ylamino)acetamide)
Figure imgf000093_0003
The title compound of Example 78 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-me//zy/-1H-indazol-4-amine. 1H NMR (400 MHz, DMSO-i¼) δ 1.5-1.7 (m, 2H), 1.9-2.0 (m, 2H), 3.32 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.78 (d, J= 6 Hz, 2H), 3.8-3.9 (m, 1H), 3.90 (s, 3H), 4.22 (d, J = 12 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 5.88 (d, J = 8 Hz, 1H), 6.70 (d, J = 8 Hz, 1H), 6.94 (s, 1H), 7.01 (t, J = 7 Hz, 1H), 7.37 (s, 1H), 8.0-8.1 (m, 2H), 8.29 (s, 1H), 12.56 (s, 1H). ES (+) MS m/z = 405 (M+l).
[0234] Example 79 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l -phenyl-
1H-pyrazol-3-ylamino)acetamide).
Figure imgf000094_0001
The title compound of Example 79 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for l-phenyl-1H-pyrazol-3-amine. 1H NMR (400 MHz, DMSO-ί ί) δ 1.5-1.7 (m, 2H), 1.9-2.0 (m, 2H), 3.32 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.78 (d, J= 6 Hz, 2H), 3.8-3.9 (m, 1H), 4.22 (d, J = 12 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 5.79 (s, 1H), 6.98 (s, 1H), 7.07 (t, J = 7 Hz, 1H), 7.3-7.4 (m, 3H), 7.60 (d, J = 8 Hz, 2H), 8.03 (d, J = 7 Hz, 1H), 8.12 (s, 1H), 8.31 (s, 1H), 12.62 (s, 1H). ES (+) MS m z = 417 (M+l).
[0235] Example 80 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(l -methyl-
1H-pyrazol-3-ylamino)acetamide).
Figure imgf000094_0002
The title compound of Example 80 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 1 -methyl- 1H-pyrazol-3 -amine. 1H NMR (400 MHz, DMSO-ί ί) δ 1.5-1.7 (m, 2H), 1.9-2.0 (m, 2H), 3.32 (t, J = 10 Hz, 1H), 3.40 (t, J = 1 1 Hz, 1H), 3.58 (s, 3H), 3.78 (d, J = 6 Hz, 2H), 3.8-3.9 (m, 1H), 4.22 (d, J = 12 Hz, 1H), 4.37 (d, J = 13 Hz, 1H), 5.47 (s, 1H), 7.02 (s, 1H), 7.4-7.5 (m, 2H), 7.80 (d, J = 7 Hz, 1H), 8.85 (s, 1H), 12.72 (s, 1H). ES (+) MS m/z = 355 (M+l).
[0236] Example 81 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(quinolin-
8-ylamino)acetamide).
Figure imgf000095_0001
The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for quinolin-8-amiriQ.1H NMR (400 MHz, DMSO-<¾) δ 1.4-1.6 (m, 2H), 1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 3.09 (t, J= 11 Hz, 1H), 3.18 (t, J= 11 Hz, 1H), 3.7-3.9 (m, 3H), 4.35 (d, J= 13 Hz, 1H), 4.46 (d, J= 13 Hz, 1H), 6.48 (d, J = 7 Hz, 1H), 6.62 (s, 1H), 7.08 (d, J = 8 Hz, 1H), 7.13 (s, 1H), 7.32 (t, J = 8 Hz, 1H), 7.49 (s, 1H), 8.06 (s, 1H), 8.19(d,J=8Hz, 1H), 8.74 (s, 1H), 11.62 (s, 1H). ES (+) MS mz = 402 (M+l).
[0237] Example 82 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-
(trifluoromethylthio)phenylamino)acetamide).
Figure imgf000095_0002
The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-(trifluoromethylthio)aniline.1H NMR (400 MHz, DMSO-i¼) δ 1.4-1.6 (m, 2H), 1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 3.07 (t, J= 10 Hz, 1H), 3.18 (t, J = 11 Hz, 1H), 3.6-3.7 (m, 2H), 3.7-3.8 (m, 1H), 4.33 (d,J= 13 Hz, 1H), 4.41 (d,J= 13 Hz, 1H), 6.36 (s, 1H), 6.58 (s, 1H), 6.71 (d,J=8Hz, 1H), 6.9-6.9 (m, 2H), 7.11 (s, 1H), 7.17 (t, J= 7 Hz, 1H), 8.02 (d,J=7Hz, 1H), 8.07 (s, 1H), 11.63 (s, 1H). ES (+) MS mz = 451 (M+l).
[0238] Example 83 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3- morpholinophenylamino)acetami
Figure imgf000095_0003
The title compound of Example 83 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 3-morpholinoaniline.1H NMR (400 MHz, CD3OD) δ 1.4-1.6 (m, 2H), 1.7-1.8 (m, 1H), 18-1.9 (m, 1H), 2.97 (s, 4H), 3.1-3.3 (m, 2H), 3.68 (s, 2H), 3.70 (s, 4H), 3.75 (s, 1H), 4.30 (d, J= 14 Hz, 1H), 4.39 (d, J= 13 Hz, 1H), 6.00 (d, J = 8 Hz, 1H), 6.08 (s, 1H), 6.17 (d, J= 8 Hz, 1H), 6.57 (s, 1H), 6.88 (t, J= 8 Hz, 1H), 7.09 (s, 1H), 7.86 (d, J= 7 Hz, 1H), 8.06 (s, 1H). ES (+) MS m/z = 436 (M+l).
[0239] Example 84 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2,3- dimethylphenylamino)acetamide).
Figure imgf000096_0001
The title compound of Example 82 was prepared in similar manner as described in Example 16 except N-methylaniline was substituted for 2,3-dimethyloaniline.1H NMR (400 MHz, DMSO- i/ff) δ 1.4-1.6 (m, 2H), 1.7-1.9 (m, 2H), 1.97 (s, 3H), 2.15 (s, 3H), 3.11 (t,J= 10 Hz, 1H),3.20(t, J= 10 Hz, 1H), 3.63 (s, 2H), 3.74 (s, 1H), 4.29 (d, J= 12 Hz, 1H), 4.87 (d, J= 13 Hz, 1H), 6.18 (d, J= 8 Hz, 1H), 6.44 (d, J= 7 Hz, 1H), 6.58 (s, 1H), 6.83 (t, J= 8 Hz, 1H), 7.13 (s, 1H), 7.87 (d,J=6Hz, 1H), 8.07 (s, 1H), 11.64 (s, 1H). ES (+) MS mz = 379 (M+l).
Example 85 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-methyl-2- (phenylamino)acetamide)
Figure imgf000096_0002
[0240] tert-Bu yX methyl(l -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate. The tert-bvAyX l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- ylcarbamate intermediate (0.28 g, 0.6 mmol) synthesized from the corresponding 4-chloro-7- tosyl-7H-pyrrolo[2,3-d]pyrimidine and tert-bvXyX piperidin-3 -ylcarbamate in a similar fashion as described in example 155 was dissolved in DMF (3 mL) was added NaH (26 mg, 0.66 mmol), and the reaction mixture was stirred at rt for 30 min. The solution was treated with Mel (0.1 g, 46 uL, 0.72 mmol) and allowed to stir at rt for 30 min. The reaction was quenched by adding several drops of sat. aq. NH4CI and then concentrated in vacuo to afford a residue. The residue was suspended in sat. aq. NaHC03 (20 mL) and extracted with CH2CI2 (3 x 20 mL). The organic phases were combined, dried (Na2S04), and concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, gradient EtOAc in hexane) to afford 85.1 which was used without further purification.
Note: The tert-bvAyX l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate intermediate was synthesized from the corresponding 4-chloro-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine and te/ -butyl piperidin-3-ylcarbamate in a similar fashion as described in example 155.
[0241] N-methyl-2-(phenylamino)-N-(l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acetamide. A solution of tert-bvAyX methyl(l -(7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperidin-3-yl)carbamate (0.2 g, 0.4 mmol) in 4.0 N C1 in dioxane (4 mL) was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo to afford the amine, which was used without further purification. To a solution of EDCI (68 mg, 0.44 mmol), HOBt (59 mg, 0.44 mmol), and DIEA (23 mg, 29 uL, 3.0 mmol) in DMF (2 mL) was added 2- (Phenylamino)acetic acid (60 mg, 0.4 mmol). The solution was stirred at rt for 4 h and concentrated in vacuo to afford a residue, which was purified by column chromatography (gradient EtOAc in hexane) to afford 85.3 which was used without further purification.
[0242] (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-methyl-2- (phenylamino)acetamide). A mixture of N-methyl-2-(phenylamino)-N-(l-(7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide (77 mg, 0.15 mmol), K2C03 (103 mg, 0.75 mmol), MeOH (2 mL) and water (0.5 mL) was stirred at 65 °C overnight. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc and washed with water and separated, and the organic phase was concentrated in vacuo. The crude material was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford the title final product. 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.33 (s, 1H), 7.40 (s, 1H), 7.07 -7.1 1 (m, 2H), 6.86 (m, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.55-6.62 (m, 2H), 4.40-4.57 (m, 2H), 3.94 (m, 3H), 3.16-3.52 (m, 2H), 3.00 (s, 3H), 2.87 (s, 1H), 1.88-2.00 (m, 2H), 1.64-1.77 (m, 2H) ppm. EIMS (m/z): calcd. for C2oH24 60 (M++l) 365.2, found 365.0.
Example 86 (N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-benzyl-2- (phenylamino)acetamide)
Figure imgf000098_0001
[0243] l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-one. A mixture of 4- chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.32 mmol) (synthesized as describe by Cox, P. J.; Majid, T.; Amendola, S.; Deprets, S. D.; Edlin, C; Pedgrift, B.; Halley, F.; Edwards, M.; Baudoin, B., Mclay, L; Aldous, D. J. PCT Int. Appl. (2003), 66 pp. WO 2003000695), piperidin-3-one (32 mg, 0.32 mmol) and Et3N (90 μί, 0.64 mmol) in DMF (4 mL) was heated at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with aq. citric acid and aq. NaHC03, dried ( a2S04), filtered and concentrated in vacuo to afford a residue which was purified by chromatography (silica gel, gradient EtOAc in hexanes) to afford 86.2.
[0244] N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. To a solution of l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-one (75 mg, 0.2 mmol) and benzylamine (25 \L, 0.22 mmol) in MeOH (3 mL) was added AcOH (20 \L, 0.4 mmol) and NaBH3CN (32 mg, 0.5 mmol). The solution was stirred at rt for 16 hr after which time the solvent was removed in vacuo to afford a residue which was diluted with water and extracted with EtOAc. The organic phase was separated, washed with aq. NaHC03 and water, dried ( a2S04) and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes). EIMS (m/z): calcd. for C25H27 502S (M++l) 462.2, found 462.2.
[0245] N-benzyl-2-(phenylamino)-N-(l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)acetamide. To a solution of N-phenylglycine (29 mg, 0.2 mmol), HATU (75 mg, 0.2 mmol), Et3N (50 μί, 0.4 mmol) in DMF (3 mL) was added N-benzyl-l -(7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (90 mg, 0.2 mmol). After stirring at rt for 4 h, the solution was diluted with EtOAc and washed with water, aq. citric acid and aq. NaHC03. The organic phase was dried ( a2S04), filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the title compound.
[0246] (N-( 1 -(7H-pyrrolo [2,3 -d]pyrimidin-4-yl)piperidin-3 -y l)-N-benzy 1-2-
(phenylamino)acetamide). A solution of N-benzyl-2-(phenylamino)-N-(l-(7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide (65 mg, O. l lmmol) and K2C03 (76 mg, 0.55 mmol in MeOH (3 mL) and water (1 mL) was heated to 65 °C. The solution was concentrated to afford a residue which was dissolved in water and EtOAc. The organic phase was collected, washed with water and aq. NaHC03, separated, dried ( a2S04) and concentrated in vacuo to afford a residue which was purified by reversed phase chromatography yielding 25 mg, 52% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 12.05 Hz, 1H), 7.41 (d, J = 7.28 Hz, 1H), 7.24 - 7.38 (m, 2H), 7.22 - 7.24 (m, 1H), 7.13 - 7.21 (m, 2H), 7.00 - 7.13 (m, 2H), 6.65 (d, J = 8.03 Hz, 2H), 6.42 - 6.61 (m, 2H), 5.62 - 5.69 (m, 1H), 4.49 - 4.72 (m, 2H), 4.19 - 4.29 (m, 2H), 3.87 - 4.06 (m, 2H), 2.96 - 3.20 (m, 2H), 2.80 - 2.95 (m, 1H), 1.81 (br. s., 2H), 1.42 - 1.68 (m, 1H). EIMS (m/z): calcd. for
Figure imgf000099_0001
(M++l) 441.2, found (M+ + 1) = 441.3.
[0247] Examples 87-89 were prepared according to Example 86 above.
Figure imgf000100_0001
[0248] Example 87 (TSi-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-phenethyl-
2-(phenylamino)acetamide). Compound 87 was prepared according to the procedure of Scheme 4 using phenethylamine in place of benzylamine . 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 12.04 Hz, 1H), 7.23 - 7.38 (m, 5H), 7.00 - 7.13 (m, 2H), 6.89 - 6.97 (ddd, J = 7.65, 7.78, 15.18 Hz, 3H), 6.41 - 6.68 (m, 2H), 5.54 - 5.73 (m, 1H), 4.52 - 4.82 (m, 2H), 3.94 (dd, J = 5.15, 16.94 Hz, 2H), 3.53 - 3.75 (m, 2H), 2.97 - 3.20 (m, 2H), 1.71 - 1.95 (m, 4H), 1.44 - 1.67 (m, 2H). EIMS (m/z): calcd. for C27H30N6O (M++l) 455.2, found (M+ + 1) = 455.3.
[0249] Example 88 (N-(l -(7H-pjrro/o[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-
(cyclohexylmethyl)-2-(phenylamino)acetamide).
Figure imgf000100_0002
The title compound was prepared according to the above procedure using cyclohexylmethylamine in place of benzylamine. 1H NMR (400 MHz, DMSO-i¾) δ 8.13 (d, J = 12.05 Hz, 1H), 7.23 - 7.38 (m, 2H), 6.89 - 6.97 (ddd, J = 7.68, 7.76, 15.15 Hz, 3H), 6.42 - 6.61 (m, 2H), 6.26 (br.s., 1H), 3.94 (dd, J = 5.15, 16.94 Hz, 2H), 3.53 - 3.75 (m, 2H), 2.96 - 3.20 (m, 4H), 2.80 - 2.95 (m, 4H), 1.71 - 1.95 (m, 4H), 1.41 - 1.69 (m, 8H). EIMS (m/z): calcd. for C26H34N6O (M++l) 447.4, found (M+ + 1) = 447.4.
[0250] Example 89 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-N-(2-
(dimethylamino)ethyl)-2-(phenylamino)acetamide).
Figure imgf000101_0001
The title compound was prepared according to the above procedure using N,N-dimethyl- 1 ,2- ethanediamine in place of benzylamine. H NMR (400 MHz, DMSO-d6) d 8.1 1 (d, J = 12.03 Hz, 1H), 7.22 - 7.40 (m, 2H), 6.90 - 6.99 (ddd, J = 7.63, 7.75, 15.20 Hz, 3H), 6.24 (br.s., 1H), 3.97 (dd, J = 5.15, 16.94 Hz, 2H), 3.53 - 3.75 (m, 4H), 2.96 - 3.20 (m, 4H), 2.26 (s, 4H) 1.71 - 1.95 (m, 3H), 1.42 - 1.68 (m, 4H). EIMS (m/z): calcd. for C23H31N7O (M++l) 422.4, found (M+ + 1) = 422.4.
[0251] Example 92 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-2-chlorobenzamide).
Figure imgf000101_0002
