WO2016127074A1 - 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors - Google Patents

2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors Download PDF

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WO2016127074A1
WO2016127074A1 PCT/US2016/016808 US2016016808W WO2016127074A1 WO 2016127074 A1 WO2016127074 A1 WO 2016127074A1 US 2016016808 W US2016016808 W US 2016016808W WO 2016127074 A1 WO2016127074 A1 WO 2016127074A1
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compound
alkylene
pyrazol
methyl
ring
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PCT/US2016/016808
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French (fr)
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Paul E. Fleming
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Blueprint Medicines Corporation
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Priority to US15/548,925 priority Critical patent/US10202365B2/en
Publication of WO2016127074A1 publication Critical patent/WO2016127074A1/en
Priority to US16/228,381 priority patent/US10774070B2/en

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    • 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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to inhibitors of RET that are active against wild-type RET and its resistant mutants.
  • RET is a receptor tyrosine kinase that activates multiple downstream pathways involved in ceil proliferation and survival. RET fusions are implicated in several cancers including papillary thyroid carcinoma and non-small cell lung cancer. A genomics analysis on the landscape of kinase fusions identified RET fusions in breast and colon cancer patient samples, providing therapeutic rationale for the use of RET inhibitors in multiple patient subpopulations.
  • RET fusions as drivers in some cancers prompted the use of approved multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express a RET fusion protein.
  • these drugs cannot always be dosed at the levels required to sufficiently inhibit RET due to toxicities that result from inhibition of targets other than RET.
  • Kinase reactivation via mutation is a common mechanism of resistance. When resistance occurs, the patient's treatment options are often very limited, and the cancer progresses, unchecked, in most instances. There is thus a need for compounds that inhibit RET, as well as its resistant mutants.
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:
  • Rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
  • each L and L is independently selected from a bond, -(Ci-C 6 alkylene)-, -(C 2 -C 6 alkenylene)-, -(C 2 -C 6 alkynylene)-, -(Ci-C 6 haloalkylene)-, -(Ci-C 6 heteroalkylene)-, -C(O)-, -0-, -S-, -S(O), -S(0) 2 -, -NCR 1 )-, -0-(Ci-C 6 alkylene)-, -(Ci-C 6 alkylene)-0-, -NCR ⁇ -CCO)-, -C(O)- NiR 1 )-, -(Ci-C 6 alkylene)-N(R 1 )-, alkylene)-, -N(R 1 )-C(0)-(d-C 6 alkylene)-, - (Ci-C 6 alkylene)-N(R 1
  • each R and R is independently selected from Ci-C 6 alkyl, Ci-C 6 alkoxy, halo, Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, Ci-C 6 heteroalkyl, and -N ⁇ R ⁇ R 1 ); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of
  • each R and R is independently selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, halo, Ci-C 6 heteroalkyl, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, Ci-C 6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, - C(0)R 1 , -OC(0)R 1 , -C(0)OR 1 , -(Ci-C 6 alkylene)-C(0)R 1 , -SR 1 , -SCO ⁇ R 1 , -S(0) 2 -N(R 1 )(R 1 ) , -(Ci-C 6 alkylene)-S(0) 2 R 1 , -(Ci-C 6 alkylene)-S(0) 2 -N
  • haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a ; or 2 R c or 2 R D together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R a ;
  • each R 1 is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C 6 alkyl, Q- C 6 thioalkyl, Q-C 6 alkoxy, Q-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, Ci-C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl,
  • heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R b , or 2 R 1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;
  • each R a and R b is independently Ci-C 6 alkyl, halo, hydroxyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, Ci-C 6 hydroxyalkyl, Ci-C 6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl is
  • each R' is Ci-C 6 alkyl, Ci-C 6 heteroalkyl, halo, hydroxyl, Ci-C 6 haloalkyl, Ci-C 6 hydroxyalkyl, cycloalkyl or cyano; or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • p and q are each independently 0, 1, 2, 3, or 4.
  • a "patient,” “subject,” “individual,” and “host” refer to either a human or a non-human animal suffering from or suspected of suffering from a disease or disorder associated with aberrant RET expression (i.e., increased RET activity caused by signaling through RET) or biological activity.
  • Treat” and “treating” such a disease or disorder refers to ameliorating at least one symptom of the disease or disorder.
  • These terms when used in connection with a condition such as a cancer, refer to one or more of: impeding growth of the cancer, causing the cancer to shrink by weight or volume, extending the expected survival time of the patient, inhibiting tumor growth, reducing tumor mass, reducing size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonging survival, prolonging progression- free survival, prolonging time to progression, and/or enhancing quality of life.
  • preventing when used in relation to a condition or disease such as cancer, refers to a reduction in the frequency of, or delay in the onset of, symptoms of the condition or disease.
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • therapeutic effect refers to a beneficial local or systemic effect in animals, particularly mammals, and more particularly humans, caused by administration of a compound or composition of the invention.
  • therapeutically-effective amount means that amount of a compound or composition of the invention that is effective to treat a disease or condition caused by over expression of RET or aberrant RET biological activity at a reasonable benefit/risk ratio.
  • the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of skill in the art.
  • developing resistance means that when a drug is first administered to the patient, the patient's symptoms improve, whether measured by decrease in tumor volume, a decrease in the number of new lesions, or some other means that a physician uses to judge disease progression; however, those symptoms stop improving, or even worsen at some point. At that time, the patient is said to have developed resistance to the drug.
  • Aliphatic group means a straight-chain, branched-chain, or cyclic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, and an alkynyl group.
  • Alkylene refers to a divalent radical of an alkyl group, e.g. , -CH 2 -, -CH 2 CH 2 -, and CH 2 CH 2 CH 2 -.
  • Alkenyl means an aliphatic group containing at least one double bond.
  • Alkoxyl or "alkoxy” means an alkyl group having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • haloalkoxy refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g. , perfluoroalkoxy) .
  • Alkyl refers to a monovalent radical of a saturated straight or branched hydrocarbon, such as a straight or branched group of 1- 12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Ci 2 alkyl, Ci-Cio alkyl, and Ci-C 6 alkyl, respectively.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl,
  • Alkenylene refers to an alkenyl group having two connecting points.
  • Alkenylene groups can also be in an unsubstituted form or substituted form with one or more substituents.
  • Alkynyl refers to a straight or branched hydrocarbon chain containing 2- 12 carbon atoms and characterized in having one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
  • One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
  • Alkynylene refers to an alkynyl having two connecting points. For example,
  • ethynylene represents the group -C ⁇ C-.
  • Alkynylene groups can also be in an unsubstituted form or substituted form with one or more substituents.
  • Hydroxy alky lene or “hydroxyalkyl” refers to an alkylene or alkyl moiety in which an alkylene or alkyl hydrogen atom is replaced by a hydroxyl group. Hydroxyalkylene or hydroxyalkyl includes groups in which more than one hydrogen atom has been replaced by a hydroxyl group.
  • Aromatic ring system is art-recognized and refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.
  • Aryl refers to a monovalent radical of an aromatic ring system.
  • Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl, and ring systems where an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.
  • Arylalkyl or “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of “arylalkyl” or “aralkyl” include benzyl, 2- phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
  • Aryloxy refers to -O-(aryl), wherein the heteroaryl moiety is as defined herein.
  • Halo refers to a radical of any halogen, e.g. , -F, -CI, -Br, or -I.
  • Haloalkyl and haloalkoxy refers to alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Haloalkylene refers to a divalent alkyl, e.g. , -C3 ⁇ 4-, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo.
  • Heteroalkyl refers to an optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given, e.g. Ci-C 6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a "C 3 " heteroalkyl. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain.
  • Heteroalkylene refers to a divalent optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • Carbocyclic ring system refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic.
  • Carbocyclyl refers to a monovalent radical of a carbocyclic ring system.
  • carbocyclyl groups include cycloalkyl groups (e.g. , cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g. , cyclopentenyl,
  • Cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g. , by one or more substituents).
  • the cycloalkyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
  • Cycloalkylalkyl refers to a -(cycloalkyl)-alkyl radical where cycloalkyl and alkyl are as disclosed herein.
  • the "cycloalkylalkyl” is bonded to the parent molecular structure through the cycloalkyl group.
  • Heteroaromatic ring system is art-recognized and refers to monocyclic, bicyclic or polycyclic ring system wherein at least one ring is both aromatic and comprises at least one heteroatom (e.g. , N, O or S); and wherein no other rings are heterocyclyl (as defined below).
  • a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in such ring.
  • Heteroaryl refers to a monovalent radical of a heteroaromatic ring system.
  • heteroaryl groups include ring systems where (i) each ring comprises a heteroatom and is aromatic, e.g. , imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or e.g. , indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
  • each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g. , 4H-quinolizinyl.