N-(l-(7H-pyrrolo[2,3-d]pyrimidiii-4-yl)piperidin-3-yl)-2-aminoacetamide. To a solution of 2-(ter£-butoxycarbonylamino)acetic acid (0.7 g, 4 mmol), HATU (1.5 g, 4 mmol), Et3N (1.1 mL, 4 mmol) in DMF (60 mL) was added N-benzyl-1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3 -amine (1.8 g, 40 mmol). After stirring at RT for 4 h, the solution was diluted with EtOAc and washed with water, aq. citric acid and aq. NaHC03. The organic phase was dried ( a2S04), filtered and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to a solid. The Boc protected amine was dissolved in 1 ,4-dioxane (10 mL) and treated with 4 N C1 (10 equiv.) at rt for 5 h. The solvent was concentrated in vacuo to afford N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- aminoacetamide as a solid which was used without any additional purification.
(N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2-oxoethyl)-2- chlorobenzamide). To a solution of N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- aminoacetamide (0.25 mmol) in DMF (3 mL) can be added 2-chlorobenzoic acid (0.25 mmol), HOBt (0.25 mmol), EDCI (0.25 mmol), and DIEA (0.50 mmol) in DMF (3 mL). The reaction mixture can be stirred at RT overnight. The reaction mixture can be concentrated in vacuo and the residue purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1 % TFA to afford the title compound 92. 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.55 (d, 1H), 7.47(s, 2H), 7.37 (m, 2H), 6.62 (m, 1H), 7.12 (d, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.08 (m, 1H), 4.00 (s, 2H), 3.75-3.65 (m, 2H), 2.15-2.04 (m, 2H), 1.82 (m, 2H). EIMS (m/z): calcd. for
Figure imgf000102_0002
(M+)+l 414.4.
[0252] Examples 93-99 were prepared according to the method outlined in example 92 above.
[0253] Example 93 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-3-chlorobenzamide).
Figure imgf000102_0003
The title compound of Example 93 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 3-chlorobenzoic acid. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.85 (s, 1H), 7.77(d, 2H), 7.75(d, 1H), 7.56 (d, 1H), 7.47 (m, 2H), 7.34(s, 1H), 7.10 (d, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.31 (m, 1H), 4.01 (d, 2H), 3.75-3.65(m, 2H), 2.15-2.04 (m, 2H), 1.82 (m, 2H). EIMS (m/z): calcd. for C19H23CIN6O2 (M+)+l 414.4.
[0254] Example 94 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-4-chlorobenzamide).
Figure imgf000103_0001
The title compound of Example 94 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 4-chlorobenzoic acid. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.84 (d, 2H), 7.50 (d, 2H), 7.34 (s, 1H), 7.10 (s, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.31 (m, 1H), 4.01(d, 2H), 3.75-3.65 (m, 2H), 2.15-2.04 (m, 2H), 1.82 (m, 2H). EIMS (m/z): calcd. for C19H23CIN6O2 (M+)+i 414.4.
[0255] Example 95 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-4-ieri-butylbenzamide)
Figure imgf000103_0002
The title compound of Example 95 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 4-ieri-butylbenzoic acid.1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.78 (d, 2H), 7.51 (d, 2H), 7.34 (s, 1H), 7.10 (s, 1H), 4.54 (d, 1H), 4.30 (d, 1H), 4.31 (m, 1H), 4.01 (d, 2H), 3.75-3.65(m, 2H), 2.15-2.04(m, 2H), 1.82 (m, 2H). EIMS (m/z): calcd. for C24H30N6O2 (M+)+l 435.4.
[0256] Example 96 (N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(2- phenylacetamido)acetamide).
Figure imgf000104_0001
The title compound of Example 96 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 2-phenylacetic acid. 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 7.26-7.22 (m, 6H), 7.15 (s, 1H), 7.01 (s, 1H), 4.42 (d, 1H), 4.25 (d, 1H), 3.95 (m, 1H), 3.72 (d, 2H), 4.00 (s, 2H), 3.48 (d, 2H), 3.51-3.42 (m, 2H), 2.05-1.89 (m, 2H), 1.71-1.65 (m, 2H). EIMS (m/z): calcd. for C21H24N6O2 (M+)+i 394.5.
[0257] Example 97 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)- 1 -naphthamide) .
Figure imgf000104_0002
The title compound of Example 97 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 1 -naphthoic acid. 1H NMR (400 MHz, CD3OD) δ 8.32 (d, 1H), 8.26 (s, 1H), 7.98 (d, 1H), 7.90 (s, 1H), 7.71 (d, 2H), 7.53-7.62 (m, 3H), 7.33 (s, 1H), 7.12 (s, 1H), 4.55 (d, 1H), 4.33 (d, 1H), 4.09 (s, 2H), 3.71 -3.63 (m, 2H), 2.14-2.03 (m, 2H), 1.84-1.80 (m, 2H). EIMS (m/z): calcd. for C24H24 602 (M +1) 429.6.
[0258] Example 98 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)-2-naphthamide) .
Figure imgf000104_0003
The title compound of Example 98 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for 2-naphthoic acid. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.27 (s, 1H), 8.00-7.90 (m, 6H), 7.60(m, 2H), 7.32 (s, 1H), 7.12 (s, 1H), 4.55 (d, 1H), 4.33 (d, 1H), 4.07 (d, 2H), 3.71-3.63 (m, 2H), 2.14-2.03 (m, 2H), 1.84-1.80 (m, 2H). EIMS (m/z): calcd. for C24H24N6O2 (M +1) 429.6.
[0259] Example 99 (N-(2-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylamino)-2- oxoethyl)cyclohexanecarboxamide).
Figure imgf000105_0001
The title compound of Example 98 was prepared in similar manner as described in Example 92 except 2-chlorobenzoic acid was substituted for cyclohexanecarboxylic acid. 1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 4.51(d, 1H), 4.34 (d, 1H), 4.02 (s, 2H), 3.78 (d, 2H), 3.67-3.57 (m, 2H), 2.25-2.20 (m, 1H), 2.05- 1.89 (m, 2H), 1.82-1.79 (m, 8H), 1.71- 1.68 (m, 2H), 1.14-1.26 (m, 4H). EIMS (m/z): calcd. for C20H28N6O2 (M +1) 386.5.
Example 100. ((R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- (phen lamino)propanamide)
Figure imgf000105_0002
[0260] (R)-2-(phenylamino)propanoic acid. A solution of (R)-2-aminopropanoic acid
(89 mg, 1 mmol), iodobenzene (203 mg, 1.0 mmol), CS2CO3 (0.65 g, 2 mmol), and Cul (7 mg, 0.04 mmol) in DMF (2mL) can be heated at 90 °C for 12 h under an atmosphere of nitrogen. The solution can be cooled to rt and diluted with EtOAc-water (2: 1 , 15 mL) and adjusted to pH 3-5 by added concentrated C1 . The organic layer can be separated, washed with brine, dried (Na2SC>4), filtered, and concentrated in vacuo to afford the title intermediate as an oil, which can be used without further purification. [0261] ((R)-N-((R)- l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- (phenylamino)propanamide). To a solution of (R)-2-(phenylamino)propanoic acid (49 mg, 0.3 mmol) and (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (65 mg, 0.3 mmol) in DMF (2 mL) was added DIEA (1 16 mg, 156 uL, 0.9 mmol), EDCI (50 mg, 0.33 mmol), and HOBt (44 mg, 0.33 mmol). The resulting solution was then stirred at rt for 1 h. The solvent was removed in vacuo to afford a residue, which was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1 % TFA to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 1.39 (d, J = 6.85 Hz, 3 H), 1.73 (m, 3 H), 1.96 (d, J = 6.36 Hz, 1 H), 3.58 (m, 2 H), 3.77 (d, J = 6.85 Hz, 1 H), 3.95 (s, 1 H), 4.10 (m, 2 H), 6.53 (d, J = 7.83 Hz, 2 H), 6.62 (m, 2 H), 7.04 (t, J = 7.34 Hz, 2 H), 7.10 (s, 1 H), 8.05 (s, 1 H). EIMS (m/z): 364 (M+l).
[0262] Examples 101 -132 were prepared according to the method outlined in example
100 above.
[0263] Example 101 ((2R)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)propanamide) .
Figure imgf000106_0001
The title compound of Example 101 was prepared in similar manner as described in Example 100 except (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine was substituted for 1 -(7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine. 1H NMR (400 MHz, CD3OD) δ 1.40 (d, J = 7.34 Hz, 3 H), 1.77 (s, 2 H), 2.01 (m, 2 H), 3.68 (d, J = 9.29 Hz, 2 H), 3.84 (m, 1 H), 3.99 (d, J = 22.01 Hz, 1 H), 4.22 (m, 2 H), 6.60 (m, 2 H), 6.69 (t, J = 7.09 Hz, 1 H), 6.97 (d, J = 10.76 Hz, 1 H), 7.05 (m, 2 H), 7.34 (d, J = 18.10 Hz, 1 H), 8.23 (d, J = 1 1.74 Hz, 1 H). EIMS (m/z): 364 (M+l).
[0264] Example 102 ((2S)-N-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)propanamide) .
Figure imgf000107_0001
The title compound of Example 102 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (S)-2-aminopropanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.41 (d, J = 6.85 Hz, 3 H), 1.78 (m, 2 H), 1.94 (m, 2 H), 3.71 (m, 2 H), 3.81 (m, 1 H), 4.04 (m, 1 H), 4.28 (m, 2 H), 6.52 (m, 2 H), 6.63 (t, J = 7.34 Hz, 1 H), 7.00 (m, 3 H), 7.35 (d, J = 20.54 Hz, 1 H), 8.23 (d, J = 12.23 Hz, 1 H). EIMS (m/z): 364 (M+l).
[0265] Example 103 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- methyl-2-(phenylamino)butanamide).
Figure imgf000107_0002
The title compound of Example 103 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-methyl-2-aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.20 (s, 2 H), 0.36 (s, 1 H), 0.51 (d, J = 20.05 Hz, 2 H), 2.00 (m, 1 H), 2.10 (s, 1 H), 2.46 (s, 1 H), 2.61 (d, J = 13.69 Hz, 1 H), 2.73 (d, J = 13.21 Hz, 1 H), 5.03 (m, 3 H), 5.44 (m, 3 H), 5.80 (s, 1 H), 6.64 (s, 1 H). EIMS (m/z): 393 (M+l).
[0266] Example 104 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- phenyl-2-(phenylamino)propanamide)
Figure imgf000107_0003
The title compound of Example 104 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-phenyl-2-aminopropanoic acid. 1H MR (400 MHz, CD3OD) δ 1.67 (m, 2 H), 1.87 (d, J = 13.69 Hz, 1 H), 1.96 (d, J = 8.31 Hz, 1 H), 3.08 (d, J = 6.85 Hz, 2 H), 3.56 (t, J = 10.52 Hz, 1 H), 3.94 (s, 1 H), 4.09 (t, J = 7.09 Hz, 2 H), 4.21 (d, J = 12.23 Hz, 2 H), 6.59 (d, J = 7.83 Hz, 1 H), 6.66 (t, J = 6.85 Hz, 1 H), 6.97 (d, J = 2.93 Hz, 1 H), 7.04 (t, J=7.58 Hz, 2 H), 7.20 (s, 1 H), 7.27 (d, J = 3.42 Hz, 5 H), 7.39 (s, 1 H), 8.23 (s, 1 H). EIMS (m/z): 440 (M+l).
[0267] Example 105 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-4- methyl-2-(phenylamino)pentanamide
Figure imgf000108_0001
The title compound of Example 105 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-4-methyl-2-aminopentanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.89 (dd, J = 28.37, 6.36 Hz, 6 H), 1.57 (s, 2 H), 1.72 (m, 3 H), 1.97 (m, 2 H), 3.75 (m, 3 H), 4.03 (m, 2 H), 4.18 (d, J = 13.21 Hz, 1 H), 6.58 (d, J = 7.83 Hz, 1 H), 6.67 (t, J = 7.34 Hz, 1 H), 6.94 (s, 1 H), 7.03 (t, J = 7.34 Hz, 3 H), 7.35 (s, 1 H), 8.20 (s, 1 H). EIMS (m/z): 407 (M+l).
[0268] Example 106 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- phenyl-2-(phenylamino)acetamide).
Figure imgf000108_0002
The title compound of Example 106 was prepared in similar manner as described in Example
100 except (R)-2-aminopropanoic acid was substituted for (R)-2-phenyl-2-aminoacetic acid. H NMR (400 MHz, CD3OD) δ 1.64 (dd, J = 8.56, 3.18 Hz, 1 H), 1.77 (dd, J = 20.05, 8.31 Hz, 3 H), 1.97 (d, J = 6.85 Hz, 1 H), 3.49 (dd, J = 12.96, 7.58 Hz, 1 H), 3.59 (m, 1 H), 3.95 (s, 1 H), 4.08 (t, J = 1 1.98 Hz, 2 H), 6.54 (m, 1 H), 6.63 (m, 3 H), 7.05 (m, 3 H), 7.27 (d, J = 5.87 Hz, 3 H), 7.41 (d, J = 6.85 Hz, 2 H), 8.03 (s, 1 H). EIMS (m/z): 427 (M+l).
[0269] Example 107 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(phenylamino)acetamid
Figure imgf000109_0001
The title compound of Example 107 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-cyclopropyl-2-aminoacetic acid. 1H NMR (400 MHz, CD3OD) δ 0.35 (dd, J = 9.29, 4.89 Hz, 1 H), 0.49 (m, 2 H), 0.64 (d, J = 4.40 Hz, 1 H), 1.14 (m, 1 H), 1.75 (m, 2 H), 1.97 (m, 2 H), 3.14 (d, J = 8.80 Hz, 1 H), 3.67 (m, 2 H), 4.00 (s, 1 H), 4.15 (d, J = 13.21 Hz, 1 H), 4.29 (d, J = 13.21 Hz, 1 H), 6.71 (d, J = 7.83 Hz, 2 H), 6.80 (t, J = 7.34 Hz, 1 H), 6.99 (d, J = 2.93 Hz, 1 H), 7.1 1 (t, J = 7.58 Hz, 2 H), 7.36 (d, J = 2.93 Hz, 1 H), 8.23 (s, 1 H). EIMS (m/z): 391 (M+l).
[0270] Example 108 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-
3 ,3 -dimethyl-2-(phenylamino)butanamide) .
Figure imgf000109_0002
The title compound of Example 108 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3,3-dimethyl-2-aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.04 (d, J = 22.99 Hz, 9 H), 1.77 (m, 2 H), 1.99 (m, 2 H), 3.50 (dd, J = 12.47, 9.05 Hz, 1 H), 3.61 (m, 2 H), 4.01 (s, 1 H), 4.25 (d, J =13.21 Hz, 1 H), 4.37 (d, J =13.21 Hz, 1 H), 6.64 (d, J =7.83 Hz, 3 H), 7.04 (m, 3 H), 7.38 (s, 1 H), 8.24 (s, 1 H). EIMS (m/z): 407 (M+l). [0271] Example 109 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclohexyl-2-(phenylamino)acetamide
Figure imgf000110_0001
The title compound of Example 109 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-cyclohexyl-2-aminoacetic acid. 1H NMR (400 MHz, CD3OD) δ 1.19 (m, 5 H), 1.70 (m, 7 H), 1.96 (m, 3 H), 3.64 (m, 2 H), 3.73 (m, 1 H), 4.01 (s, 1 H), 4.14 (d, J =13.21 Hz, 1 H), 4.26 (d, J =13.21 Hz, 1 H), 6.64 (m, 3 H), 6.97 (d, J =2.45 Hz, 1 H), 7.04 (t, J =7.34 Hz, 2 H), 7.37 (d, J =2.93 Hz, 1 H). EIMS (m/z): 433 (M+l).
[0272] Example 1 10 ((2R,3R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-hydroxy-2-(phenylamino)butanamide).
Figure imgf000110_0002