  • Heterocyclic ring system refers to monocyclic, bicyclic and polycyclic ring systems where at least one ring is saturated or partially unsaturated (but not aromatic) and comprises at least one heteroatom.
  • a heterocyclic ring system 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.
  • Heterocyclyl refers to a monovalent radical of a heterocyclic ring system.
  • heterocyclyls include ring systems in which (i) every ring is non-aromatic and at least one ring comprises a heteroatom, e.g. , tetrahydro furanyl, tetrahydropyranyl,
  • At least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, e.g. ,
  • heterocyclyl can include:
  • base structure can be through any of the atoms on the heterocyclyl, e.g. , through a carbon atom or a nitrogen atom of the heterocyclyl.
  • Heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group.
  • Cyano refers to a -CN radical.
  • Niro refers to -N0 2 .
  • Hydroalkylene refers to a divalent alkyl, e.g. , -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, in which one or more hydrogen atoms are replaced by a hydroxy, and includes alkyl moieties in which all hydrogens have been replaced by hydroxy.
  • Substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each expression e.g. , alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • enantiomeric excess or "% enantiomeric excess” of a composition can be calculated using the equation shown below.
  • a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.
  • composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
  • the compounds or compositions described herein may contain an enantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one form of the compound, e.g., the S-enantiomer. In other words such compounds or compositions contain an enantiomeric excess of the S-enantiomer.
  • the compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example deuterium ( H), tritium ( 3 H), carbon- 13 ( 13 C), or carbon- 14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In addition, all tautomeric forms of the compounds described herein are intended to be within the scope of the invention.
  • the compound can be useful as the free base or as a salt.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • each of L 1 and L 2 is other than a bond; and the com ound is other than:
  • ring A is heteroaryl. In some aspects of these embodiments, ring A is IH-pyrazolyl. In some more specific aspects of these embodiments, ring A is lH-pyrazol-3-yl.
  • p is 1 or more and at least one R c is Ci-C 4 alkyl. In some aspects of these embodiments, p is 1. In some aspects of these embodiments, at least one R c is methyl. In more specific aspects of these embodiments, p is 1 and R c is methyl. In even more specific aspects of these embodiments, the portion of the compound represented by: is 5-methyl-lH-pyrazol-3-yl.
  • L 1 is alkylene)- ⁇ , or -N(R 1 )-C(0)-(Ci-C 6 alkylene)- ⁇ , wherein " ⁇ " represents a portion of L 1 bound to ring A. In some aspects of these embodiments, L 1 is -NCR 1 )-. In more specific aspects of these embodiments,
  • L 1 is -NH-.
  • L is selected from *-C(0)-, *-N(R )-C(0)- and
  • L 2 is *-C(0)-. In other aspects of these embodiments, L 2 is
  • L 2 is *-(d-C
  • the compound has structural Formula 1(b): 1(b), or a pharmaceutically acceptable salt thereof, wherein L 2 is *-(Ci-C 6 alkylene)-N(R 1 )-C(0)-, each of R A , R B , R D , ring B, m, n and q are defined as for Formula I, and wherein the Ci-C 6 alkylene portion of L is substituted with 0-5 occurrences of R'.
  • L is selected from
  • L 2 is selected from *-CH 2 -NH-C(0)-, *-CH(CH 3 )-NH-C(0)-, and
  • R 1 , R A , R B , R D , ring B, m, n and q are defined as for Formula I.
  • the invention provides a compound of Formula 1(d):
  • the invention provides a compound of Formula 1(e):
  • R 1 is hydrogen.
  • n is 0 or 1. In some aspects of these embodiments, n is 0. In alternate aspects of these embodiments, n is 1. In more specific aspects of these embodiments, n is 1 and R is C C 4 alkyl. In even more specific aspects of these embodiments, n is 1 and R is methyl.
  • m is 0 or 1. In some aspects of these embodiments, m is 0. In alternate aspects of these embodiments, m is 1. In more specific aspects of these embodiments, m is 1 and R A is Ci-C 4 alkyl or halo. In even more specific aspects of these embodiments, m is 0, or m is 1 and R A is methyl or fluoro.
  • ring B is selected from aryl, heteroaryl and heterocyclyl. In some aspects of these embodiments, ring B is selected from phenyl, furanyl, thiazolyl, pyridinyl, pyrazinyl and isoindolinyl. In more specific aspects of these embodiments, ring B is selected from phenyl, furan-3-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl and, when L is -C(O)-, isoindolin-l-yl.
  • q is 0, 1, or 2. In one aspect of these embodiments, q is 0. In another aspect of these embodiments, q is 1 or 2 and each q is independently selected from halo, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, -0-Ci-C 4 alkyl, -0-Ci-C 4 fluoroalkyl, and optionally substituted heteroaryl. In more specific aspects of these
  • q is 1 or 2 and each q is independently selected from fluoro, chloro, methyl, -O-CH 3 , -O-CH 2 CH 3 , -0-CH(CH 3 ) 2 , -0-CHF 2 , -0-CF 3 , and optionally substituted lH-pyrazol-1- yl.
  • q is 1 or 2 and each q is independently selected from fluoro, chloro, methyl, -0-CH 3 , -0-CH 2 CH 3 , -0-CH(CH 3 ) 2 , -0-CHF 2 , -0-CF 3 , 4- methyl-lH-pyrazol-l-yl, IH-pyrazol-l-yl, 4-fluoro-lH-pyrazol-l-yl, 4-cyano-lH-pyrazol-l-yl, 3,5-dimethyl-lH-pyrazol-l-yl, 3-cyclopropyl-lH-pyrazol-l-yl, 4-cyclopropyl-lH-pyrazol-l-yl, 4-(l-hydroxyethyl)-lH-pyrazol-l-yl, 4-difluoromethyl-lH-pyrazol-l-yl, and 3-methyl-4- difluoromethyl- lH-pyrazol
  • “Pharmaceutically acceptable salt” refers to any salt of a compound of the invention which retains its biological propeilies and which is not toxic or otherwise undesirable for pharmaceut cal use.
  • Pharmaceutically acceptable salts may be derived from a variety of organic and inorganic counter-ions well known in the art and include.
  • Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifiuoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glyceric, glutamic, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethane sulfonic, 1 ,2-ethane-disulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic
  • Pharmaceutically acceptable salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylaramonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromi.de, tartrate, mesylate, besylate, acetate, maleate, oxalate and the like.
  • compositions of the invention comprise one or more compounds of the invention and one or more physiologically or pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions of the invention are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tween, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally
  • any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • the LD 50 is the dose lethal to 50% of the population.
  • the ED 50 is the dose therapeutically effective in 50% of the population.
  • the dose ratio between toxic and therapeutic effects (LD 50 / ED 50 ) is the therapeutic index. Compounds that exhibit large therapeutic indexes are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the dosage of such compounds may lie within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • RET fusions have been implicated in several types of cancers. Generally, these RET fusions have a RET kinase domain that is the same as in wild-type RET; therefore, as used herein, any RET protein with the same kinase domain as wild-type RET will be referred to as "wild-type RET.” Mutations can occur in the RET kinase domain, leading to resistant mutants of RET.
  • exemplary compounds that are approved or in development for RET- related conditions are shown below. As shown, the compounds are active against the wild-type RET, but are much less active against the mutated forms.
  • the invention provides compounds that inhibit both wild-type RET and resistant mutants of RET.
  • the compounds of the invention can be selective for wild-type RET, over other kinases, thus leading to reduced toxicities associated with inhibiting other kinases.
  • mutant RET provides inhibitors of mutant RET. Mutations can be predicted using structural biology and computational analyses, as well as by examining codon sequences in which a sequence change gives rise to a codon for a different amino acid. Using such methods, resistant mutants for RET are predicted to have point mutations at the 804 gatekeeper residue in the RET protein and/or at residues at or near the gatekeeper residue. In some embodiments, the mutation may be at one or more of the 804, 806, 810, 865, 870, 891, and 918 residues.
  • RET resistant mutants include: V804L, V804M, V804E, Y806C, Y806S, Y806H, Y806N, G810R, G810S, L865V, L870F, S891A and M918T mutants.
  • Mutations occurring from administration of a particular inhibitor can be determined experimentally by exposing cells to a mutation-promoting agent, such as ENU. The cells are washed, then plated with increasing concentrations (2-100X proliferation IC 50 ) of the compound of choice. The wells with cellular outgrowth are then collected after 3-4 weeks. The RET kinase domain is then sequenced to identify resistance mutations (i.e., altered forms of the RET protein that retain enzymatic activity). Resistance can be confirmed by exposing these cells with the compound of choice. Resistant mutants that have been identified experimentally include the V804L, V804E, V804M, and Y806H mutants.