The title compound of Example 1 10 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3R)-3-hydroxy-2-aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.26 (d, J = 6.36 Hz, 3 H), 0.74 (m, 3 H), 0.98 (d, J = 6.36 Hz, 1 H), 2.52 (m, 2 H), 2.77 (d, J = 4.40 Hz, 1 H), 2.99 (s, 1 H), 3.18 (m, 2 H), 5.65 (m, 4 H), 6.10 (m, 3 H), 7.06 (s, 1 H). EIMS (m/z): 395 (M+l).
[0273] Example 1 1 1 ((2R,3S)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-hydroxy-2-(phenylamino)butanamide).
Figure imgf000111_0001
The title compound of Example 1 1 1 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3S)-3-hydroxy-2-aminobutanoic acid. 'H NMR (400 MHz, CD3OD) δ 1.23 (d, J = 6.36 Hz, 3 H), 1.73 (d, J = 5.87 Hz, 2 H), 1.88 (s, 1 H), 1.96 (d, J = 10.27 Hz, 1 H), 3.71 (m, 3 H), 4.01 (s, 1 H), 4.10 (d, J = 13.21 Hz, 1 H), 4.17 (m, 1 H), 4.25 (d, J =13.21 Hz, 1 H), 6.71 (d, J = 7.83 Hz, 2 H), 6.79 (t, J = 7.34 Hz, 1 H), 6.94 (s, 1 H), 7.10 (t, J = 7.34 Hz, 2 H), 7.33 (s, 1 H), 8.21 (s, 1 H). EIMS (m/z): 395 (M+l).
[0274] Example 1 12 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chlorophenylamino)-3-methylbutanamide).
Figure imgf000111_0002
The title compound of Example 1 12 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3-methyl-2-aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.01 (dd, J = 17.36, 6.60 Hz, 6 H), 1.77 (m, 2 H), 1.96 (s, 1 H), 2.05 (m, 2 H), 3.54 (m, 2 H), 3.63 (d, J = 10.27 Hz, 1 H), 4.02 (s, 1 H), 4.20 (d, J =12.72 Hz, 1 H), 4.31 (d, J = 12.72 Hz, 1 H), 6.46 (d, J = 8.31 Hz, 1 H), 6.53 (d, J = 7.83 Hz, 1 H), 6.57 (s, 1 H), 6.94 (m, 3 H), 7.32 (s, 1 H), 8.22 (s, 1 H) ppm. EIMS (m/z): 427 (M+l).
[0275] Example 1 13 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3,5-dichlorophenylamino)-3-hydroxy-3-methylbutanamide).
Figure imgf000111_0003
The title compound of Example 1 13 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-3 -hydro xy-3-methyl-2- aminobutanoic acid. 1H NMR (300 MHz, MeOD) δ 8.17 (s, 1H), 8.12 (s, 1H), 7.24 (d, J = 3.78 Hz, 1H), 7.14 (d, J = 3.40 Hz, 1H), 6.91 (d, J = 3.40 Hz, 1H), 6.78 (d, J = 3.78 Hz, 1H), 6.47 (s, 1H), 6.43 (d, J = 1.51 Hz, 2H), 6.35 (d, J = 1.89 Hz, 3H), 4.26 (dd, J = 3.21 , 13.41 Hz, 1H), 4.02 - 4.18 (m, 2H), 3.81 - 4.02 (m, 5H), 3.58 - 3.72 (m, 6H), 1.62 - 1.82 (m, 5H), 1.21 (s, 6H). EIMS (m/z): calcd. for C22H26CI2F 6O2 (M+H) 477, found 477.
[0276] Example 1 14 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(phenylamino)butanamide) .
Figure imgf000112_0001
The title compound of Example 1 14 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-2-aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.99 (t, J = 6.85 Hz, 3 H), 1.78 (m, 4 H), 1.90 (m, 1 H), 2.02 (s, 1 H), 3.63 (m, 3 H), 4.00 (s, 1 H), 4.1 1 (s, 1 H), 4.26 (d, J =13.21 Hz, 1 H), 6.54 (d, J = 7.34 Hz, 2 H), 6.62 (s, 1 H), 6.99 (m, 3 H), 7.34 (s, 1 H), 8.19 (s, 1 H). EIMS (m/z): calcd. for C2iH26 60 (M+H) 379, found 379 (M+H).
[0277] Example 1 15 ((2R,3S)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-methyl-2-(phenylamino)pentanamide).
Figure imgf000112_0002
The title compound of Example 1 15 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3S)-3-methyl-2-aminopentanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.75 (m, 3 H), 0.85 (t, J Hz, 1 H), 1.33 (m, 1 H), 1.63 (s, 2 H), 1.85 (m, 3 H), 3.56 (m, 3 H), 3.87 (d, J = 26.41 Hz, 2 H), 4.09 (m, 1 H), 6.46 (m, 3 H), 6.84 (m, 3 H), 7.19 (d, J = 22.01 Hz, 1 H), 8.07 (d, J = 13.21 Hz, 1 H). EIMS (m/z): 407 (M+l).
[0278] Example 1 16 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-4-
(methylsulfonyl)-2-(phenylamino)butanamide).
Figure imgf000113_0001
The title compound of Example 1 16 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (R)-4-(methylsulfonyl)-2- aminobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.81 (m, 3 H), 1.96 (m, 1 H), 2.09 (d, J = 10.27 Hz, 2 H), 2.19 (m, 1 H), 2.97 (m, 3 H), 3.23 (m, 1 H), 3.84 (m, 2 H), 3.98 (dd, J = 7.58, 4.16 Hz, 1 H), 4.05 (s, 2 H), 4.21 (d, J=13.69 Hz, 1 H), 6.57 (d, J = 8.31 Hz, 2 H), 6.64 (t, J = 6.85 Hz, 1 H), 7.03 (m, 3 H), 7.37 (s, 1 H), 8.25 (s, 1 H). EIMS (m/z): 457 (M+l).
[0279] Example 1 17 ((2R,3R)-N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-methyl-2-(phenylamino)pentanamide).
Figure imgf000113_0002
The title compound of Example 1 17 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid was substituted for (2R,3R)-2-amino-3-methylpentanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.94 (t, J = 7.34 Hz, 3 H), 0.99 (d, J = 6.85 Hz, 3 H), 1.30 (m, 1 H), 1.65 (m, 1 H), 1.78 (d, J = 4.40 Hz, 2 H), 1.87 (m, 1 H), 1.96 (m, 1 H), 2.05 (s, 1 H), 3.63 (m, 3 H), 4.04 (s, 1 H), 4.19 (d, J = 1 1.74 Hz, 1 H), 4.31 (d, J = 12.72 Hz, 1 H), 6.62 (m, 3 H), 7.02 (m, 3 H), 7.38 (d, J= 2.93 Hz, 1 H), 8.22 (s, 1 H). EIMS (m/z): 407 (M+l). [0280] Example 1 18 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamide).
Figure imgf000114_0001
The title compound of Example 1 18 was prepared in similar manner as described in Example 107 except iodobenzene was substituted for l -chloro-3-fluoro-5-iodobenzene. 1H NMR (400 MHz, CD3OD) δ 0.38 (d, J =4.40 Hz, 1 H), 0.49 (m, 2 H), 0.64 (d, J =5.38 Hz, 1 H), 1.12 (d, J =4.89 Hz, 1 H), 1.82 (t, J =8.56 Hz, 2 H), 2.02 (s, 1 H), 2.09 (d, J =13.69 Hz, 1 H), 3.06 (d, J =8.31 Hz, 1 H), 3.61 (dd, J =12.23, 9.29 Hz, 1 H), 3.72 (d, J =8.80 Hz, 1 H), 4.06 (s, 1 H), 4.22 (s, 1 H), 4.37 (d, J =13.21 Hz, 1 H), 6.18 (d, J =1 1.25 Hz, 1 H), 6.35 (m, 2 H), 7.01 (s, 1 H), 7.37 (s, 1 H), 8.27 (s, 1 H). EIMS (m/z): 443 (M+l).
[0281] Example 1 19 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chlorophenylamino)-2-cyclopropylacetamide).
Figure imgf000114_0002
The title compound of Example 1 19 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l-chloro-3-iodobenzene. 1H NMR (400 MHz, CD3OD) δ 0.36 (m, 1 H), 0.49 (s, 2 H), 0.61 (s, 1 H), 1.1 1 (d, J = 4.40 Hz, 1 H), 1.82 (m, 2 H), 1.99 (s, 1 H), 2.08 (d, J = 7.83 Hz, 1 H), 3.05 (d, J = 8.31 Hz, 1 H), 3.59 (dd, J = 12.23, 9.29 Hz, 1 H), 3.68 (d, J = 9.78 Hz, 1 H), 4.05 (s, 1 H), 4.21 (d, J = 12.23 Hz, 1 H), 4.34 (d, J =13.21 Hz, 1 H), 6.43 (d, J =8.31 Hz, 1 H), 6.55 (m, 2 H), 6.97 (m, 2 H), 7.37 (s, 1 H), 8.25 (s, 1 H). EIMS (m/z): 425 (M+l);
[0282] Example 120 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(3,5-difluorophenylamino)acetamide).
Figure imgf000115_0001
The title compound of Example 120 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3,5-difluorobenzene. 1H NMR (400 MHz, CD3OD) δ 0.36 (d, J = 3.91 Hz, 1 H), 0.48 (d, J = 5.87 Hz, 2 H), 0.62 (s, 1 H), 1.10 (s, 1 H), 1.82 (m, 2 H), 2.10 (s, 2 H), 3.05 (d, J = 8.80 Hz, 1 H), 3.62 (m, 1 H), 3.73 (m, 1 H), 4.03 (s, 1 H), 4.19 (s, 1 H), 4.35 (d, J = 13.69 Hz, 1 H), 6.07 (d, J = 8.31 Hz, 3 H), 6.99 (s, 1 H), 7.36 (s, 1 H), 8.25 (s, 1 H). EIMS (m/z): 426 (M+l).
[0283] Example 121 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(3-fluoro-5-(trifluoromethyl)phenylamino)acetamide).
Figure imgf000115_0002
The title compound of Example 121 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3-fluoro-5-trifluoromethylbenzene. 1H NMR (400 MHz, CD3OD) δ 0.38 (m, 1 H), 0.47 (s, 2 H), 0.63 (s, 1 H), 1.14 (d, J = 3.91 Hz, 1 H), 1.81 (t, J = 8.31 Hz, 2 H), 2.06 (d, J = 32.28 Hz, 2 H), 3.12 (d, J = 8.80 Hz, 1 H), 3.57 (m, 1 H), 3.67 (m, 1 H), 4.04 (s, 1 H), 4.27 (d, J = 12.23 Hz, 1 H), 4.42 (d, J = 13.21 Hz, 1 H), 6.45 (d, J = 1 1.25 Hz, 1 H), 6.56 (d, J = 8.80 Hz, 1 H), 6.65 (s, 1 H), 7.02 (s, 1 H), 7.36 (s, 1 H), 8.27 (s, 1 H). EIMS (m/z): 476 (M+l).
[0284] Example 122 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-5- methyl-2-(phenylamino)hexanamide).
Figure imgf000116_0001
The title compound of Example 122 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for (R)-2-amino-5-methylhexanoic acid. 1H NMR (400 MHz, CD3OD) δ 0.88 (t, J = 5.87 Hz, 6 H), 1.26 (m, 1 H), 1.37 (m, 1 H), 1.53 (m, 1 H), 1.73 (m, 4 H), 1.93 (s, 1 H), 2.05 (t, J = 9.78 Hz, 1 H), 4.03 (s, 1 H), 4.10 (d, J = 10.76 Hz, 1 H), 4.24 (d, J= 13.21 Hz, 1 H), 6.56 (d, J = 7.34 Hz, 1 H), 6.64 (t, J= 7.09 Hz, 1 H), 7.01 (m, 2 H), 7.37 (s, 1 H), 8.22 (s, 1 H). EIMS (m/z): 420 (M+l).
[0285] Example 123 ( -((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-4,4,4- trifluoro-2-(phenylamino)butanamide
Figure imgf000116_0002
The title compound of Example 123 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 2-amino-4,4,4-trifluorobutanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.81 (m, 2 H), 1.99 (m, 2 H), 2.60 (m, 1 H), 2.76 (m, 1 H), 3.72 (m, 2 H), 3.99 (dd, J = 9.05, 4.65 Hz, 1 H), 4.17 (m, 2 H), 4.33 (d, J = 13.21 Hz, 1 H), 6.62 (m, 3 H), 7.01 (m, 3 H), 7.32 (d, J = 26.90 Hz, 1 H), 8.23 (d, J = 7.34 Hz, 1 H). EIMS (m/z): 433 (M+l);
[0286] Example 124 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chloro-5-fluorophenylamino)-3,3-dimethylbutanamide).
Figure imgf000117_0001
The title compound of Example 124 was prepared in similar manner as described in Example 1 18 except (R)-2-amino-2-cyclopropylacetic acid that was substituted for 1 (R)-2-amino-3,3- dimethylbutanoic acid. 1H NMR (400 MHz, CD3OD) δ 1.05 (s, 9 H), 1.80 (t, J = 8.80 Hz, 2 H), 2.04 (m, 2 H), 3.53 (dd, J = 12.23, 9.29 Hz, 1 H), 3.63 (m, 2 H), 4.03 (s, 1 H), 4.31 (d, J = 12.72 Hz, 1 H), 4.44 (d, J = 13.21 Hz, 1 H), 6.34 (m, 1 H), 6.51 (s, 1 H), 7.03 (s, 1 H), 7.37 (s, 1 H), 8.15 (d, J = 6.36 Hz, 1 H), 8.28 (s, 1 H) ppm. EIMS (m/z): 459 (M+l).
[0287] Example 125 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyclopropyl-2-(3,5-dichlorophenylamino)acetamide).
Figure imgf000117_0002
The title compound of Example 125 was prepared in similar manner as described in Example 107 except iodobenzene that was substituted for l -bromo-3,5-dichlorobenzene. 1H NMR (400 MHz, CD3OD) δ 0.38 (m, 1 H), 0.50 (m, 2 H), 0.64 (d, J = 4.89 Hz, 1 H), 1.12 (s, 1 H), 1.84 (m, 2 H), 2.07 (d, J = 34.24 Hz, 2 H), 3.07 (d, J = 8.80 Hz, 1 H), 3.59 (dd, J = 12.47, 9.54 Hz, 1 H), 3.70 (m, 1 H), 4.07 (s, 1 H), 4.24 (s, 1 H), 4.39 (d, J = 13.21 Hz, 1 H), 6.48 (s, 2 H), 6.59 (s, 1 H), 7.02 (s, 1 H), 7.37 (s, 1 H), 8.28 (s, 1 H). EIMS (m/z): 460 (M+l).
[0288] Example 126 ((R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-1-
(phenylamino)cyclopropanecarboxamide).
Figure imgf000118_0001
The title compound of Example 126 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 1 1 - aminocyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.29 (s, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.41 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.55 (t, J =7.3 Hz, 1H), 6.49 (d, J = 7.8 Hz, 2H), 6.26 (br s, 1H), 4.22 (d, J = 1 1.7 Hz, 1H), 4.14 (d, J = 13.2 Hz, 1H), 3.85 (s, 1H), 3.42 (m, 2H), 1.65-1.78 (m, 4H), 1.37 (m, 2H), 0.87 (m, 2H). EIMS (m/z): calcd. for C2iH24 60 (M++l) 377.20, found 377.25
[0289] Example 127 ((R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-1-
(phenylamino)cyclopentanecarboxamide).
Figure imgf000118_0002
The title compound of Example 126 was prepared in similar manner as described in Example 100 except (R)-2-aminopropanoic acid that was substituted for 1-aminocyclopentanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.31 (s, 1H), 7.68 (d, J =7.3 Hz, 1H), 7.44 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.54 (t, J =7.1 Hz, 1H), 6.45 (d, J =7.8 Hz, 2H), 5.80 (br s, 1H), 4.24 (m, 2H), 3.82 (m, 1H), 3.21 -3.33 (m, 2H), 2.1 1 (m, 2H), 1.56-1.76 (m, 10H). EIMS (m/z): calcd. for C23H28 60 (M++l) 405.23, found 405.25
[0290] Example 128 ((R)-N-(l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- methyl-2-(phenylamino)propanamide).
Figure imgf000119_0001
The title compound of Example 126 was prepared in similar manner as described in Example 100 except 2-amino-2-methylpropanoic acid that was substituted for 1- aminocyclopentanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.33 (s, 1H), 7.80 (d, J =7.3 Hz, 1H), 7.46 (s, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.90 (s, 1H), 6.62 (m, 1H), 6.52 (m, 2H), 4.27-4.37 (m, 2H), 3.84 (m, 1H), 3.21 -3.31 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H), 1.35 (s, 3H), 1.34 (s, 3H). EIMS (m/z): calcd. for C2iH26 60 (M++l) 379.22, found 379.00.
[0291] Example 129 ((R)-N-((R)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chloro-5-fluorophenylamino)butanamide .
Figure imgf000119_0002
The title compound of Example 129 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3-chloro-5-fluorophenylamino)butanoic acid. 1H NMR (400 MHz, CD3OD) 13.7 (br.s., 1H), 9.13 (br.s., 1H), 8.27 (d, J = 12.05 Hz, 1H), 8.14 (br.s., 1H), 7.55(s, 1H), 7.26-7.34(m, 1H), 6.55-6.67( m, 1H), 6.42-6.49 (m, 1H), 3.45-3.52 (m, 1H), 2.55-2.89 (m, 4H), 1.97-2.22 (m, 2H), 1.79-1.89 (m, 2H), 1.77 ( m, 2H), 0.90 (t, J = 4.1 1 , 8.06 Hz, 3H). EIMS (m/z): calcd. for C2oH23ClFN70 (M+1H) 432.30, found 432.30.