  • the compounds described herein can be used to treat a patient with a condition associated with aberrant RET activity. They can also be used to treat various cancers.
  • the cancer is selected from papillary thyroid carcinoma (PTC), medullary thyroid cancer (MTC),
  • PC pheochromocytoma
  • MEN2A and MEN2B pancreatic ductal adenocarcinoma
  • metastatic breast cancer testicular cancer, small cell lung cancer, non- small cell lung cancer, chronic myelomonocytic leukemia, colorectal cancer, ovarian cancer, and cancers of the salivary gland.
  • the compounds can also be used to treat a patient who has developed resistance to a wild-type RET inhibitor, or a patient with a particular RET mutant.
  • the method includes the step of administering a compound or composition of the invention that is active against one or more RET resistant mutants.
  • the RET resistant mutant is selected from V804L, V804M, V804E, Y806C, Y806S, Y806N, Y806H, G810R, G810S, L865V, L870F, S891A and M918T.
  • active is meant that a compound has an IC 50 of less than 1 ⁇ , 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 10 nM, or 5 nM when measured in a biochemical assay, against at least one resistant mutant.
  • the compounds and compositions described herein can be administered alone or in combination with other compounds, including other RET-modulating compounds, or other therapeutic agents.
  • the compound or composition of the invention may be administered in combination with one or more compounds selected from Cabozantinib (COMETRIQ), Vandetanib (CALPRESA), Sorafenib (NEXAVAR), Sunitinib (SUTENT), Regorafenib (STAVARGA), Ponatinib (ICLUSIG), Bevacizumab (AVASTIN), Crizotinib (XALKORI), or Gefitinib (IRESSA).
  • the compound or composition of the invention may be administered simultaneously or sequentially with the other therapeutic agent by the same of different routes of administration.
  • the compound of the invention may be included in a single formulation with the other therapeutic agent or in separate formulations.
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. , temperatures which can range from the solvent' s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry data (sample analyzed for purity and identity) were obtained with an Agilent model- 1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C 18, 2.7um particle size, 3.0 x 50mm dimensions) reverse- phase column at 22.4 degrees Celsius.
  • the mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized. The flow rate was constant at lmL/min.
  • R lower alkyl group
  • the pyrimidine can be coupled to Ring A under nucleophilic aromatic substitution reaction conditions using a base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solvent to provide the bicyclic ring system.
  • DIPEA diisopropylethylamine
  • TEA triethylamine
  • the pyrimidine of the bicyclic ring system can be coupled to a boron, tin or zinc aryl or heteroaryl reagent via a Palladium-mediated coupling reaction, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system.
  • the carboxylic acid can be coupled to a variety of amines, such as those described below under the heading "Synthesis of Amine Intermediates,” to provide the amide final product.
  • Step 2 Synthesis of 5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)picolinic acid
  • Step 3 Synthesis of (S)-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4-methyl- 6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
  • bromo R lower alkyl e.g., halo, e.g., CI or Br
  • the organometallic intermediate can be coupled to the substituted pyrimidine under Palladium- mediated coupling conditions, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system.
  • Palladium- mediated coupling conditions e.g. , Suzuki, Stille, Negishi coupling
  • the resultant carboxylic acid can be reacted with an amine, such as an amine as described below under the heading "Synthesis of Amine Intermediates," using amide coupling reaction conditions (such as HATU and diisopropylethylamine) to provide the final compound.
  • amide coupling reaction conditions such as HATU and diisopropylethylamine
  • Step 4 Synthesis of 3-methyl-5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin- 2-yl)picolinic acid
  • Step 5 Synthesis of (S)-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-3-methyl-5- (4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
  • M metal, e.g.,
  • R lower alkyl e.g., halo, e.g., CI or Br
  • the carboxylic acid substituted pyridine can be reacted with an amine, such as those described below under the heading "Synthesis of Amine Intermediates," using amide coupling reaction conditions (such as HATU and diisopropylethylamine) to provide the bicyclic amide.
  • the bicyclic amide can be converted to the organometallic intermediate and then coupled to the substituted pyrimidine under Palladium-mediated coupling conditions, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system.
  • Step 1 Synthesis of (S)-5-bromo-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)picolinamide
  • Step 2 Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide
  • Step 3 Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4- methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
  • tert-butyl ((6-(4-cyano-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
  • tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (1.0 g, 2.83 mmol), Zn(CN)2 (200 mg, 1.70 mmol), Zn (185 mg, 2.83 mmol) and Pd(dppf)C12 (200 mg, 0.28 mmol) in DMF (10 mL) was stirred at 150 °C for 6 hours. LCMS showed the reaction was completed.
  • 5-(4-fluoro-lH-pyrazol-l-yl)pyrazine-2-carbonitrile To a solution of 5-chloropyrazine-2-carbonitrile (280 mg, 2.0 mmoL) in DMF was added 4-fluoro-lH-pyrazole (170 mg,2.0 mmoL), and potassium acetate (395 mg, 4.0 mmoL). The mixture was stirred at the 100°C for 4 hours. The reaction mixture was cooled to 20°C, poured into brine (25 mL), and extracted with ethyl acetate.
  • the Caliper LifeSciences electrophoretic mobility shift technology platform is used. Fluorescently labeled substrate peptide is incubated in the presence of kinase and ATP so that a reflective proportion of the peptide is phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides are passed through the microfluidic system of the Caliper EZ Reader 2, under an applied potential difference. The presence of the phosphate group on the product peptide provides a difference in mass and charge between those of the substrate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass a LEDS within the instrument, these pools are detected and resolved as separate peaks. The ratio between these peaks therefore reflects the activity of the chemical matter at that concentration in that well, under those conditions. RET wild type assay at KM
  • 7.5 nM - 10 nM of wild type RET (ProQinase 1090- 0000-1) is incubated in a total of 12.5 of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl 2 , ImM DTT) with 1 ⁇ CSKtide (FITC - AHA- KKKKD DIYFFFG-NH2) and 25 ⁇ ATP at 25°C for 120 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration).
  • buffer 100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl 2 , ImM DTT
  • 1 ⁇ CSKtide FITC - AHA- KKKKD DIYFFFG-NH2
  • the reaction is stopped by the addition of 70 ⁇ ⁇ of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)).
  • Stop buffer 100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)
  • the plate is then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data is normalized to 0% and 100% inhibition controls and the IC 50 calculated using a 4-parameter fit in the CORE LIMS.
  • 7.5 nM - 10 nM of mutant RET (ProQinase 1096-0000- 1) is incubated in a total of 12.5 ⁇ , of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgC12, ImM DTT) with 1 ⁇ CSKtide (FITC-AHA-KKKKDDIYFFFG-NH2) and 10 ⁇ ATP at 25°C for 120 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration).
  • buffer 100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgC12, ImM DTT
  • 1 ⁇ CSKtide FITC-AHA-KKKKDDIYFFFG-NH2
  • the reaction is stopped by the addition of 70 ⁇ ⁇ of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)).
  • Stop buffer 100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)
  • the plate is then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data is normalized to 0% and 100% inhibition controls and the IC 50 calculated using a 4-parameter fit in the CORE LIMS.

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Abstract

Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

Description

2-(PYRIDIN-3-YL)-PYRIMIDINE DERIVATIVES AS RET INHIBITORS
This invention relates to inhibitors of RET that are active against wild-type RET and its resistant mutants.
BACKGROUND
RET is a receptor tyrosine kinase that activates multiple downstream pathways involved in ceil proliferation and survival. RET fusions are implicated in several cancers including papillary thyroid carcinoma and non-small cell lung cancer. A genomics analysis on the landscape of kinase fusions identified RET fusions in breast and colon cancer patient samples, providing therapeutic rationale for the use of RET inhibitors in multiple patient subpopulations.
The identification of RET fusions as drivers in some cancers prompted the use of approved multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express a RET fusion protein. However, these drugs cannot always be dosed at the levels required to sufficiently inhibit RET due to toxicities that result from inhibition of targets other than RET. Further, one of the greatest challenges in treating cancer is the ability of tumor cells to become resistant to therapy. Kinase reactivation via mutation is a common mechanism of resistance. When resistance occurs, the patient's treatment options are often very limited, and the cancer progresses, unchecked, in most instances. There is thus a need for compounds that inhibit RET, as well as its resistant mutants.