[0292] Example 130 ((R)-N-((R)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3,5-dichlorophenylamino)butanamide).
Figure imgf000120_0001
The title compound of Example 130 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3,5-dichlorophenylamino)butanoic acid. 1H NMR (400 MHz, MeOD) 13.5 (br.s., 1H), 9.17 (br.s., 1H), 8.29 (d, J = 12.05 Hz, 1H), 8.14 (br.s., 1H), 7.55(s, 1H), 7.16-7.22(m, 1H), 6.49- 6.55( m, 1H), 6.38-6.44 (m, 1H), 3.43-3.51 (m, 1H), 2.56-2.95 (m, 4H), 1.97-2.22 (m, 2H), 1.79- 1.89 (m, 2H), 1.69- 1.77 ( m, 2H), 1.10-0.90 (t, J = 4.14, 8.08 Hz, 3H). EIMS (m/z): calcd. for C20H23CI2N7O (M+1H) 448.20, found 448.20.
[0293] Example 131 ((R)-N-((R)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)-2-
(3-chlorophenylamino)butanamide).
Figure imgf000120_0002
The title compound of Example 131 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-2-(3-chlorophenylamino)butanoic acid. 'll NMR (400 MHz, CD3OD) δ 13.4 (br.s., 1H), 9.19 (br.s., 1H), 8.39 (d, J = 12.05 Hz, 1H), 8.17 (br.s., 1H), 7.48(s, 1H), 7.28-7.37(m, 1H), 7.14- 7.22(m, 1H), 6.49-6.57( m, 1H), 6.38-6.46 (m, 1H), 3.42-3.51 (m, 1H), 2.58-2.95 (m, 4H), 1.97- 2.24 (m, 2H), 1.79-1.89 (m, 2H), 1.69-1.78( m, 2H), 1.1 1 -0.91 (t, J = 4.15, 8.04 Hz, 3H). EIMS (m/z): calcd. for C20H24CIN7O (M+1H) 414.17, found 414.3.
[0294] Example 132 ((R)-N-((R)-l -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3- cyclopropyl-2-(3,5-dichlorophenylamino)propanamide).
Figure imgf000121_0001
The title compound of Example 132 was prepared in similar manner as described in Example 139 except (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid was substituted for (R)-3-cyclopropyl-2-(3,5-dichlorophenylamino)propanoic acid. 1H NMR (400 MHz, DMSO-i¾) δ 1 1.65 (br. s., 1H), 8.23 (d, J = 7.28 Hz, 1H), 8.03 - 8.17 (m, 1H), 7.04 - 7.14 (m, 1H), 6.58 - 6.67 (m, 3H), 6.40 - 6.58 (m, 2H), 4.37 - 4.59 (m, 2H), 3.89 (q, J = 7.61 Hz, 1H), 3.63 - 3.80 (m, 1H), 3.30 (s, 1H), 3.13 (t, J = 10.54 Hz, 1H), 3.03 (dd, J = 9.79, 12.80 Hz, 1H), 1.71 - 1.92 (m, 2H), 1.32 - 1.61 (m, 3H), 0.67 - 0.89 (m, 1H), 0.30 - 0.53 (m, 2H), 0.04 - 0.21 (m, 2H). EIMS (m/z): calcd. for C23H26CI2N6O (M+1H) 473.4, found 474.4.
Example 133 (N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)-2-(oxetan-3-yl)acetamide
Figure imgf000121_0002
[0295] Oxetan-3-one. Pyridine (162 g, 2.05 mol) was added dropwise to a 10 °C solution of Cr03 (100 g, 1.02 mol) in CH2C12 (2.4 L). Reaction mixture was stirred at RT for 1 h to obtain Collin's reagent. The reaction mixture was cooled to 5 °C, and a mixture of oxetan-3-ol (13 g , 0.18 mol) in CH2C12 (300 mL) was added drop wise over 20 min. The resulting reaction mixture was stirred at 5 °C for 30 min. After the consumption of the starting material (monitored by GC), the reaction mixture was filtered through a plug of silica gel. The solvent was evaporated under reduced pressure to afford 7.2 g crude oxetan-3-one in pyridine (150 mL) as brown oil. The crude material was directly taken to the next step without purification. [0296] (Methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate). To a -70 °C stirred solution of N-benzyloxy carbonyl-(phosphono glycine trimethylester) (34.4 g 0.104 mol) under N2 was added tetra methyl guanidine (12.6 mL, 0.1 mol). The reaction mixture was further stirred at -70 °C under N2 for 1 h. Oxetan-3-one (7.2 g, 0.1 mol) was added to the reaction mixture at -70 °C, and the resulting reaction mixture was stirred at RT. After consumption of starting material (by TLC), the reaction mixture was diluted with EtOAc (200 mL) and filtered, and the solid residue was washed with EtOAc (2x 300 mL). The combined organic layers were washed with 1 % citric acid (2 x 300 mL) and brine solution (300 mL), dried over Na2SC>4, and filtered, and the solvent was removed under reduced pressure. The crude material was purified with flash chromatography (20% EtOAc/Hexane) to afford the title intermediate (10 g, 37%) as an off-white solid. 1H-NMR: (200 MHz, CDC13): δ 7.39 (s, 5H), 6.78 (bs, 1H), 5.39- 5.48 (m, 4H), 5.12 (s, 2H), 3.8 (s, 3H). [TLC system: 30% EtOAc/Hexane, Rf: 0.4].
[0297] Methyl 2-amino-2-(oxetan-3-yl)acetate. To a stirred solution of (methyl 2-
(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate) (5 g, 0.0179 mol) in MeOH:CH2Cl2 (1 : 1 , 800 mL) was added 10% Pd(OH)2 (526 mg). The reaction mixture was stirred under H2 (40 psi) at RT for 2 h. After consumption of starting material (by TLC), the reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography [3-5% MeOH-DCM] to afford the title intermediate (1.16 g, 44.6%) as a brown liquid. Ή-NMR: (200 MHz, CDC13): δ 4.74 - 4.82 (m, 2H), 4.54 - 4.67 (m, 2H), 3.87 - 3.76 (m, 3H), 3.72 (s, 3H), 3.18 - 3.23 (m, 1H). [TLC system: 10% MeOH/DCM, Rf: 0.3].
[0298] (2-Amino-2-(oxetan-3-yl)acetic acid). To a stirred solution of methyl 2-amino-2-
(oxetan-3-yl)acetate (1.2 g, 8.27 mmol) in H20 (12 mL) was added TEA (6 mL, 43.4 mmol) at 0 °C, and the resulting mixture was stirred 4 h at rt. After complete consumption of starting material (by TLC), volatile solvents were evaporated under reduced pressure to afford the crude compound. The crude material was washed with hexane and co-evaporated with CCI4 to afford the title intermediate (600 mg, 35.2%) as a white powder. 1H NMR: (500 MHz, D20): δ 4.78- 4.72 (m, 3H), 4.62 (m, 1H), 3.98 (d, J = 12.0 Hz, 1H), 3.43- 3.38 (m, 1H). Mass: 132.1 [M+ + l]. [TLC system: n.BuO: AcOH: H20 4: 1 : 1 , Rf, 0.4]. [0299] ( -((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)-2-(oxetan-3-yl)acetamide). To a solution of 2-amino-2-(oxetan-3- yl)acetic acid (0.3 mmol) and (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (0.3 mmol) in DMF (2 mL) was added DIEA (0.9 mmol), EDCI (0.33 mmol), and HOBt (0.33mmol). The resulting solution was then stirred at rt for 1 h. The solvent was removed in vacuo to afford a residue, which was purified by reverse phase chromatography Cis column and 10% acetonitrile/water containing 0.1% TFA to afford the title compound. 1H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.03 (d, J = 3.51 Hz, 1H), 6.55 (d, J = 3.51 Hz, 1H), 6.41 (t, J = 1.76 Hz, 1H), 6.37 (d, J = 1.76 Hz, 1H), 4.64 - 4.69 (m, 1H), 4.54 - 4.60 (m, 1H), 4.42 (t, J = 6.27 Hz, 1H), 4.07 (d, J = 9.29 Hz, 1H), 3.71 - 3.97 (m, 3H), 1.83 - 1.93 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H). EIMS (m/z): calcd. for C22H24C12 602 (M+1H) 475, found 475.
Example 134 ((R)-N-((R)-1-(6-amino-5-cyanopyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-5- fluorophenylamino)-2-cyclopropylacetamide)
Figure imgf000123_0001
[0300] (R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetic acid. A solution of amino acid (R)-2-amino-2-cyclopropylacetic acid (1 mmol), l -bromo-3-chloro-5-fluorobenzene (1 mmol), Cs2C03 (2 mmol), and Cul (0.04 mmol) in DMF (2 mL) can be heated at 90 °C for 12 h under an atmosphere of nitrogen. The solution can be cooled to rt, diluted with EtOAc-water (2: 1 , 15 mL), and adjusted to a pH 3-5 with 1 N C1 . The organic layer can be separated, washed with brine, dried ( a2S04), and concentrated in vacuo to afford the title intermediate as an oil, which can be used without further purification.
[0301] (R)-teri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate. To a solution of (R)-2-(3-chloro-5- fluorophenylamino)-2-cyclopropylacetic acid (0.3 mmol) and (R)-iert-butyl 3-aminopiperidine- 1-carboxylate (0.3 mmol) in DMF (2 mL) can be added DIEA (0.9 mmol), EDCI (0.33 mmol), and HOBt (0.33mmol). The resulting solution can then be stirred at RT for 1 h. The solvent can be removed in vacuo to afford a residue, which can be purified by column chromatography (silica gel, gradient EtOAc in hexane) to afford the title intermediate.
[0302] ((R)-N-((R)-1-(6-amino-5-cyanopyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro-5- fluorophenylamino)-2-cyclopropylacetamide) To a solution of (R)-ieri-butyl 3-((R)-2-(3-chloro- 5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate (0.3 mmol) in 1 ,4- dioxane (1 mL) can be added 4 N C1 in dioxane (2 mL). The solution can be stirred for 1 h with the solvent concentrated in vacuo to afford a solid, which can be used without further purification. The solid can be dissolved in DMF (4 mL), treated with DIEA (6 mmol) and 4- amino-6-chloropyrimidine-5-carbonitrile (1 mmol), and heated to 100 °C for 4 h. The solution can be cooled to RT, diluted with water, and extracted with EtOAc, and the organic phase can be dried ( a2S04), filtered, and concentrated in vacuo to afford an oil, which can be purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1 % TFA to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 0.37 (d, J = 3.91 Hz, 1 H), 0.55 (m, 2 H), 0.63 (m, 1 H), 1.15 (m, 1 H), 1.77 (t, J = 7.58 Hz, 2 H), 1.99 (d, J = 26.90 Hz, 2 H), 3.05 (d, J = 8.80 Hz, 1 H), 3.75 (dd, J = 12.47, 7.09 Hz, 2 H), 3.98 (s, 1 H), 4.16 (m, 2 H), 6.18 (d, J = 1 1.74 Hz, 1 H), 6.37 (d, J = 14.18 Hz, 2 H), 8.1 1 (s, 1 H). EIMS (m/z): 444 (M+l).
[0303] Example 135 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-1-(7- oxo-5,6,7, 8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000124_0001
The title compound of Example 135 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-5,6- dihydropyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CD3OD) δ 0.38 (d, J = 3.91 Hz, 1 H), 0.58 (m, 3 H), 0.64 (m, 1 H), 1.14 (d, J = 3.91 Hz, 1 H), 1.74 (d, J = 6.85 Hz, 2 H), 1.94 (m, 2 H), 2.60 (m, 2 H), 2.88 (t, J = 7.09 Hz, 2 H), 3.04 (d, J = 8.80 Hz, 1 H), 3.17 (dd, J = 12.47, 8.07 Hz, 1 H), 3.67 (m, 2 H), 4.01 (s, 1 H), 6.20 (d, J = 1 1.25 Hz, 1 H), 6.36 (d, J = 14.18 Hz, 2 H), 8.30 (s, 1 H). EIMS (m/z): 473 (M+l).
[0304] Example 136 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-l -(7- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000125_0001
The title compound of Example 136 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-7-methyl- 7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400 MHz, CD3OD) δ 0.37 (s, 1 H), 0.50 (m, 2 H), 0.64 (s, 1 H), 1.13 (d, J = 5.38 Hz, 1 H), 1.82 (m, 2 H), 2.08 (m, 2 H), 3.06 (d, J = 8.80 Hz, 1 H), 3.56 (dd, J = 12.72, 8.80 Hz, 1 H), 3.68 (d, J = 8.80 Hz, 1 H), 3.89 (s, 3 H), 4.07 (m, 2 H), 4.30 (d, J = 13.69 Hz, 1 H), 6.17 (d, J = 1 1.74 Hz, 1 H), 6.35 (m, 2 H), 7.02 (d, J = 12.23 Hz, 1 H), 7.41 (s, 1 H), 8.27 (s, 1 H). EIMS (m/z): 458 (M+l).
[0305] Example 137 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-l -(l- methyl- 1 H-pyrazolo[3 ,4-d]pyrimid -4-yl)piperidin-3-yl)acetamide).
Figure imgf000125_0002
The title compound of Example 137 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro- 1 -methyl- 1H-pyrazolo[3,4-d]pyrimidine. 1H NMR (400 MHz, CDC13) δ 8.36 (br. s., 1H), 8.23 - 8.34 (m, 1H), 6.31 - 6.50 (m, 2H), 6.20 (d, J = 1.76 Hz, 1H), 4.30 (br. s., 1H), 4.16 - 4.26 (m, 1H), 3.95 - 4.10 (m, 4H), 3.57 - 3.82 (m, 3H), 3.07 (br. s., 1H), 2.08 (br. s., 2H), 1.81 (br. s., 2H), 1.10 (br. s., 1H), 0.28 - 0.72 (m, 4H). EIMS (m/z): calcd. for C22H25C1F 70 (M+1H) 457, found 457. [0306] Example 138 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((R)-1-(5- fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000126_0001
The title compound of Example 138 was prepared in similar manner as described in Example 134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-Chloro-5-fluoro- 7H-pyrrolo[2,3-d]pyrimidine. The 4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine was synthesized as reported by Wang, X.; Seth, P. P.; Ranken, R.; Swayze, E. E; Migawa M. T. Synthesis and Biological Activity of 5-Fluorotubercidiny. Nucleosides, Nucleotides Nucleic Acids 2004, 23, 161. 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 3H), 7.22 (d, J = 2.26 Hz, 3H), 6.34 (t, J = 1.63 Hz, 3H), 6.28 - 6.30 (m, 1H), 6.25 - 6.27 (m, 1H), 6.15 (t, J = 2.13 Hz, 1H), 6.12 (t, J = 2.13 Hz, 1H), 3.98 - 4.1 1 (m, 9H), 3.66 - 3.77 (m, 6H), 3.03 (d, J = 8.78 Hz, 3H), 2.65 (s, 1H), 1.95 - 2.12 (m, 6H), 1.77 - 1.86 (m, 6H), 1.04 - 1.17 (m, 3H), 0.56 - 0.68 (m, 3H), 0.46 - 0.55 (m, 6H), 0.31 - 0.41 (m, 3H). EIMS (m/z): calcd. for C22H23C1F2 60 (M+1H) 461 , found 461.
Example 138.1 (R)-2-(3-chloro-5-fluorophenylamino)-N-((R)-1-(5-cyano-1H-pyrrolo[2,3- b]pyridin-4-yl)piperidin-3-yl)-2-cyclopropylacetamide.
Figure imgf000126_0002
The title compound of Example 138.1 was prepared in similar manner as described in Example
134 except 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-1H- pyrrolo[2,3-b]pyridine-5-carbonitrile. 1H NMR (400 MHz, CD3OD) δ 0.36 (s, 1 H), 0.58 (m, 5
H), 1.14 (d, J=6.85 Hz, 1 H), 1.82 (m, 1 H), 2.08 (s, 1 H), 2.97 (d, J = 8.80 Hz, 1 H), 3.1 1 (d, J = 8.80 Hz, 1 H), 3.58 (dd, J = 1 1.74, 7.83 Hz, 1 H), 3.81 (d, J = 16.63 Hz, 1 H), 4.07 (d, J = 12.72 Hz, 1 H), 4.17 (s, 1 H), 6.1 1 (d, J = 1 1.25 Hz, 1 H), 6.24 (m, 1 H), 6.40 (s, 1 H), 6.87 (s, 1 H), 7.36 (s, 1 H), 8.33 (s, 1 H). EIMS (m/z): 467 (M+l).
Example 139 ((R)-N-((R)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3-chloro- 5-fluorophenylamino)-2-cyclopropylacetamide)
Figure imgf000127_0001
[0307] 4,6-dichloropyrimidine-5-carbaldehyde. Dry DMF (1.3 L, 16.5 mol) was added dropwise to POCI3 (4 L, 42.9 mol) at 10-20 °C with stirring. After the addition was completed, the slurry was further stirred at rt for 5 min. Pyrimidine-4,6-diol (1 Kg, 8.9 mol) was slowly added to the mixture. The resulting mixture was heated to reflux, stirred for 3 h, then slowly poured into crushed ice with stirring. The reaction mixture was stirred for another 5 min and then extracted with EtOAc (3 x3 L). The organic layers were combined and adjusted to pH 8 with saturated aqueous Na2C03. After washing with brine, the organic layer was dried over Na2SC>4, filtered, and concentrated to dryness under vacuum to give crude title intermediate (800 g, 53.3%) as a yellow solid.
[0308] 4-chloro-1H-pyrazolo[3,4-d]pyrimidine. Hydrazine hydrate (1 1.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol) and triethylamine (30 mL, 22 mmol) in 1 ,4-dioxane (600 mL) with cooling to maintain an internal temperature below 20 °C. After the addition was completed, the reaction was warmed to rt. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford the title intermediate (29 g, 83 %) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (br. s, 1 H), 8.83 (s, 1 H), 8.45 (s, 1 H). MS m/z 155 [M+l]+.
[0309] 4-chloro- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazolo [3 ,4-d]pyrimidine.
Diisopropylethylamine (35 mL, 0.20 mol) was added to a solution of 4-chloro- 1 H-pyrazolo [3, 4- d]pyrimidine (25 g, 0.16 mol) and [ -(trimethylsilyl)ethoxy]methyl chloride (36 mL, 0.20 mol) in THF (200 mL, 2 mol) and DMF (100 mL, 1 mol) at -20 °C. After 1 h, the reaction mixture was warmed to rt. The reaction mixture was diluted with CH2CI2, washed with 0.5 N C1 , and concentrated under reduced pressure. The residue was purified by flash chromatography using hexane/EtOAc (Si02, 100/0 to 0/100) to afford the title intermediate (26 g, 56%) as a clear oil. 1H NMR (400 MHz, CDC13) 8.84, (s, 1 H), 8.24 (s, 1 H), 5.86, (s, 2 H), 3.68 (m, 2 H), 0.95 (m, 2 H), 0.03 (s, 9 H). MS m/z 285 [M+l]+.
[0310] ((R)-N-((R)- 1 -( 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)piperidin-3 -yl)-2-(3 -chloro-5 - fluorophenylamino)-2-cyclopropylacetamide). The (R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropyl-N-((R)-piperidin-3-yl)acetamide (1 mmol) prepared in a similar fashion as descrided for example 134 was dissolved in 1-butanol (4 mL) to which was added DIEA (6 mmol) and 4- chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (1 mmol). The reaction mixture was heated to 80 °C and stirred for 4 h. The solution was cooled to rt, diluted with water, and extracted with EtOAc. The organic phase was dried ( a2S04), filtered, and concentrated in vacuo to afford an oil, which was purified by column chromatography (silica gel, gradient EtOAc in hexane) to afford the SEM protected compound. A solution of SEM protected compound (0.3 mmol) in EtOH (3 mL) was treated 4 N C1 in dioxane (2 mL). The solution was heated at reflux for 2 h, and the solvent was concentrated in vacuo to afford a solid, which was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford the title compound. 1H NMR (300 MHz, CDC13) δ 8.83 (br. s., 2H), 8.44 (s, 2H), 8.15 (br. s., 1H), 6.37 - 6.40 (m, 2H), 6.32 - 6.37 (m, 2H), 6.15 - 6.23 (m, 2H), 4.42 (br. s., 2H), 4.04 (d, J = 3.59 Hz, 2H), 3.87 (dd, J = 9.06, 13.03 Hz, 2H), 3.70 - 3.80 (m, 1H), 3.09 (d, J = 8.69 Hz, 2H), 1.96 - 2.18 (m, 4H), 1.76 - 1.93 (m, 4H), 1.03 - 1.16 (m, 2H), 0.56 - 0.69 (m, 2H), 0.42 - 0.51 (m, 3H), 0.38 (dd, J = 4.72, 9.82 Hz, 2H). EIMS (m/z): calcd. for C21H23CIFN7O (M+H) 444, found 444.
[0311] Examples 140-146 were prepared according to Example 139 above.
[0312] Example 140 ((R)-N-(l-(6-amino-5-chloropyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
Figure imgf000129_0001
The title compound of Example 140 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 5,6-dichloropyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 7.91 (s, 1H), 6.51 - 6.63 (m, 1H), 6.34 (d, J = 1.51 Hz, 2H), 3.93 - 4.10 (m, 1H), 3.47 - 3.57 (m, 3H), 3.20 - 3.31 (m, 2H), 2.76 - 3.01 (m, 1H), 1.72 - 1.85 (m, 2H), 1.54 - 1.67 (m, 2H). EIMS (m/z): calcd. for C17H19CI3 6O (M+1H) 431 , found 431.
[0313] Example 141 ((R)-N-(l-(6-acetamidopyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
Figure imgf000129_0002
The title compound of Example 141 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for N-(6-chloropyrimidin-4-yl)acetamide. 1H NMR (400 MHz, DMSO-i¼) δ 10.32 (s, 1H), 8.17 (s, 1H), 7.96 (d, J = 7.78 Hz, 1H), 6.56 (t, J = 1.88 Hz, 1H), 6.47 (d, J = 1.76 Hz, 2H), 4.02 (br. s., 1H), 3.79 (br. s., 1H), 3.61 (d, J = 9.29 Hz, 3H), 2.84 - 3.17 (m, 2H), 2.00 (s, 3H), 1.75 (br. s., 2H), 1.33 - 1.57 (m, 2H). EIMS (m/z): calcd. for Ci9H22Ci2N602 (M+1H) 437, found 437.
[0314] Example 142 ((R)-2-(3,5-dichlorophenylamino)-N-(l-(6-
(isopropylamino)pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000130_0001
The title compound of Example 142 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-isopropylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J = 1.89 Hz, 2H), 6.48 (d, J = 1.89 Hz, 3H), 5.72 (s, 1H), 3.78 - 4.05 (m, 5H), 3.42 - 3.60 (m, 3H), 1.90 - 2.08 (m, 2H), 1.80 (td, J = 3.59, 8.97 Hz, 3H), 1.65 (td, J = 3.21 , 8.03 Hz, 2H), 1.13 - 1.39 (m, 13H). EIMS (m/z): calcd. for C20H26CI2N6O (M+1H) 437, found 437.
[0315] Example 143 ((R)-2-(3,5-dichlorophenylamino)-N-(l -(6-(ethylamino)pyrimidin-
4-yl)piperidin-3-yl)acetamide).
Figure imgf000130_0002
The title compound of Example 143 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-ethylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J = 1.70 Hz, 1H), 6.48 (d, J = 1.89 Hz, 2H), 5.70 (s, 1H), 3.89 - 4.03 (m, 2H), 3.74 (s, 2H), 3.55 (d, J = 7.55 Hz, 2H), 1.91 - 2.03 (m, 1H), 1.76 - 1.87 (m, 2H), 1.65 (dt, J = 4.20, 8.59 Hz, 1H), 1.26 (t, J = 7.18 Hz, 3H). EIMS (m/z): calcd. for C19H24CI2N6O (M+1H) 423, found 423.
[0316] Example 144 ((R)-2-(3,5-dichlorophenylamino)-N-(l-(6-
(methylamino)pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000131_0001
The title compound of Example 144 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloro-N-methylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (s, 1H), 6.48 (d, J = 1.51 Hz, 2H), 5.69 (s, 1H), 3.91 (dd, J = 3.78, 7.55 Hz, 3H), 3.74 (s, 2H), 3.50 - 3.67 (m, 2H), 2.90 (s, 3H), 1.96 (dt, J = 4.53, 9.06 Hz, 1H), 1.73 - 1.88 (m, 2H), 1.57 - 1.73 (m, 1H). EIMS (m/z): calcd. for C18H22CI2N6O (M+1H) 409, found 409.
[0317] Example 145 ((R)-N-(l -(6-aminopyrimidin-4-yl)piperidin-3-yl)-2-(3,5- dichlorophenylamino)acetamide) .
Figure imgf000131_0002
The title compound of Example 145 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- dichlorophenylamino)acetamido)piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 6-chloropyrimidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.00 (d, J = 7.28 Hz, 1H), 7.50 (br. s., 2H), 6.54 - 6.70 (m, 1H), 6.47 (d, J = 1.76 Hz, 3H), 3.98 (br. s., 1H), 3.84 (br. s., 1H), 3.55 - 3.71 (m, 6H), 3.06 (dd, J = 8.91 , 12.93 Hz, 2H), 1.76 (br. s., 3H), 1.38 - 1.60 (m, 3H). EIMS (m/z): calcd. for C17H20CI2N6O (M+1H) 395, found 395.
[0318] Example 146 ((R)-2-(3,5-dichlorophenylamino)-N-(l-(6-oxo-6,7-dihydro-5H- pyrrolo [2 ,3 -d]pyrimidin-4-yl)piperidin-3 -yl)acetamide) .
Figure imgf000132_0001
The title compound of Example 146 was prepared in similar manner as described in Example 134 except the key intermediate (R)-ieri-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2- cyclopropylacetamido)piperidine-l -carboxylate was replaced with (R)-ter£-butyl 3-(2-(3,5- di chlorophenylamino)acetami do )piperidine- 1 -carboxylate and the 4-amino-6-chloropyrimidine- 5-carbonitrile was substituted for 4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. 1H NMR (300 MHz, DMSO-ί ί) δ 10.99 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 7.18 Hz, 1H), 6.62 (t, J = 1.70 Hz, 1H), 6.54 (d, J = 1.89 Hz, 2H), 4.13 (d, J = 12.46 Hz, 3H), 3.69 (dd, J = 1 1.33, 15.86 Hz, 10H), 2.84 - 3.22 (m, 2H), 1.82 (d, J = 3.40 Hz, 1H), 1.66 - 1.76 (m, 1H), 1.43 - 1.63 (m, 2H). EIMS (m/z): calcd. for C19H20CI2N6O (M+1H) 435, found 435.
Example 147 ((R)-2-(3-Chloro-5-fluorophenvlamino)-2-cvclopropvl-N-((3R.,5S)-5-methvl- l-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)acetamide)
[0319] tert-BvXy\ 5-methylpyridin-3-ylcarbamate. A solution of 5-methyl-pyridin-3- ylamine (250 mg, 2.31 mmol) and di-ieri-butyldicarbonate (505 mg, 2.31 mmol) in THF (5 mL) was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo to afford a residue, which was suspended in EtOAc and washed with aq. NaHC03 and water. The organic phase was collected, dried (Na2S04), filtered, and concentrated in vacuo to give an oil, which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to yield the title intermediate.
[0320] tert- utyl (3R,5S)-5-methylpiperidin-3-ylcarbamate. A Parr bottle was charged with tert-bu yl 5-methylpyridin-3-ylcarbamate (365 mg, 1.75 mmol) and AcOH (10 mL, 0.17 mol). Nitrogen was bubbled through the mixture for several minutes with stirring before 5% Pt/C (365 mg, 0.027 mol) was added, and the bottle was placed under an atmosphere of hydrogen (60 psi) for 24 h. The mixture was filtered and the solvent concentrated in vacuo to afford the title intermediate as an oil, which was used without further purification.
[0321] teri-Butyl (3R,5S)-5-methyl-1-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-ylcarbamate. A mixture of te/ -butyl (3R,5S)-5- methylpiperidin-3-ylcarbamate (150 mg, 0.7 mmol), 4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.7 mmol) and Et3N (195 \iL, 1.4 mmol) in DMF (5 mL) was heated at 80 °C for 16 h. The solution was cooled, diluted with water, extracted with EtOAc, washed with aq. citric acid and aq. NaHC03, dried (Na2S04), filtered, and concentrated in vacuo to afford a residue, which was purified by column chromatography (silica gel, gradient EtOAc in hexanes).
[0322] (3R,5S)-5-Methyl-l -(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-amine5. A solution of te/ -butyl (3R,5S)-5-methyl-1-(l -((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-ylcarbamate (75 mg, 0.16 mmol) and 12N C1 (0.5 mL, 6 mmol) in EtOH (1.5 mL) was heated to reflux for 4 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2C12 (3 mL) and MeOH (1 mL), treated with a polymer supported carbonate resin, filtered, and concentrated in vacuo to afford a residue, which was used without further purification.
[0323] ((i?)-2-(3-Chloro-5-fluorophenylamino)-2-cyclopropyl-N-((3R,5S)-5-methyl-l - (1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)acetamide). A mixture of (R)-2-(3-chloro-5- fluorophenylamino)-2-cyclopropylacetic acid (21 mg, 0.086 mmol) and 1 -hydroxybenzotriazole (12 mg, 0.086 mmol) in DMF (5 mL) was treated with EDCI (17 mg, 0.086 mmol), (3R,5S)-5- methyl- l -(1H-pyrazolo [3, 4-d]pyrimidin-4-yl)piperidin-3 -amine (20 mg, 0.086 mmol), and Et3N (40 \L, 0.26 mmol). After 16 h, the reaction mixture was diluted with water, and the organics were extracted into EtOAc, washed with aq. citric acid, aq. NaHC03, dried (Na2SC>4), filtered, and concentrated in vacuo to afford a residue, which was purified by reversed phase chromatography. 1H NMR (400 MHz, CD3OD) δ 8.87 (br. s., 2H), 8.47 (s, 2H), 8.28 (br. s., 2H), 6.34 - 6.47 (m, 4H), 6.27 (d, J = 1 1.29 Hz, 2H), 3.94 (dd, J = 4.77, 10.79 Hz, 2H), 3.08 - 3.19 (m, 3H), 2.66 (s, 2H), 2.01 - 2.22 (m, 2H), 1.90 (br. s., 2H), 1.35 - 1.55 (m, 2H), 1.21 (tt, J = 4.1 1 , 8.06 Hz, 3H), 1.01 - 1.15 (m, 6H), 0.51 - 0.79 (m, 7H), 0.43 (dq, 2H). (M+ +1) = 458.30. EIMS (m/z): calcd. for C22H25C1FN70 (M+1H) 458.18, found 458.30.
[0324] Example 148 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((3R,6S)-
6-methyl- 1 -(1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000134_0001
The title compound was synthesized according to Example 147 above using 6-methyl-pyridin-3- ylamine in place of 5-methyl-pyridin-3-ylamine. 1H NMR (400 MHz, CD3OD) δ 8.63 (br. s., 1H), 8.30 (br. s., 2H), 6.10 - 6.31 (m, 3H), 5.95 (d, J = 1 1.04 Hz, 3H), 4.15 (br. s., 2H), 4.03 (br. s., 1H), 2.93 (d, J = 8.78 Hz, 2H), 2.56 (s, 3H), 1.95 - 2.30 (m, 5H), 1.66 (d, J = 1 1.04 Hz, 5H), 1.33 (d, J = 4.27 Hz, 7H), 0.43 (br. s., 3H), 0.22 (dd, 4H). EIMS (m/z): calcd. for C22H25C1FN70 (M+1H) 458.18, found 458.30.
[0325] Example 149 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-(4-phenyl-