SUMMARY
In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000002_0001
(I)
Rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
1 2
each L and L is independently selected from a bond, -(Ci-C6 alkylene)-, -(C2-C6 alkenylene)-, -(C2-C6 alkynylene)-, -(Ci-C6 haloalkylene)-, -(Ci-C6 heteroalkylene)-, -C(O)-, -0-, -S-, -S(O), -S(0)2-, -NCR1)-, -0-(Ci-C6 alkylene)-, -(Ci-C6 alkylene)-0-, -NCR^-CCO)-, -C(O)- NiR1)-, -(Ci-C6 alkylene)-N(R1)-,
Figure imgf000003_0001
alkylene)-, -N(R1)-C(0)-(d-C6 alkylene)-, - (Ci-C6 alkylene)-N(R1)-C(0)-, -C(0)-N(R1)-(d-C6 alkylene)-, -(Ci-C6 alkylene)-C(0)-N(R1)-, -NiR^-SiO)^, -S(0)2-N(R1)-, -N(R1)-S(0)2-(Ci-C6 alkylene)-, and -S(0)2-N(R1)-(Ci-C6 alkylene)-; wherein each alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene is independently substituted with 0-5 occurrences of R' ;
A B
each R and R is independently selected from Ci-C6 alkyl, Ci-C6 alkoxy, halo, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, and -N^R^R1); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of
Ra;
C D
each R and R is independently selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, Ci-C6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, - C(0)R1, -OC(0)R1, -C(0)OR1, -(Ci-C6 alkylene)-C(0)R1, -SR1, -SCO^R1, -S(0)2-N(R1)(R1), -(Ci-C6 alkylene)-S(0)2R1, -(Ci-C6 alkylene)-S(0)2-N(R1)(R1), -NCR^R1), -C(0)-N(R1)(R1), - N(R1)-C(0)R1, -N(R1)-C(0)OR1, -(Ci-C6 alkylene)-N(R1)-C(0)R1, -NCR^SCO^R1, and - P(0)(R1)(R1); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl,
haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or 2 Rc or 2 RD together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Ra;
each R1 is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C6 alkyl, Q- C6 thioalkyl, Q-C6 alkoxy, Q-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb, or 2 R1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;
each Ra and Rb is independently Ci-C6 alkyl, halo, hydroxyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, Ci-C6 hydroxyalkyl, Ci-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl is
independently substituted with 0-5 occurrences of R' ;
each R' is Ci-C6 alkyl, Ci-C6 heteroalkyl, halo, hydroxyl, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, cycloalkyl or cyano; or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
m is 0, 1, 2, or 3;
n is 0, 1, or 2; and
p and q are each independently 0, 1, 2, 3, or 4.
EMBODIMENTS OF THE INVENTION
Definitions
As used herein, the terms a "patient," "subject," "individual," and "host" refer to either a human or a non-human animal suffering from or suspected of suffering from a disease or disorder associated with aberrant RET expression (i.e., increased RET activity caused by signaling through RET) or biological activity.
"Treat" and "treating" such a disease or disorder refers to ameliorating at least one symptom of the disease or disorder. These terms, when used in connection with a condition such as a cancer, refer to one or more of: impeding growth of the cancer, causing the cancer to shrink by weight or volume, extending the expected survival time of the patient, inhibiting tumor growth, reducing tumor mass, reducing size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonging survival, prolonging progression- free survival, prolonging time to progression, and/or enhancing quality of life.
The term "preventing" when used in relation to a condition or disease such as cancer, refers to a reduction in the frequency of, or delay in the onset of, symptoms of the condition or disease. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, particularly mammals, and more particularly humans, caused by administration of a compound or composition of the invention. The phrase "therapeutically-effective amount" means that amount of a compound or composition of the invention that is effective to treat a disease or condition caused by over expression of RET or aberrant RET biological activity at a reasonable benefit/risk ratio. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of skill in the art.
As used herein, "developing resistance" means that when a drug is first administered to the patient, the patient's symptoms improve, whether measured by decrease in tumor volume, a decrease in the number of new lesions, or some other means that a physician uses to judge disease progression; however, those symptoms stop improving, or even worsen at some point. At that time, the patient is said to have developed resistance to the drug.
"Aliphatic group" means a straight-chain, branched-chain, or cyclic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, and an alkynyl group.
"Alkylene" refers to a divalent radical of an alkyl group, e.g. , -CH2-, -CH2CH2-, and CH2CH2CH2-.
"Alkenyl" means an aliphatic group containing at least one double bond.
"Alkoxyl" or "alkoxy" means an alkyl group having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term "haloalkoxy" refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g. , perfluoroalkoxy) .
"Alkyl" refers to a monovalent radical of a saturated straight or branched hydrocarbon, such as a straight or branched group of 1- 12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Ci2 alkyl, Ci-Cio alkyl, and Ci-C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl,
2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl- l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
"Alkenylene" refers to an alkenyl group having two connecting points. For example, "ethenylene" represents the group -CH=CH-. Alkenylene groups can also be in an unsubstituted form or substituted form with one or more substituents.
"Alkynyl" refers to a straight or branched hydrocarbon chain containing 2- 12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
"Alkynylene" refers to an alkynyl having two connecting points. For example,
"ethynylene" represents the group -C≡C-. Alkynylene groups can also be in an unsubstituted form or substituted form with one or more substituents.
"Hydroxy alky lene" or "hydroxyalkyl" refers to an alkylene or alkyl moiety in which an alkylene or alkyl hydrogen atom is replaced by a hydroxyl group. Hydroxyalkylene or hydroxyalkyl includes groups in which more than one hydrogen atom has been replaced by a hydroxyl group.
"Aromatic ring system" is art-recognized and refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.
"Aryl" refers to a monovalent radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl, and ring systems where an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.
"Arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2- phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
"Aryloxy" refers to -O-(aryl), wherein the heteroaryl moiety is as defined herein.
"Halo" refers to a radical of any halogen, e.g. , -F, -CI, -Br, or -I.
"Haloalkyl" and "haloalkoxy" refers to alkyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine. "Haloalkylene" refers to a divalent alkyl, e.g. , -C¾-, -CH2CH2-, and -CH2CH2CH2-, in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo.
"Heteroalkyl" refers to an optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given, e.g. Ci-C6 heteroalkyl which refers to the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms. For example, a -CH2OCH2CH3 radical is referred to as a "C3" heteroalkyl. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain.
"Heteroalkylene" refers to a divalent optionally substituted alkyl, which has one or more skeletal chain atoms selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
"Carbocyclic ring system" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic.
"Carbocyclyl" refers to a monovalent radical of a carbocyclic ring system.
Representative carbocyclyl groups include cycloalkyl groups (e.g. , cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g. , cyclopentenyl,
cyclohexenyl, cyclopentadienyl, and the like).
"Cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g. , by one or more substituents). The cycloalkyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
"Cycloalkylalkyl" refers to a -(cycloalkyl)-alkyl radical where cycloalkyl and alkyl are as disclosed herein. The "cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl group.
"Heteroaromatic ring system" is art-recognized and refers to monocyclic, bicyclic or polycyclic ring system wherein at least one ring is both aromatic and comprises at least one heteroatom (e.g. , N, O or S); and wherein no other rings are heterocyclyl (as defined below). In certain instances, a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in such ring.
"Heteroaryl" refers to a monovalent radical of a heteroaromatic ring system.
Representative heteroaryl groups include ring systems where (i) each ring comprises a heteroatom and is aromatic, e.g. , imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or e.g. , indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3-b]- l,4-oxazin-3- (4H)-one, 5,6,7, 8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g. , 4H-quinolizinyl.
"Heterocyclic ring system" refers to monocyclic, bicyclic and polycyclic ring systems where at least one ring is saturated or partially unsaturated (but not aromatic) and comprises at least one heteroatom. A heterocyclic ring system 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.
"Heterocyclyl" refers to a monovalent radical of a heterocyclic ring system.
Representative heterocyclyls include ring systems in which (i) every ring is non-aromatic and at least one ring comprises a heteroatom, e.g. , tetrahydro furanyl, tetrahydropyranyl,
tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is an aromatic carbon ring, e.g. , 1,2,3,4-tetrahydroquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl; and (iii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, e.g. ,
1 3,4-dihydro- lH-pyrano[4,3-c]pyridine, and l,2,3,4-tetrahydro-2,6-naphthyridine. In some embodiments, heterocyclyl can include:
Figure imgf000009_0001
base structure can be through any of the atoms on the heterocyclyl, e.g. , through a carbon atom or a nitrogen atom of the heterocyclyl.
"Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group.
"Cyano" refers to a -CN radical.
"Nitro" refers to -N02.
"Hydroxy" or "hydroxyl" refers to -OH.
"Hydroxyalkylene" refers to a divalent alkyl, e.g. , -CH2-, -CH2CH2-, and -CH2CH2CH2-, in which one or more hydrogen atoms are replaced by a hydroxy, and includes alkyl moieties in which all hydrogens have been replaced by hydroxy.
"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 each position. Combinations of substituents envisioned under 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.