1 -( 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)piperidin-3 -yl)acetamide) .
Figure imgf000135_0001
The title compound was synthesized according to Example 147 above using tert-buty\ 4- phenylpiperidine-1-carboxylate in place of tert-bu y\ 5-methylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, CD3OD) δ 8.77 - 8.99 (m, 2H), 8.53 (s, 2H), 8.06 (dd, J = 7.66, 15.69 Hz, 2H), 6.93 - 7.38 (m, 7H), 6.29 - 6.47 (m, 2H), 6.24 (s, 1H), 5.97 - 6.20 (m, 2H), 4.25 - 4.38 (m, 1H), 4.19 (td, J = 3.64, 7.22 Hz, 1H), 3.03 - 3.19 (m, 3H), 2.83 - 3.01 (m, 3H), 2.66 (s, 1H), 2.15 (d, J = 13.05 Hz, 2H), 1.94 (br. s., 2H), 0.39 - 0.58 (m, 2H), 0.15 - 0.37 (m, 2H). EIMS (m/z): calcd. for C27H27CIFN7O (M+1H) 520.19, found 520.30.
[0326] Example 150 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((3R,4S)-
4-methyl- 1 -(1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000135_0002
The title compound was synthesized according to Example 147 above using iert-butyl (4S,3R) 4- methylpiperidin-3-ylcarbamate in place of tert-butyl 5-methylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 19.83 Hz, 1H), 8.35 (s, 1H), 8.19 (br. s., 1H), 6.27 - 6.35 (m, 2H), 6.18 (tt, J = 2.16, 1 1.01 Hz, 1H), 3.43 - 3.59 (m, 1H), 2.99 - 3.06 (m, 1H), 1.89 - 1.98 (m, 1H), 1.84 (br. s., 1H), 1.35 (br. s., 1H), 1.06 - 1.17 (m, 1H), 0.97 (d, J = 6.53 Hz, 1H), 0.84 (d, J = 6.53 Hz, 1H), 0.45 - 0.66 (m, 3H), 0.29 - 0.39 (m, 1H). EIMS (m/z): calcd. for C22H25C1F 70 (M+1H) 458.18, found 458.30. [0327] Example 151 ((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropyl-N-((3R,4R)-
4-methyl- 1 -(1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)piperidin-3-yl)acetamide).
Figure imgf000136_0001
The title compound was synthesized according to Example 147 above using tert-butyl (4R,3R) 4- methylpiperidin-3-ylcarbamate in place of tert-butyl 5-methylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, MeOD) δ 8.30 (br. s., 1H), 7.62 (br. s., 1H), 7.48 (d, J= 8.53 Hz, 1H), 6.15 - 6.20 (m, 2H), 5.99 (dt, J = 2.20, 1 1.42 Hz, 1H), 4.16 (br. s., 1H), 4.04 (br. s., 1H), 2.90 - 3.00 (m, 2H), 2.09 - 2.19 (m, 2H), 1.75 (br. s., 2H), 1.57 - 1.70 (m, 2H), 0.92 (dd, J = 7.03, 17.32 Hz, 8H), 0.46 - 0.55 (m, 1H), 0.38 (d, J = 4.77 Hz, 3H), 0.10 - 0.25 (m, 2H). EIMS (m/z): calcd. for C22H25C1FN70 (M+1H) 458.18, found 458.30.
[0328] Example 152 ((R)-2-cyclopropyl-2-(3,5-dichlorophenylamino)-N-((3R,4S)-4- methyl- 1 -( 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)piperidin-3 -yl)acetamide) .
Figure imgf000136_0002
The title compound was synthesized according to Example 147 above using tert-butyl (4S,3R) 4- methyl-piperidin-3-yl carbamate in place of tert-butyl 5-methylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, MeOD) δ 8.45 (d, J = 1.25 Hz, 1H), 6.59 - 6.62 (m, 1H), 6.53 (d, J = 1.76 Hz, 1H), 6.51 (d, J = 1.76 Hz, 1H), 3.52 - 3.69 (m, 2H), 3.04 - 3.15 (m, 2H), 1.83 - 2.10 (m, 3H), 1.47 (br. s., 1H), 1.15 - 1.29 (m, 1H), 1.06 (d, J = 6.53 Hz, 1H), 0.93 (d, J = 6.53 Hz, 2H), 0.55 - 0.75 (m, 3H), 0.37 - 0.46 (m, 1H). EIMS (m/z): calcd. for C22H25C12N70 (M+1H) 474.18, found 474.20. [0329] Example 153 ((R)-2-(3,5-dichlorophenylamino)-N-((3R,4S)-4-methyl-l -(1H- pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-3-yl)pentanamide).
Figure imgf000137_0001
The title compound was synthesized according to Example 147 above using iert-butyl (4S,3R) 4- methylpiperidin-3-ylcarbamate in place of te/ -butyl 5-methylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, MeOD) δ 8.51 (br. s., 1H), 6.68 (q, J = 1.84 Hz, 1H), 6.64 (d, J = 1.76 Hz, 1H), 6.61 (d, J = 1.76 Hz, 1H), 3.86 (br. s., 1H), 3.59 - 3.73 (m, 1H), 2.09 (br. s., 1H), 1.93 - 2.02 (m, 1H), 1.81 - 1.91 (m, 2H), 1.47 - 1.69 (m, 3H), 1.03 - 1.13 (m, 4H), 0.97 (d, J = 6.53 Hz, 2H). EIMS (m/z): calcd. for C22H27CI2N7O (M+1H) 476.4, found 476.3.
[0330] Example 154 ((R)-2-(3-chloro-5-fluorophenylamino)-N-((3R,4S)-4-methyl-l -
( 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)piperidin-3 -yl)butanamide) .
Figure imgf000137_0002
The title compound was synthesized according to Example 147 above using iert-butyl (4S,3R) 4- methylpiperidin-3-ylcarbamate in place of tert-butyl 5-methylpiperidin-3-ylcarbamate. H NMR
(300 MHz, CHLOROFORM-d) δ 12.71 (br. s., 1H), 12.40 (s, 1H), 12.28 (d, J = 12.46 Hz, 1H), 10.31 - 10.45 (m, 2H), 10.20 - 10.31 (m, 1H), 7.65 - 7.76 (m, 1H), 7.45 - 7.65 (m, 2H), 5.73 - 6.06 (m, 4H), 5.42 (d, J = 1 1.33 Hz, 1H), 4.96 - 5.09 (m, 5H), 4.87 (d, J = 6.42 Hz, 2H). EIMS (m/z): calcd. for C22H27CI2N7O (M+1H) 446.2, found 446.3. Example 155 ((Z)-1-(l-(7H-pyrrolo[2.,3-dlpvrimidiii-4-vl)piperidiii
chloro henyl)-2-cyanoguanidine).
Figure imgf000138_0001
[0331] Phenyl N'-cyano-N-(l -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamimidate. To a solution tert-butyl l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin- 3-ylcarbamate (6.3 g, 20 mmol) in dioxane (50 ml) was added 4.0 N C1 (50 mL, 200 mmol) and stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give the deprotected amine. A solution of l -(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (580 mg, 1.29 mmol) and diphenyl cyanocarbonimidate (370 mg, 1.5 mmol) in DMF (20 mL) was heated at 65 C for 16 h. the reaction mixture was cooled to rt and diluted with EtOAc and water (1 :2, 200 mL). The organic phase was separated washed subsequently with sat. NaHC03 brine, water, dried (Na2SC>4) and concentrated in vacuo to afford 155.
Figure imgf000138_0002
[0332] ((Z)-1-(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(2-chlorophenyl)-2- cyanoguanidine). To a solution of phenyl N'-cyano-N-(l-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperidin-3-yl)carbamimidate (48 mg, 0.087 mmol) in DMF (2 mL) was added ortho- chloroaniline (28 mg, 0.22 mmol) and the solution was heated in a microwave to 180 °C for 20 min. The solution was diluted with EtOAc and water (1 :2, 20 mL). The organic phase was separated washed subsequently with sat. NaHC03, 1 N C1 , water and dried (Na2SC>4) and concentrated in vacuo to afford a solid. To a solution of l-(2-chlorophenyl)-2-cyano-3-(l-(7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)guanidine was dissolved in water/MeOH (1 :4, 2.5 mL) was added K2C03 (60 mg, 0.44 mmol) and heated to 65 °C for 3 h. The solution was concentrated in vacuo to afford a solid which was purified by reverse phase chromatography C 18 column and 10% acetonitrile/water 0.1 % TFA to afford example 1 15. 1H NMR (d6-DMSO, 400 MHz): δ 12.38 (br. s., 1H), 9.01 (s, 1H), 8.25 (s, 1H), 7.39 - 7.54 (m, 2H), 7.15 - 7.40 (m, 7H), 7.07 (br. s., 1H), 6.79 (br. s., 1H), 4.37 (br. s., 1H), 4.22 (br. s., 1H), 3.74 - 3.96 (m, 1H), 3.38 (dd, J= 9.29, 13.05 Hz, 2H), 1.90 (br. s., 1H), 1.76 (br. s., 1H), 1.40 - 1.72 (m, 2H).
[0333] Examples 156-160 were prepared according to Example 155 above.
[0334] Example 156 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(3- chlorophenyl)-2-cyanoguanidine).
Figure imgf000139_0001
The title compound of Example 156 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 3-chloroaniline. 1H NMR (400 MHz, DMSO-d6): δ 12.46 (br. s., 1H), 9.32 (br. s., 1H), 8.32 (s, 1H), 7.53 (d, J = 7.53 Hz, 1H), 7.40 (d, J = 2.76 Hz, 1H), 7.21 - 7.35 (m, 2H), 7.08 - 7.21 (m, 2H), 6.89 (d, J = 1.51 Hz, 1H), 4.42 (d, J = 13.30 Hz, 1H), 4.24 (br. s., 1H), 3.86 - 4.05 (m, 1H), 3.37 - 3.67 (m, 2H), 1.92 - 2.1 1 (m, 1H), 1.85 (br. s., 1H), 1.73 (d, J= 14.05 Hz, 2H).
[0335] Example 157 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(4- chlorophenyl)-2-cyanoguanidine).
Figure imgf000139_0002
The title compound of Example 157 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-chloroaniline. 1H NMR (d6-DMSO 400 MHz): δ 12.32 (br. s., 1H), 9.18 (s, 1H), 8.24 (s, 1H), 7.22 - 7.42 (m, 3H), 7.12 (d, J = 9.04 Hz, 2H), 6.80 (br. s., 1H), 4.34 (br. s., 1H), 4.19 (br. s., 1H), 3.88 (br. s., 1H), 3.26 - 3.52 (m, 2H), 1.91 (d, J - 4.02 Hz, 1H), 1.77 (br. s., 1H), 1.40 - 1.71 (m, 2H).
[0336] Example 158 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyano-3-(3-(trifluoromethyl)phen l)guanidine .
Figure imgf000140_0001
The title compound of Example 158 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 3-(trifluoromethyl)aniline. 1H NMR (d6-DMSO, 400 MHz): δ 12.44 (br. s., 1H), 9.44 (br. s., 1H), 8.32 (s, 1H), 7.33 - 7.66 (m, 6H), 6.89 (br. s., 1H), 4.45 (d, J = 10.04 Hz, 1H), 4.26 (br. s., 1H), 3.51 (dd, J = 9.04, 12.80 Hz, 2H), 1.94 - 2.06 (m, 1H), 1.85 (br. s., 1H), 1.73 (d, J = 12.55 Hz, 2H).
[0337] Example 159 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2- cyano-3-(4-(trifluoromethyl)phen l)guanidine).
Figure imgf000140_0002
The title compound of Example 159 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-(trifluoromethyl)aniline. 1H NMR (d6-DMSO, 400 MHz): δ 12.08 (br. s., 1H), 9.74 - 10.05 (m, 1H), 9.48 (br. s., 1H), 8.31 - 8.45 (m, 1H), 8.26 (s, 1H), 7.44 - 7.77 (m, 2H), 7.15 - 7.34 (m, 2H), 6.57 (d, J = 8.28 Hz, 1H), 4.49 (br. s., 1H), 4.36 (br. s., 1H), 4.21 - 4.32 (m, 1H), 3.84 (br. s., 1H), 3.31 - 3.43 (m, 1H), 1.83 (br. s., 2H), 1.57 (br. s., 1H).
[0338] Example 160 ((Z)-l -(l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-3-(4- ieri-butylphenyl)-2-cyanoguanidine).
Figure imgf000141_0001
The title compound of Example 158 was prepared in similar manner as described in Example 155 except 2-chloroaniline was substituted for 4-iert-butylaniline. 1H NMR (d6-DMSO, 400 MHz): δ 12.32 (br. s., 1H), 9.02 (s, 1H), 8.21 (s, 1H), 7.32 (d, J = 2.76 Hz, 1H), 7.17 - 7.28 (m, 2H), 7.09 (d, J = 7.78 Hz, 1H), 7.03 (d, J = 8.53 Hz, 2H), 6.80 (br. s., 1H), 4.30 (d, J = 3.26 Hz, 1H), 4.16 (br. s., 1H), 3.80 - 3.97 (m, 1H), 3.46 (dd, J= 8.91 , 13.18 Hz, 1H), 3.26 - 3.41 (m, 1H), 2.43 (dt, J = 1.79, 3.70 Hz, 12H), 1.91 (d, J = 6.02 Hz, 1H), 1.62 - 1.84 (m, 2H), 1.45 - 1.61 (m, 1H).
Example 161
[0339] In vitro BTK kinase assay: BTK-POL YGA T-LS ASSA Y. The purpose of the BTK in vitro assay is to determine compound potency against BTK through the measurement of IC50. Compound inhibition is measured after monitoring the amount of phosphorylation of a fluorescein-labeled polyGAT peptide (Invitrogen PV361 1) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitor. The BTK kinase reaction was done in a black 96 well plate (costar 3694). A 24 \L aliquot of a ATP/peptide master mix (final concentration; ATP 10 μΜ, polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgC12, 200 μΜ Na3V04, 5 mM DTT, 0.01 % Triton X- 100, and 0.2 mg/ml Casein) is added to each well. Next, 1 \L of a 4-fold, 40X compound titration in 100% DMSO solvent is added, followed by adding 15 xL of BTK enzyme mix in 1 X kinase buffer (with a final concentration of 0.25 nM). The assay is incubated for 30 minutes before being stopped with 28 \L of a 50 mM EDTA solution. Five xL of the kinase reaction is transferred to a low volume white 384 well plate (Corning 3674) and 5 \L of a 2X detection buffer (Invitrogen PV3574, with 4nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate is covered and incubated for 45 minutes at room temperature. Time resolved fluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nm emission; 518 nm fluorescein emission) is measured. IC50 values are calculated using a four parameter fit with 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control.
Example 162
[0340] Protocol for human B cell stimulation. Human B cells were purified from 150 ml of blood. Briefly, the blood was diluted 1/2 with PBS and centrifuged through a Ficoll density gradient. The B cells were isolated from the mononuclear cells by negative selection using the B cell isolation kit II from Milenyi (Auburn, CA). 50,000 B cells per well were then stimulated with 10 g/ml of goat F(ab')2 anti-human IgM antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA) in a 96-well plate. Compounds were diluted in DMSO and added to the cells. Final concentration of DMSO was 0.5%. Proliferation was measured after 3 days using Pro mega CellTiter-Glo® (Madison, WI). Certain compounds of formula I were tested and found to be active.
[0341] Table 1 shows the activity of selected compounds of this invention in the in vitro
Btk kinase assay. Compounds have an activity designated as "A" provided an IC50 < 100 nM; compounds having an activity designated as "B" provided an IC50 of 100-999 nM; compounds having an activity designated as "C" provided an IC50 of 1000- 10,000 nM; and compounds having an activity designated as "D" provided an IC50 of > 10,000 nM. In some instances where a compound tested has activity "D", other structurally similar compounds beyond the measurable limits of the assay are not included in Table 1.
Table 1. Exemplary compounds of formula I.
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
See Example 161.