As used herein, the definition of each expression, e.g. , alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof.
The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.
ee = (90-10)/100 = 80%.
Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
The compounds or compositions described herein may contain an enantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one form of the compound, e.g., the S-enantiomer. In other words such compounds or compositions contain an enantiomeric excess of the S
enantiomer over the R enantiomer.
The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example deuterium ( H), tritium ( 3 H), carbon- 13 ( 13 C), or carbon- 14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In addition, all tautomeric forms of the compounds described herein are intended to be within the scope of the invention.
The compound can be useful as the free base or as a salt. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1- 19.)
Compounds
In some embodiments of Formula I each of L 1 and L 2 is other than a bond; and the com ound is other than:
Figure imgf000011_0001
Figure imgf000012_0001
In some embodiments of Formula I, ring A is heteroaryl. In some aspects of these embodiments, ring A is IH-pyrazolyl. In some more specific aspects of these embodiments, ring A is lH-pyrazol-3-yl.
In some embodiments of Formula I, p is 1 or more and at least one R c is Ci-C4 alkyl. In some aspects of these embodiments, p is 1. In some aspects of these embodiments, at least one R c is methyl. In more specific aspects of these embodiments, p is 1 and R c is methyl. In even more specific aspects of these embodiments, the portion of the compound represented by:
Figure imgf000012_0002
is 5-methyl-lH-pyrazol-3-yl.
In some embodiments of Formula I, L1 is
Figure imgf000012_0003
alkylene)-†, or -N(R1)-C(0)-(Ci-C6 alkylene)-†, wherein "†" represents a portion of L1 bound to ring A. In some aspects of these embodiments, L1 is -NCR1)-. In more specific aspects of these
embodiments, L1 is -NH-.
2 1
In some embodiments of Formula I, L is selected from *-C(0)-, *-N(R )-C(0)- and
1 2
*- C\-C alkylene)-N(R )-C(0)-, wherein the Ci-C6 alkylene portion of L is substituted with 0-5 occurrences of R', and wherein "*" represents a portion of L2 bound to ring B. In some aspects of these embodiments, L2 is *-C(0)-. In other aspects of these embodiments, L2 is
^-NCR^-CCO)-. In still other aspects of these embodiments, L2 is *-(d-C
1 2
alkylene)-N(R )-C(0)-, wherein the Ci-C6 alkylene portion of L is substituted with 0-5 occurrences of R' . In certain more specific aspects of these embodiments, the compound has structural Formula 1(b):
Figure imgf000013_0001
1(b), or a pharmaceutically acceptable salt thereof, wherein L2 is *-(Ci-C6 alkylene)-N(R1)-C(0)-, each of RA, RB, RD, ring B, m, n and q are defined as for Formula I, and wherein the Ci-C6 alkylene portion of L is substituted with 0-5 occurrences of R'.
In some more specific embodiments of Formula I or 1(b), L is selected from
^CHrNiR^-CiO)- and *-CH(Ci-C4 alkyli-NCR^-CiO)-. In some aspects of these
embodiments, L2 is selected from *-CH2-NH-C(0)-, *-CH(CH3)-NH-C(0)-, and
*-CH(CH2CH3)-NH-C(0)-.
a compound Formula 1(c):
Figure imgf000013_0002
or a pharmaceutically acceptable salt
wherein each of R1, RA, RB, RD, ring B, m, n and q are defined as for Formula I.
In some embodiments, the invention provides a compound of Formula 1(d):
Figure imgf000013_0003
1(d), wherein each of R1, RA, RB, RD, ring B, m, n and q are defined as for Formula I.
In some embodiments, the invention provides a compound of Formula 1(e):
Figure imgf000013_0004
1(e), wherein each of R1, RA, RB, RD, ring B, m, n and q are defined as for Formula I. In some embodiments of Formulae 1, 1(b), 1(c), 1(d), or 1(e), R1 is hydrogen.
In some embodiments of Formulae 1, 1(b), 1(c), 1(d), or 1(e), n is 0 or 1. In some aspects of these embodiments, n is 0. In alternate aspects of these embodiments, n is 1. In more specific aspects of these embodiments, n is 1 and R is C C4 alkyl. In even more specific aspects of these embodiments, n is 1 and R is methyl.
In some embodiments of Formulae 1, 1(b), 1(c), 1(d), or 1(e), m is 0 or 1. In some aspects of these embodiments, m is 0. In alternate aspects of these embodiments, m is 1. In more specific aspects of these embodiments, m is 1 and RA is Ci-C4 alkyl or halo. In even more specific aspects of these embodiments, m is 0, or m is 1 and RA is methyl or fluoro.
In some embodiments of Formulae 1, 1(b), 1(c), 1(d), or 1(e), ring B is selected from aryl, heteroaryl and heterocyclyl. In some aspects of these embodiments, ring B is selected from phenyl, furanyl, thiazolyl, pyridinyl, pyrazinyl and isoindolinyl. In more specific aspects of these embodiments, ring B is selected from phenyl, furan-3-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl and, when L is -C(O)-, isoindolin-l-yl.
In some embodiments of Formulae 1, 1(b), 1(c), 1(d), or 1(e), q is 0, 1, or 2. In one aspect of these embodiments, q is 0. In another aspect of these embodiments, q is 1 or 2 and each q is independently selected from halo, Ci-C4 alkyl, Ci-C4 fluoroalkyl, -0-Ci-C4 alkyl, -0-Ci-C4 fluoroalkyl, and optionally substituted heteroaryl. In more specific aspects of these
embodiments, q is 1 or 2 and each q is independently selected from fluoro, chloro, methyl, -O-CH3, -O-CH2CH3, -0-CH(CH3)2, -0-CHF2, -0-CF3, and optionally substituted lH-pyrazol-1- yl. In even more specific aspects of these embodiments, q is 1 or 2 and each q is independently selected from fluoro, chloro, methyl, -0-CH3, -0-CH2CH3, -0-CH(CH3)2, -0-CHF2, -0-CF3, 4- methyl-lH-pyrazol-l-yl, IH-pyrazol-l-yl, 4-fluoro-lH-pyrazol-l-yl, 4-cyano-lH-pyrazol-l-yl, 3,5-dimethyl-lH-pyrazol-l-yl, 3-cyclopropyl-lH-pyrazol-l-yl, 4-cyclopropyl-lH-pyrazol-l-yl, 4-(l-hydroxyethyl)-lH-pyrazol-l-yl, 4-difluoromethyl-lH-pyrazol-l-yl, and 3-methyl-4- difluoromethyl- lH-pyrazol- 1-yl. The table below shows the structures of exemplary compounds of the invention.
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Pharmaceutically acceptable salts of these compounds are also contemplated for the uses described herein.
"Pharmaceutically acceptable salt" refers to any salt of a compound of the invention which retains its biological propeilies and which is not toxic or otherwise undesirable for pharmaceut cal use. Pharmaceutically acceptable salts may be derived from a variety of organic and inorganic counter-ions well known in the art and include. Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifiuoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glyceric, glutamic, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethane sulfonic, 1 ,2-ethane-disulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4- toiuenesuifonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucohe onic, 3-phenylpropionic, trimethylacedc, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton presen in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanoiamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, Ν,Ν'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N- methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like. Pharmaceutically acceptable salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylaramonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromi.de, tartrate, mesylate, besylate, acetate, maleate, oxalate and the like.
Pharmaceutical Compositions
Pharmaceutical compositions of the invention comprise one or more compounds of the invention and one or more physiologically or pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions of the invention are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutically acceptable compositions of this invention may be orally
administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
Dosages
Toxicity and therapeutic efficacy of compounds of the invention, including
pharmaceutically acceptable salts and deuterated variants, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The LD50 is the dose lethal to 50% of the population. The ED50 is the dose therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects (LD50/ ED50) is the therapeutic index. Compounds that exhibit large therapeutic indexes are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
Data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds may lie within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
Treatment
RET fusions have been implicated in several types of cancers. Generally, these RET fusions have a RET kinase domain that is the same as in wild-type RET; therefore, as used herein, any RET protein with the same kinase domain as wild-type RET will be referred to as "wild-type RET." Mutations can occur in the RET kinase domain, leading to resistant mutants of RET.
The activity of exemplary compounds that are approved or in development for RET- related conditions is shown below. As shown, the compounds are active against the wild-type RET, but are much less active against the mutated forms.
Figure imgf000025_0001
The invention provides compounds that inhibit both wild-type RET and resistant mutants of RET. In addition, the compounds of the invention can be selective for wild-type RET, over other kinases, thus leading to reduced toxicities associated with inhibiting other kinases.