Claims

What is claimed is:
1. A compound having the formula:
Figure imgf000221_0001
wherein:
X1 is -0-, -CR6R7- or -NR8-;
X2 is =CR9- or =N-;
p is 0-5;
y is 0, 1 , or 2;
z is 0, 1, or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
each R1 is independently halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -
C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, - N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, -C=NOR,
-N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, -OC(0)N(R)2, or an optionally substituted group selected from C1-i2 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bi cyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- 10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-, or: two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or an optionally substituted group selected from C1-6
aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3- 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 heteroaryl ring having 1-3 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 an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R2, R4, and R8 is independently R, -CN, -C(0)R, -C02R, -C(0)C(0)R,
-C(0)CH2C(0)R, -C(0)N(R)2, -S(0)R, -S(0)2R, or -S(0)2N(R)2, or:
R2 and R1 are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
R2 and R7 are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
R2 and R8 are optionally taken together with their intervening atoms to form an
optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R3, R5, R6, R7, and R9 is independently R, halogen, -N02, -CN, -OR, -SR, -N(R)2, -C(0)R, -C02R, -C(0)C(0)R, -C(0)CH2C(0)R, -S(0)R, -S(0)2R, -C(0)N(R)2, -S02N(R)2, -OC(0)R, -N(R)C(0)R, -N(R)N(R)2, -N(R)C(=NR)N(R)2, -C(=NR)N(R)2, - C=NOR, -N(R)C(0)N(R)2, -N(R)S02N(R)2, -N(R)S02R, or -OC(0)N(R)2, or:
R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx is hydrogen or optionally substituted C1-6 aliphatic, or:
Rx and R2 are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bi cyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring A1 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bi cyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is a covalent bond or an optionally substituted, bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, - C(0)N(R)-, -N(R)S02-, -S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, - C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-; and
each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
2. The compound of claim 1, wherein L is an optionally substituted, bivalent C 1-4 saturated hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -C(R)2-, -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S02-,
-S02N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO-, -S02-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-.
3. The compound of claim 1, wherein L is an optionally substituted bivalent C 1-4 saturated hydrocarbon chain, wherein one methylene unit of L is replaced by -C(O)- and one methylene unit of L is replaced by -N(R)-.
4. The compound of claim 1, wherein one methylene unit of L is replaced by -
C(R)2-.
5. The compound of claim 1, wherein L is -C(0)C(R)2NR-.
6. The compound of claim 5, wherein each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic or 3-7 membered saturated carbocyclic.
7. The compound of claim 6, wherein each R is independently hydrogen, a substituted C 1-6 aliphatic, or a substituted 3-7 membered saturated carbocyclic ring, wherein a substituent on R is selected from -CF3 or -OH.
8. The compound of claim 1, wherein the compound is of formula IV-a:
Figure imgf000226_0001
Figure imgf000226_0002
Figure imgf000226_0003
The compound of claim 10, wherein L is:
Figure imgf000227_0001
12. The compound of claim 1, wherein the compound is of formula l-a-i or l-a-ii:
Figure imgf000227_0002
13. The compound of claim 1, wherein the compound is of formula l-b-i or I-b-w:
Figure imgf000227_0003
l-b-ii
14. The compound of claim 1, wherein R1 is optionally substituted C 1-6 aliphatic.
15. The compound of claim 14, wherein R1 is C1-4 unsubstituted alkyl or halogen- substituted Ci-4 alkyl.
16. The compound of claim 15, wherein R1 is methyl or -CF3.
17. The compound of claim 1, wherein p is 0.
18. The compound of claim 1 , wherein p is 1.
19. The compound of claim 1, wherein p is at least two, and:
two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by -NR-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-S-, or -S-, or:
two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
20. The compound of claim 19, wherein two R1 groups are taken together with their intervening atoms to form a bicyclic ring having a formula:
Figure imgf000229_0001
wherein the bicyclic ring is optionally further substituted with one, two, or three
R1 groups.
21. The compound of claim 1, wherein R is hydrogen or optionally substituted C1-6 aliphatic.
22. The compound of claim 21, wherein R2 is hydrogen.
23. The compound of claim 21, wherein R2 is optionally substituted C1-4 alkyl.
24. The compound of claim 1 , wherein R2 and Rx are taken together to form an optionally substituted spirocyclic heterocyclic ring selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
25. The compound of claim 24, wherein the compound is of formula VI:
Figure imgf000230_0001
wherein h is 0-4.
26. The compound of claim 1, wherein the compound is of formula X or XI:
XI
Figure imgf000230_0002
wherein j and k are each 0-4.
27. The compound of claim 1, wherein Rx is hydrogen.
28. The compound of claim 1, wherein z is 1.
29. The compound of claim 28, wherein X1 is -CR6R7- or -NR8-.
30. The compound of claims 29, wherein X1 is -CR6R7-.
31. The compound of claim 1 , wherein z is 2.
32. The compound of claim 31 , wherein the compound is of formula l-a-iii:
Figure imgf000231_0001
33. The compound of claim 31 , wherein the compound is of formula l-b-iii:
Figure imgf000231_0002
The compound of claim 1, wherein
The compound of claim 1, wherein R5 is hydrogen, C 1-6 aliphatic, or -N(R)2
36. The compound of claim 35, wherein R5 is hydrogen.
37. The compound of claim 30, wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from C1-i2 aliphatic or phenyl.
38. The compound of claim 37, wherein R6 and R7 are independently hydrogen, phenyl, or C1-4 alkyl.
39. The compound of claim 38, wherein R6 and R7 are hydrogen.
40. The compound of claim 1, wherein the compound is of formula Il-a:
Figure imgf000232_0001
The compound of claim 1, wherein the compound is of formula Il-b
Figure imgf000232_0002
42. The compound of claim 1, wherein R3 and R4 are taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole or pyrazole. The compound of claim 42, wherein the compound is of formula Vll-a, or VIII-
V VHI-a
Figure imgf000233_0001
44. The compound of claim 1, wherein R4 is hydrogen, -C(0)R, or optionally substituted C1-6 aliphatic.
45. The compound of claim 1, wherein R3 is halogen, -CN, or substituted or unsubstituted C1-6 alkyl.
46. The compound of claim 1, wherein Ring A1 is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
47. The compound of claim 46, wherein Ring A1 is bicyclic.
48. The compound of claim 46, wherein Ring A1 is substituted phenyl.
49. The compound of claim 48, wherein substituents on Ring A1 are selected from halogen, -CN, -CF3, -OH, -NH2, -N(R)2, -COOH, -SR, -S(0)R, -S(0)2R, -S(0)N(R)2, -S(0)2N(R)2, or C 1-6 aliphatic.
The compound of claim 49, wherein Ring A1 is of the formula:
Figure imgf000234_0001
51. The compound of claim 49, wherein Ring A1 is of the formula:
Figure imgf000235_0001
52. The compound of claim 1, wherein each R is an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
53. The compound of claim 1, wherein two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
54. The compound of claim 53, wherein two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted group selected from piperidine or pyrrolidine.
55. The compound of claim 1, wherein said compound is a compound as shown in Table 1.
56. A pharmaceutical formulation comprising a compound of any one of claims 1-55 and a pharmaceutically acceptable excipient.
57. A method of reducing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a compound of any one of claims 1-55 or a composition thereof.
58. A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase comprising administering to a subject an effective amount of a compound of any one of claims 1-55 or a composition thereof.
59. A method of treating a disorder selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers comprising administering to a subject an effective amount of a compound of any one of claims 1-55 or a composition thereof.
60. The method of claim 59, wherein the disorder is rheumatoid arthritis.
61. The method of claim 59, wherein the disorder is lupus.
62. The method of claim 59, wherein the disorder is leukemia or lymphoma.
PCT/US2010/047879 2009-09-04 2010-09-03 Heteroaryl btk inhibitors WO2011029043A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US13/393,191 US9029359B2 (en) 2009-09-04 2010-09-03 Heteroaryl Btk inhibitors
EP10814583A EP2485589A4 (en) 2009-09-04 2010-09-03 Heteroaryl btk inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24000309P 2009-09-04 2009-09-04
US61/240,003 2009-09-04

Publications (1)

Publication Number Publication Date
WO2011029043A1 true WO2011029043A1 (en) 2011-03-10

Family

ID=43649667

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/047879 WO2011029043A1 (en) 2009-09-04 2010-09-03 Heteroaryl btk inhibitors

Country Status (3)

Country Link
US (1) US9029359B2 (en)
EP (1) EP2485589A4 (en)
WO (1) WO2011029043A1 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012022265A1 (en) * 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
CN102702110A (en) * 2012-05-24 2012-10-03 盛世泰科生物医药技术(苏州)有限公司 Preparation method of 4-amino-5, 6-dichloropyrimidine
WO2012170976A3 (en) * 2011-06-10 2013-04-11 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
US8609647B2 (en) 2009-07-31 2013-12-17 Japan Tobacco Inc. Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
US20150126484A1 (en) * 2011-09-12 2015-05-07 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
WO2015089327A1 (en) 2013-12-11 2015-06-18 Biogen Idec Ma Inc. Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology
US9233111B2 (en) 2011-07-08 2016-01-12 Novartis Ag Pyrrolo pyrimidine derivatives
US9273028B2 (en) 2010-10-29 2016-03-01 Biogen Ma Inc. Heterocyclic tyrosine kinase inhibitors
WO2016065138A1 (en) 2014-10-22 2016-04-28 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US9353087B2 (en) 2012-06-08 2016-05-31 Biogen Ma Inc. Inhibitors of Bruton's tyrosine kinase
US9394277B2 (en) 2012-06-08 2016-07-19 Biogen Ma Inc. Pyrimidinyl tyrosine kinase inhibitors
CN105837577A (en) * 2015-02-02 2016-08-10 四川大学 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use
US9585886B2 (en) 2010-12-16 2017-03-07 Calchan Limited ASK1 inhibiting pyrrolopyrimidine derivatives
US9856223B2 (en) 2013-12-13 2018-01-02 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US9908872B2 (en) 2013-12-13 2018-03-06 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
WO2018053437A1 (en) 2016-09-19 2018-03-22 Mei Pharma, Inc. Combination therapy
CN109096274A (en) * 2013-12-11 2018-12-28 比奥根Ma公司 It can be used for treating the aryl-linking compound of human tumor, neurology and amynologic disease
US10577374B2 (en) 2009-09-04 2020-03-03 Sunesis Pharmaceuticals, Inc. Bruton's tyrosine kinase inhibitors
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US11174243B2 (en) 2016-07-21 2021-11-16 Sunesis Pharmaceuticals, Inc. Succinate forms and compositions of Bruton's tyrosine kinase inhibitors
US11345681B1 (en) 2020-06-05 2022-05-31 Kinnate Biopharma Inc. Inhibitors of fibroblast growth factor receptor kinases
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11459310B2 (en) 2020-10-22 2022-10-04 Landos Biopharma, Inc. LANCL ligands
WO2022212893A1 (en) 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2881070A1 (en) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibitors of bruton's tyrosine kinase
AU2013344886B2 (en) 2012-11-13 2017-06-29 Array Biopharma Inc. Bicyclic urea, thiourea, guanidine and cyanoguanidine compounds useful for the treatment of pain
DK2989106T3 (en) 2013-04-25 2017-03-20 Beigene Ltd CONDENSED HETEROCYCLIC COMPOUNDS AS PROTEINKINASE INHIBITORS
EP2832358A1 (en) 2013-08-02 2015-02-04 Bionsil S.r.l. Pharmaceutical kit for use in the treatment of colon and colorectal cancer
CN112457403B (en) 2013-09-13 2022-11-29 广州百济神州生物制药有限公司 anti-PD 1 antibodies and their use as therapeutic and diagnostic agents
CN106604742B (en) 2014-07-03 2019-01-11 百济神州有限公司 Anti- PD-L1 antibody and its purposes as therapeutic agent and diagnosticum
JP6993056B2 (en) 2016-07-05 2022-02-15 ベイジーン リミテッド Combination of PD-1 antagonist and RAF inhibitor for cancer treatment
TWI760356B (en) 2016-08-16 2022-04-11 英屬開曼群島商百濟神州有限公司 Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof
CN110087680B (en) 2016-08-19 2024-03-19 百济神州有限公司 Treatment of cancer using combination products comprising BTK inhibitors
WO2018137681A1 (en) 2017-01-25 2018-08-02 Beigene, Ltd. Crystalline forms of (s) -7- (1- (but-2-ynoyl) piperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahy dropyrazolo [1, 5-a] pyrimidine-3-carboxamide, preparation, and uses thereof
EP3645569A4 (en) 2017-06-26 2021-03-24 BeiGene, Ltd. Immunotherapy for hepatocellular carcinoma
US11377449B2 (en) 2017-08-12 2022-07-05 Beigene, Ltd. BTK inhibitors with improved dual selectivity
CN111801334B (en) 2017-11-29 2023-06-09 百济神州瑞士有限责任公司 Treatment of indolent or invasive B-cell lymphomas using combinations comprising BTK inhibitors
US11786531B1 (en) 2022-06-08 2023-10-17 Beigene Switzerland Gmbh Methods of treating B-cell proliferative disorder

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070135461A1 (en) * 2005-12-13 2007-06-14 Rodgers James D Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4911920A (en) 1986-07-30 1990-03-27 Alcon Laboratories, Inc. Sustained release, comfort formulation for glaucoma therapy
FR2588189B1 (en) 1985-10-03 1988-12-02 Merck Sharp & Dohme LIQUID-GEL PHASE TRANSITION PHARMACEUTICAL COMPOSITION
DE69212850T2 (en) 1991-01-15 1997-03-06 Alcon Lab Inc Use of carrageenan in topical ophthalmic compositions
US5212162A (en) 1991-03-27 1993-05-18 Alcon Laboratories, Inc. Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions
US6309853B1 (en) 1994-08-17 2001-10-30 The Rockfeller University Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof
CZ20023993A3 (en) * 2000-06-26 2004-02-18 Pfizer Products Inc. Pyrrolo[2,3-d]pyrimidine compounds functioning as immunosuppressive agents
GB0115393D0 (en) 2001-06-23 2001-08-15 Aventis Pharma Ltd Chemical compounds
US20090099165A1 (en) 2003-10-14 2009-04-16 Arizona Board Of Regents On Behalf Of The University Of Arizona Protein Kinase Inhibitors
EP1697375A2 (en) * 2003-12-02 2006-09-06 Vertex Pharmaceuticals Incorporated Heterocyclic protein kinase inhibitors and uses thereof
WO2006135383A2 (en) * 2004-08-04 2006-12-21 Myriad Genetics, Inc. Indazoles
MX2007004393A (en) 2004-10-13 2007-04-25 Merck & Co Inc Cgrp receptor antagonists.
JP2010522241A (en) 2007-03-21 2010-07-01 ブリストル−マイヤーズ スクイブ カンパニー Condensed heterocyclic compounds useful as proliferative diseases, allergic diseases, autoimmune diseases or inflammatory diseases
CA2712990C (en) * 2008-02-28 2016-09-27 Bayard R. Huck Benzonaphthyridinyl compounds as protein kinase inhibitors and use thereof
CL2009001152A1 (en) 2008-05-13 2009-10-16 Array Biopharma Inc Compounds derived from n- (4- (nitrogen cycloalkyl-1-yl) -1h-pyrrolo [2,3-b] pyridin-3-yl) amide, kinase inhibitors; Preparation process; pharmaceutical composition; and its use for the treatment of a proliferative disease.
WO2010068806A1 (en) * 2008-12-10 2010-06-17 Cgi Pharmaceuticals, Inc. Amide derivatives as btk inhibitors in the treatment of allergic, autoimmune and inflammatory disorders as well as cancer
WO2010075273A1 (en) * 2008-12-23 2010-07-01 Schering Corporation Bicyclic heterocycle derivatives and methods of use thereof
AR077465A1 (en) 2009-07-08 2011-08-31 Leo Pharma As PIRROLOPIRIMIDINE DERIVATIVES AS INHIBITORS OF JAK AND PROTEIN TIROSIN KINASE RECEPTORS AND PHARMACEUTICAL USE OF THE SAME
TWI466885B (en) * 2009-07-31 2015-01-01 Japan Tobacco Inc Nitrogen-containing spiro cyclic compounds and pharmaceutical use thereof
DK2473049T3 (en) 2009-09-04 2019-04-01 Biogen Ma Inc INHIBITORS OF BRUTON'S TYROSINKINASE
WO2011050202A1 (en) 2009-10-23 2011-04-28 Janssen Pharmaceutica Nv Fused heterocyclic compounds as orexin receptor modulators
AU2010339531A1 (en) * 2009-12-30 2012-08-23 Arqule, Inc. Substituted naphthalenyl-pyrimidine compounds
WO2012022045A1 (en) 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
KR101541086B1 (en) * 2010-08-20 2015-08-03 허치슨 메디파르마 리미티드 Pyrrolopyrimidine compounds and uses thereof
EP2632898A4 (en) 2010-10-29 2014-04-02 Biogen Idec Inc Heterocyclic tyrosine kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070135461A1 (en) * 2005-12-13 2007-06-14 Rodgers James D Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VASSILEV ET AL.: "Therapeutic Potential of Inhibiting Bruton's Tyrosine Kinase, (BTK)", CURRENT PHARMACEUTICAL DESIGN, vol. 10, 2004, pages 1757 - 1766, XP009089833 *

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8609647B2 (en) 2009-07-31 2013-12-17 Japan Tobacco Inc. Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
US10577374B2 (en) 2009-09-04 2020-03-03 Sunesis Pharmaceuticals, Inc. Bruton's tyrosine kinase inhibitors
US10111875B2 (en) 2010-08-20 2018-10-30 Hutchinson Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
WO2012022265A1 (en) * 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
CN103119045B (en) * 2010-08-20 2016-02-17 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compounds and uses thereof
AU2011291185B2 (en) * 2010-08-20 2014-11-27 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
AU2011291185C1 (en) * 2010-08-20 2015-04-16 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
CN103119045A (en) * 2010-08-20 2013-05-22 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compounds and uses thereof
US10369153B2 (en) 2010-08-20 2019-08-06 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
RU2563644C2 (en) * 2010-08-20 2015-09-20 Хатчисон Медифарма Лимитед Pyrrolopyrimidine compounds and application thereof
US9346810B2 (en) 2010-08-20 2016-05-24 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
US9273028B2 (en) 2010-10-29 2016-03-01 Biogen Ma Inc. Heterocyclic tyrosine kinase inhibitors
US9585886B2 (en) 2010-12-16 2017-03-07 Calchan Limited ASK1 inhibiting pyrrolopyrimidine derivatives
US10413562B2 (en) 2011-06-10 2019-09-17 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity
US9073947B2 (en) 2011-06-10 2015-07-07 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity
WO2012170976A3 (en) * 2011-06-10 2013-04-11 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
EA031153B1 (en) * 2011-06-10 2018-11-30 Мерк Патент Гмбх Use of pyrimidine compounds with btk inhibitory activity
US9580449B2 (en) 2011-06-10 2017-02-28 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity
JP2014517016A (en) * 2011-06-10 2014-07-17 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrimidine having BTK inhibitory activity and composition of pyrimidine compound and method for producing the same
JP2018115165A (en) * 2011-06-10 2018-07-26 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Compositions and methods for production of pyrimidine and pyridine compounds with btk inhibitory activity
US10016448B2 (en) 2011-06-10 2018-07-10 Merck Patent Gmbh Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity
EA027584B1 (en) * 2011-06-10 2017-08-31 Мерк Патент Гмбх Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
JP2016185953A (en) * 2011-06-10 2016-10-27 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
US9233111B2 (en) 2011-07-08 2016-01-12 Novartis Ag Pyrrolo pyrimidine derivatives
US9321760B2 (en) * 2011-09-12 2016-04-26 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
US20160184308A1 (en) * 2011-09-12 2016-06-30 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
US9662330B2 (en) 2011-09-12 2017-05-30 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
US20150126484A1 (en) * 2011-09-12 2015-05-07 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
US10080750B2 (en) 2011-09-12 2018-09-25 Merck Patent Gmbh Aminopyrimidine derivatives for use as modulators of kinase activity
CN102702110A (en) * 2012-05-24 2012-10-03 盛世泰科生物医药技术(苏州)有限公司 Preparation method of 4-amino-5, 6-dichloropyrimidine
US9353087B2 (en) 2012-06-08 2016-05-31 Biogen Ma Inc. Inhibitors of Bruton's tyrosine kinase
US10618887B2 (en) 2012-06-08 2020-04-14 Sunesis Pharmaceuticals, Inc. Pyrimidinyl tyrosine kinase inhibitors
US9944622B2 (en) 2012-06-08 2018-04-17 Biogen Ma Inc. Pyrimidinyl tyrosine kinase inhibitors
US9394277B2 (en) 2012-06-08 2016-07-19 Biogen Ma Inc. Pyrimidinyl tyrosine kinase inhibitors
US10189817B2 (en) 2012-06-08 2019-01-29 Biogen Ma Inc. Inhibitors of Bruton's tyrosine kinase
EP3444251A1 (en) 2013-12-11 2019-02-20 Biogen MA Inc. Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology
CN109096274A (en) * 2013-12-11 2018-12-28 比奥根Ma公司 It can be used for treating the aryl-linking compound of human tumor, neurology and amynologic disease
WO2015089327A1 (en) 2013-12-11 2015-06-18 Biogen Idec Ma Inc. Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology
CN109096274B (en) * 2013-12-11 2022-07-01 比奥根Ma公司 Biaryl compounds useful in the treatment of human oncological, neurological and immunological diseases
US10633348B2 (en) 2013-12-13 2020-04-28 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US9908872B2 (en) 2013-12-13 2018-03-06 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US9856223B2 (en) 2013-12-13 2018-01-02 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US10597387B2 (en) 2013-12-13 2020-03-24 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10464949B2 (en) 2014-10-22 2019-11-05 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
WO2016065138A1 (en) 2014-10-22 2016-04-28 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
US10112957B2 (en) 2014-10-22 2018-10-30 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
EP3715346A1 (en) 2014-10-22 2020-09-30 Dana-Farber Cancer Institute Thiazolyl-containing compounds for treating proliferative diseases
US10844077B2 (en) 2014-10-22 2020-11-24 Dana-Farber Cancer Institute, Inc. Thiazolyl-containing compounds for treating proliferative diseases
CN105837577B (en) * 2015-02-02 2019-01-25 四川大学 1- (pyrimidine-4-yl) 3- aminopiperidine derivatives and its preparation method and application
CN105837577A (en) * 2015-02-02 2016-08-10 四川大学 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use
US11174243B2 (en) 2016-07-21 2021-11-16 Sunesis Pharmaceuticals, Inc. Succinate forms and compositions of Bruton's tyrosine kinase inhibitors
WO2018053437A1 (en) 2016-09-19 2018-03-22 Mei Pharma, Inc. Combination therapy
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors
US11345681B1 (en) 2020-06-05 2022-05-31 Kinnate Biopharma Inc. Inhibitors of fibroblast growth factor receptor kinases
US11459310B2 (en) 2020-10-22 2022-10-04 Landos Biopharma, Inc. LANCL ligands
WO2022212893A1 (en) 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis

Also Published As

Publication number Publication date
EP2485589A1 (en) 2012-08-15
EP2485589A4 (en) 2013-02-06
US20120157442A1 (en) 2012-06-21
US9029359B2 (en) 2015-05-12

Similar Documents

Publication Publication Date Title
US9029359B2 (en) Heteroaryl Btk inhibitors
JP6673969B2 (en) Bruton-type tyrosine kinase inhibitors
US9273028B2 (en) Heterocyclic tyrosine kinase inhibitors
TWI788655B (en) Tyk2 inhibitors and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10814583

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13393191

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2010814583

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2010814583

Country of ref document: EP