In addition, the invention provides inhibitors of mutant RET. Mutations can be predicted using structural biology and computational analyses, as well as by examining codon sequences in which a sequence change gives rise to a codon for a different amino acid. Using such methods, resistant mutants for RET are predicted to have point mutations at the 804 gatekeeper residue in the RET protein and/or at residues at or near the gatekeeper residue. In some embodiments, the mutation may be at one or more of the 804, 806, 810, 865, 870, 891, and 918 residues. Specific examples of RET resistant mutants include: V804L, V804M, V804E, Y806C, Y806S, Y806H, Y806N, G810R, G810S, L865V, L870F, S891A and M918T mutants.
Mutations occurring from administration of a particular inhibitor (e.g., a known RET wild-type inhibitor) can be determined experimentally by exposing cells to a mutation-promoting agent, such as ENU. The cells are washed, then plated with increasing concentrations (2-100X proliferation IC50) of the compound of choice. The wells with cellular outgrowth are then collected after 3-4 weeks. The RET kinase domain is then sequenced to identify resistance mutations (i.e., altered forms of the RET protein that retain enzymatic activity). Resistance can be confirmed by exposing these cells with the compound of choice. Resistant mutants that have been identified experimentally include the V804L, V804E, V804M, and Y806H mutants.
Because of their activity against wild-type RET and mutant RET, the compounds described herein can be used to treat a patient with a condition associated with aberrant RET activity. They can also be used to treat various cancers. In some embodiments, the cancer is selected from papillary thyroid carcinoma (PTC), medullary thyroid cancer (MTC),
pheochromocytoma (PC), pancreatic ductal adenocarcinoma, multiple endocrine neoplasia (MEN2A and MEN2B), metastatic breast cancer, testicular cancer, small cell lung cancer, non- small cell lung cancer, chronic myelomonocytic leukemia, colorectal cancer, ovarian cancer, and cancers of the salivary gland.
The compounds can also be used to treat a patient who has developed resistance to a wild-type RET inhibitor, or a patient with a particular RET mutant. The method includes the step of administering a compound or composition of the invention that is active against one or more RET resistant mutants. In certain embodiments, the RET resistant mutant is selected from V804L, V804M, V804E, Y806C, Y806S, Y806N, Y806H, G810R, G810S, L865V, L870F, S891A and M918T. By "active" is meant that a compound has an IC50 of less than 1 μΜ, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 10 nM, or 5 nM when measured in a biochemical assay, against at least one resistant mutant.
The compounds and compositions described herein can be administered alone or in combination with other compounds, including other RET-modulating compounds, or other therapeutic agents. In some embodiments, the compound or composition of the invention may be administered in combination with one or more compounds selected from Cabozantinib (COMETRIQ), Vandetanib (CALPRESA), Sorafenib (NEXAVAR), Sunitinib (SUTENT), Regorafenib (STAVARGA), Ponatinib (ICLUSIG), Bevacizumab (AVASTIN), Crizotinib (XALKORI), or Gefitinib (IRESSA). The compound or composition of the invention may be administered simultaneously or sequentially with the other therapeutic agent by the same of different routes of administration. The compound of the invention may be included in a single formulation with the other therapeutic agent or in separate formulations.
Synthesis
Compounds of the invention, including salts and N -oxides thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g. , temperatures which can range from the solvent' s freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic
1 13
resonance (NMR) spectroscopy (e.g. , H or C), infrared (IR) spectroscopy, spectrophotometry (e.g. , UV- visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical instruments and methods for compound characterization:
LC-MS: Unless otherwise indicated, all liquid chromatography-mass spectrometry (LC- MS) data (sample analyzed for purity and identity) were obtained with an Agilent model- 1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C 18, 2.7um particle size, 3.0 x 50mm dimensions) reverse- phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized. The flow rate was constant at lmL/min.
Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP®
Preparative system fitted with a Luna 5u C18(2) 100A, AXIA packed, 250 x 21.2 mm reverse- phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 25 minutes was utilized. The flow rate was constant at 20 niL/min. Reactions carried out in a microwave were done so in a Biotage Initiator microwave unit.
Silica gel chromato raphy: Silica gel chromatography was performed on either a
Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit.
Proton NMR: Unless otherwise indicated, all 1H NMR spectra were obtained with a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; 16 to 64 scans). Where characterized, all protons were reported in DMSO-d6 solvent as parts-per million (ppm) with respect to residual DMSO (2.50 ppm). EXAMPLES
The following examples are intended to be illustrative, and are not meant in any way to be limiting.
The below Schemes are meant to provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.
Synthetic Protocol 1 :
Figure imgf000029_0001
Pd-mediated
e.g., -NH2 coupling reaction
X = leaving group,
e.g., halo, e.g., CI or Br M = boronic acid or ester
R = lower alkyl group
Figure imgf000029_0002
The pyrimidine can be coupled to Ring A under nucleophilic aromatic substitution reaction conditions using a base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solvent to provide the bicyclic ring system. The pyrimidine of the bicyclic ring system can be coupled to a boron, tin or zinc aryl or heteroaryl reagent via a Palladium-mediated coupling reaction, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system. For example, in Synthetic Protocol 1, the pyrimidine ring of the bicyclic ring system can be coupled to the ester substituted pyridine under Suzuki coupling reaction conditions (X = halo, e.g., chloro; and M = B(OR)2) to provide the tricyclic carboxylic acid intermediate. The carboxylic acid can be coupled to a variety of amines, such as those described below under the heading "Synthesis of Amine Intermediates," to provide the amide final product.
Example 1. General Synthesis of Compound 25 and Related Analogs
Step 1: Synthesis of 2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine
A suspension of 2,4-dichloro-6-methyl-pyrimidine (120.00 g, 736.2 mmol, 1.00 eq) , 5- methyl-lH-pyrazol-3-amine (78.65 g, 0.81 mol, 1.10 eq) and DIPEA (142.72 g, 1.10 mol, 1.50 eq) in DMSO (400.00 mL) was heated at 60 °C for 16 hrs. TLC (PE/EA, 5: 1, 1: 1) showed the reaction was complete. The reaction mixture was cooled to 30 °C and poured into ice-water (800 mL). The resulting mixture was extracted with MTBE (800 mL x 10). The combined organic layers were washed with water (400 mL x 3), brine (400 mL x 3) and dried over Na2S04. After filtration, the filtrate was concentrated under reduced pressure and the residue was recrystallized from DCM ( 10 mL/g) to afford 2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4- amine (105.60 g, 472.14 mmol, 64%) as a yellow solid. The structure was confirmed by LC-MS and NMR.
Step 2: Synthesis of 5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)picolinic acid
2-chloro-6-methyl-N-(5-methyl-lHpyrazol-3-yl)pyrimidin-4-amine (2.05g, 9.17 mmol) (6 (methoxycarbonyl)pyridin-3-yl)boronic acid (2.65g, 1.6 eq), and Pd(PPh3)4 (0.5 g, 0.05 eq)and sodium carbonate (1.94g, 2 eq) were suspended in a mixture of ethanol (22.9 mL) toluene (11.5 mL) and water (11.5 mL) in a sealed tube. The tube was capped and heated with stirring 135°C overnight. LC-MS showed the reaction was about 60-70% complete. LC-MS showed unreacted chloropyrimidine in addition to desired product. An additional 2.4 g of) (6
(methoxycarbonyl)pyridin-3-yl)boronic acid, 530 mg of Pd(PPh3)4, and 1.9 g of sodium carbonate were added. The reaction mixture was stirred overnight at 135°C after degassing with nitrogen. After heating an additional 14 hours at 135-140°C. LC-MS showed at least 90% conversion to the desired product, 100% hydrolyzed to the carboxylic acid. The reaction was treated with water (-15 mL and 3 x 10 mL washes), and a light orange solid was removed by filtration. The filtrate was concentrated down to 1/2 volume, and extracted with EtOAc (-15 mL). The layers were separated, and the aqueous layer was carefully acidified to pH 4.5-5 with concentrated HC1. A fine, light orange solid was slowly isolated by filtration (overnight). The wet cake was washed with water (2 x 5 mL). After most of the water had been filtered off, the wet cake was dissolved into 500 mL of 1: 1 MeOH/DCM. The mixture was sonicated until all the product was dissolved. The solution was dried over 5-6 g of magnesium sulfate, which was then removed by filtration. The filtrate was concentrated down and dried to yield 1.729 g of yellow /light orange solid. LC-MS confirmed desired product in 90-95% purity.
Step 3: Synthesis of (S)-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4-methyl- 6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
5-(4-Methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinic acid (299 mg, 0.942 mmol) and (S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l-amine (315 mg, 1.13 mmol) were dissolved in DMF (4.7 mL). Diisopropylethylamine (1 mL, 0.73 g, 5.7 mmol) was added followed by HATU (430 mg, 1.13 mmol). At 30 minutes, LC-MS showed the reaction was complete. The reaction was treated with 5N NaOH/water (20 mL), sonicated, and stirred. A light orange solid was isolated by filtration. The crude was eluted on a 40 gram silica gel column with a DCM to 15% MeOH/DCM gradient over 45 minutes. The desired peak eluted at around 5-9% MeOH/DCM. The fractions containing nearly pure desired product were combined, concentrated down, and dried. This solid (-320 mg) was treated with
dichloromethane (~ 2 mL). A light yellow solid was isolated by filtration, washed with small amounts of DCM, and dried to yield (S)-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)- 5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide (249.1 mg, 50.9% yield). MS: M+l = 499.2.
Synthetic Protocol 2:
Figure imgf000032_0001
Pd-mediated
X = leaving coupling reaction
group, e.g., halo, M = boronic acid
e.g., chloro or or ester X = leaving group,
bromo R = lower alkyl e.g., halo, e.g., CI or Br
group
Figure imgf000032_0002
The substituted pyridine can be esterified using known methods in the art followed by conversion to the organometallic intermediate (wherein M = metal, e.g., boronic acid). The organometallic intermediate can be coupled to the substituted pyrimidine under Palladium- mediated coupling conditions, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system. Upon hydrolysis of the ester, the resultant carboxylic acid can be reacted with an amine, such as an amine as described below under the heading "Synthesis of Amine Intermediates," using amide coupling reaction conditions (such as HATU and diisopropylethylamine) to provide the final compound. Compound 29 in Example 2 (below) and related analogs were prepared by the methods described above in Synthetic Protocol 2.
Example 2. General Synthesis of Compound 29 and Related Analogs
Step 1: Synthesis of methyl 5-bromo-3-methylpicolinate
To a mixture of 5-bromo-3-methylpicolinic acid (600 mg, 2.8 mmol) in MeOH (10 mL) was added SOCl2 (397 mg, 3.3 mmol). The mixture was stirred at reflux temperature for 6 hours. LCMS showed the reaction was complete. The reaction mixture was evaporated in vacuo to afford methyl 5-bromo-3-methylpicolinate (640 mg, 99% yield), m/z = 229.76( +H)+, as an off-white solid.
Step 2: Synthesis of (6-(methoxycarbonyl)-5-methylpyridin-3-yl)boronic acid
A mixture of methyl 5-bromo-3-methylpicolinate (640 mg, 2.78 mmol),
bis(pinacolato)diboron (1.06 g, 4.17 mmol), KOAc (681 mg, 6.96 mmol) and Pd(dppf)Cl2 (102 mg, 0.14 mmol) in 1, 4 - dioxane (8 mL) was stirred under N2 at 100 °C for 4 hours. LCMS showed the reaction was fully converted to (6-(methoxycarbonyl)-5-methylpyridin-3-yl)boronic acid. The crude product was used in the next step directly without any purification, m/z = 195.80 (M+H)+ .
Step 3: Synthesis of 3-methyl-5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin- 2-yl)picolinate
A mixture of 2-chloro-6-methyl-N-(5-methyl- lH-pyrazol-3-yl)pyrimidin-4-amine (500 mg, 2.23 mmol), (6-(methoxycarbonyl)-5-methylpyridin-3-yl)boronic acid (crude), Cs2C03 (1.46 g, 4.46 mmol) and Pd(dppf)Cl2 (163 mg, 0.22 mmol) in 1, 4-dioxane / H20 (10 mL / 1 mL) was stirred under N2 at 110 °C for 16 hours. LCMS showed the reaction was complete. Then the mixture was filtered and the filtrate was purified by prep-TLC (ethyl acetate) to afford methyl 3- methyl-5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinate (300 mg, 40% yield), m/z = 338.96 (M+H)+, as a yellow solid.
Step 4: Synthesis of 3-methyl-5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin- 2-yl)picolinic acid
A mixture of methyl 3-methyl-5-(4-methyl-6-((5-methyl- lH-pyrazol-3- yl)amino)pyrimidin-2-yl)picolinate (300 mg, 0.89 mmol) in MeOH / H20 (3 mL / 3 mL) was added lithium hydroxide (106 mg, 4.4 mmol). The mixture was stirred at room temperature for 16 hours. Then MeOH was removed in vacuo and water (5 mL) was added. HC1 (6 ) was added to adjust the reaction mixture to a pH of approximately 3. The solid in the mixture was separated and dried to afford 3-methyl-5-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyrimidin-2-yl)picolinic acid (120 mg, 41% yield), m/z =325.02 (M+H)+, as a yellow solid.
Step 5: Synthesis of (S)-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-3-methyl-5- (4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
A mixture of 3-methyl-5-(4-methyl-6-((5-methyl- lH-pyrazol-3-yl)amino)pyrimidin-2- yl)picolinic acid (30 mg, 0.09 mmol), (S)- l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethan-l- amine (0.12 mmol), DIEA (36 mg, 0.28 mmol) and HATU (42 mg, 0.11 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was purified by prep-HPLC to give the target compound. (18 mg).
Transmetallation
Figure imgf000034_0001
e.g., chloro or
bromo
Figure imgf000034_0002
Pd-mediated
coupling reaction
M = metal, e.g.,
boronic acid X = leaving group,
R = lower alkyl e.g., halo, e.g., CI or Br
group
Figure imgf000034_0003
The carboxylic acid substituted pyridine can be reacted with an amine, such as those described below under the heading "Synthesis of Amine Intermediates," using amide coupling reaction conditions (such as HATU and diisopropylethylamine) to provide the bicyclic amide. The bicyclic amide can be converted to the organometallic intermediate and then coupled to the substituted pyrimidine under Palladium-mediated coupling conditions, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system.
Example 3: Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5- (4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide (Compound 30).
Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide
Figure imgf000035_0001
Step 1: Synthesis of (S)-5-bromo-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)picolinamide
A mixture of (S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethanamine (340 mg, 1.21 mmol) and 5-bromo-3-fluoropicolinic acid (255 mg, 1.16 mmol) in diisopropylethylamine (1.2 mL, 900 mg, 7.0 mmol) and N,N-dimethylformamide (2.9 mL) was stirred and sonicated to a near solution before addition of HATU (530 mg, 1.39 mmol). After 5 minutes, the reaction was treated with 5N aqueous NaOH (20 mL), sonicated, and stirred for 20 minutes. A light yellow, sticky solid was isolated by filtration, dried, and loaded onto a 24 g silica gel column, which was eluted with a DCM to 10% MeOH/ DCM gradient over 45 minutes. The test tubes containing pure desired product by TLC were combined, concentrated down, and dried to yield (S)-5- bromo-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)picolinamide (164 mg, 34.6% yield) as a white solid. MS: M+l = 408.0.
Step 2: Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide
A mixture of (S)-5-bromo-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)picolinamide (164 mg, 0.402 mmol), bis(pinacolato)diboron (112 mg, 0.442 mmol), potassium acetate (118 mg, 1.21 mmol), and PdCl2(dppf) (14.7 mg, 0.020 mmol) in dioxane (1.8 mL) was degassed with nitrogen in a sealed tube, which was then sealed. The mixture was stirred at 90°C for 1.5 hours. The reaction turned dark red and was nearly a solution. The reaction was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with brine (200 mL). The organic layer was dried over sodium sulfate, filtered, concentrated down, and dried to yield (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide (280 mg, 65% purity, assumed 100% yield) as a crude, brown thick oil. MS: M+l (hydrolysis of boronate to boronic acid) = 374.1.
Step 3: Synthesis of (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4- methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)picolinamide
A mixture of 2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (85 mg, 0.38 mmol), (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)picolinamide (279 mg, 0.399 mmol), potassium carbonate (158 mg, 1.14 mmol), and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) in 1,2- dimethoxyethane (2.5 mL) and water (1.3 mL) was degassed with nitrogen in a sealed tube, which was then sealed and stirred at 125°C for 1.5 hours. The reaction was cooled to room temperature and treated with water (-15 mL). A beige solid was isolated by filtration, dried, and purified by silica gel chromatography to yield (S)-3-fluoro-N-(l-(6-(4-fluoro-lH-pyrazol-l- yl)pyridin-3-yl)ethyl)-5-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)picolinamide (59.5 mg, 95% purity, 28.8% yield) as a yellow, foamy solid. MS: M+l =
517.3.
Synthesis of Amine Intermediates
Synthesis of (S)-l-(6- 4-fluoro-lH-pyrazol-l- l)pyridin-3-yl)ethan-l-amine
Figure imgf000036_0001
l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l-one
4-Fluoro-lH-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred 20 hours at 100°C. The reaction mixture was then cooled to room temperature and poured into water (-700 mL). The mixture was sonicated and stirred for 20 minutes. A beige solid was isolated by filtration, washed with small amounts of water, and dried to yield l-(6-(4- fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l-one (9.81 g, 96% yield). MS: M+l = 206.0.
(R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-2-methylpropane-2- sulfinamide
To a stirred room temperature solution of l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l- one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(-)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75°C on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to - 78°C (external temperature) before the next step. To the -78°C solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of IN in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at -78°C before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to -50°C and quenched slowly with methanol (~ 10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-2- methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+l = 311.1.
(S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l-amine
A solution of (R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-2-methylpropane-2- sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred 2.5 hours. LC-MS showed reaction was completed. The reaction solution was poured into diethyl ether (300 mL). A sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (~ 200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin- 3-yl)ethan-l -amine (7.419 g, 78% yield), assumed to be the di-HCl salt.. LC-MS confirmed desired product in high purity. MS: M+l = 207.1.
Synthesis of (6-(3-cvclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
Figure imgf000038_0001
6-(3-cyclopropyl-lH-pyrazol-l-yl)nicotinonitrile
To a solution of 6-chloronicotinonitrile (100 mg, 0.74 mmol) in DMF (2 mL), was added 3-cyclopropyl-lH-pyrazole (80 mg, 0.74 mmol), and CS2CO3 (470 mg, 1.48 mmol). The mixture was stirred at 90°C for 5 hours. To the mixture was added water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2S04, and concentrated under vacuo to give 120 mg of 6-(3-cyclopropyl-lH-pyrazol-l-yl)nicotinonitrile as a light yellow solid. The structure was confirmed by LC-MS.
(6-(3-cyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
To a solution of 6-(3-cyclopropyl-lH-pyrazol-l-yl)nicotinonitrile (120 mg, 0.57 mmol) in MeOH (5 mL), was added Raney-Ni (80 mg), NH3/H20 (0.2 mL). The mixture was stirred at 25°C under an atmosphere of hydrogen for 1 hour. The mixture was filtered and concentrated under vacuo to give 100 mg of (6-(3-cyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine. The structure was confirmed by LC-MS. nthesis of (6-(4-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
Figure imgf000039_0001
6-(4-formyl-lH-pyrazol-l-yl)nicotinonitrile
To a solution of lH-pyrazole-4-carbaldehyde (500 mg, 5 mmol) and 6- chloronicotinonitrile (700 mg, 5 mmol ) in 20 mL DMSO was added KOAc (2.1 g, 15mmol). The resulting mixture was stirred at 100°C for 2 hours. The resulting mixture was concentrated and the crude product was purified by flash column chromatography to give the 6-(4-formyl-lH- pyrazol-l-yl)nicotinonitrile (1.0 g). The structure was confirmed by LC-MS
6-(4-(difluoromethyl)-lH-pyrazol-l-yl)nicotinonitrile
To a solution of 6-(4-formyl-lH-pyrazol-l-yl)nicotinonitrile (300 mg, 1.52 mmol) in 50 mL DCM was added DAST (1.2 g, 7.6 mmol) at -78 °C, and the mixture was warmed to RT overnight. Then sat. NaHC03 was added to mixture until PH=7, washed with water for 3 times. Organic phase was separated and dried over Na2S04, purified by flash column to give 6-(4- (difluoromethyl)-lH-pyrazol-l-yl)nicotinonitrile (250mg). The structure was confirmed by LC- MS.
(6- (4- (difluoromethyl) - 1 H-pyrazol- 1 -yl)pyridin-3-yl)methanamine
To a solution of 6-(4-(difluoromethyl)-l H-pyrazol- l-yl)nicotinonitrile (300 mg, 1.36 mmol) in 10 mL of MeOH and 1 mL NH3.H20 was added Raney Ni (50 mg). The reaction mixture was stirred at room temperature for 3 hours under an atmosphere of hydrogen. The resulting mixture was filtered and concentrated to give crude (6-(4-(difluoromethyl)-lH-pyrazol- l-yl)pyridin-3-yl)methanamine which was directly used in the next step. The structure was confirmed by LC-MS. Synthesis of (6-(4-cvclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
Figure imgf000040_0001
6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile
To a solution of 4-bromo-lH-pyrazole (100 mg, 0.72 mmol) in DMF (3 mL), was added 6-chloronicotinonitrile (49 mg, 0.72 mmol), and CS2CO3 (468 mg, 1.44 mmol). The mixture was stirred at 80°C for 12 h. The mixture was added water and extracted with EA. The organic layer was dried with anhydrous Na2S04 , and concentrated under vacuum to give 120 mg of 6-(4- bromo-lH-pyrazol-l-yl)nicotinonitrile as a light yellow solid. The structure was confirmed by LC-MS.
tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
To a solution of 6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile (100 mg, 0.4 mmol) in MeOH (10 mL), was added (Boc)20 (175 mg, 0.8 mmol) and NiCl2 (26 mg, 0.2 mmol), and then added NaBH4 (38 mg, 1.0 mmol ) slowly at 0°C. The mixture was stirred at 25°C for lh. The mixture was added 2 mL of water, and extracted with EA twice. The organic layer was concentrated under vacuum to give 80 mg of tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3- yl)methyl)carbamate. The structure was confirmed by LC-MS.
tert-butyl ((6-(4-cyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
A solution of tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (380 mg, 1.3 mmol), cyclopropylboronic acid (172 mg, 2.0 mmol), Pd2(dpa)3(119 mg, 0.13 mmol), Xanthpos (150 mg, 0.26 mmol) and K3P04 (828 mg, 3.9 mmol) in toluene (20 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. LC-MS showed the reaction was complete. The solvent was removed by reduce pressure. The mixture was extracted with ethyl acetate (50 mL) twice. The organic solvent was dried with anhydrous Na2S04. The crude compound was purified by column chromatograph (DCM:MeOH=100: l) to give tert-butyl ((6- (4-cyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (280 mg). The structure was confirmed by LC-MS. (6-(4-cyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
A solution of tert-butyl ((6-(4-cyclopropyl-lH-pyrazol-l-yl)pyridin-3- yl)methyl)carbamate (280 mg, 0.89 mmol) in Dioxane/HCl (6 niL) was stirred at room temperature for two hours. The LC-MS showed that the reaction was complete. The solvent was removed by reduce pressure to give (6-(4-cyclopropyl-lH-pyrazol-l-yl)pyridin-3- yl)methanamine (220 mg). The structure was confirmed by LC-MS.
nthesis of l-(5-(aminomethyl)pyridin-2-yl)-lH-pyrazole-4-carbonitrile
Figure imgf000041_0001
BocHN
Figure imgf000041_0002
6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile
To a solution of 6-chloronicotinonitrile (5.0 g, 36.0 mmol) in DMF (5 mL), was added 4- bromo-lH-pyrazole (5.3 g, 36.0 mmol), and CS2CO3 (23.5 g, 72 mmol). The reaction mixture was stirred at 80°C for 12 hours. To the reaction mixture was added water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2S04, and concentrated under vacuum to give 6.2 g of 6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile as a light yellow solid. The structure was confirmed by LC-MS.
tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
To a solution of 6-(4-bromo-lH-pyrazol-l-yl)nicotinonitrile (1.0 g, 4.0 mmol) in MeOH (10 mL), was added (Boc)20 (1.7 g, 8.0 mmol) and NiCl2 (52 mg, 0.4 mmol), and then added NaBH4 (0.4 g, 10 mmol ) slowly at 0°C. The mixture was stirred at 25°C for 1 hour. To the mixture was added 2 mL of water. The reaction mixture was dried under vacuum, water was added (20 mL), and then extracted with ethyl acetate (20 mL) twice. The organic layer was concentrated under vacuum to give 1.2 g of tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3- yl)methyl)carbamate. The structure was confirmed by LC-MS.
tert-butyl ((6-(4-cyano-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate A mixture of tert-butyl ((6-(4-bromo-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (1.0 g, 2.83 mmol), Zn(CN)2 (200 mg, 1.70 mmol), Zn (185 mg, 2.83 mmol) and Pd(dppf)C12 (200 mg, 0.28 mmol) in DMF (10 mL) was stirred at 150 °C for 6 hours. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was evaporated and purified on silica gel (petroleum ether / EtOAc, 10: 1 to 5: 1 to 2: 1) to afford tert-butyl ((6-(4- cyano-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (440 mg, 52% yield), m/z = 299.93 (M+H)+, as a white solid. The structure was confirmed by LC-MS.
l-(5-(aminomethyl)pyridin-2-yl)-lH-pyrazole-4-carbonitrile
A mixture of tert-butyl ((6-(4-cyano-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (160 mg, 0.53 mmol) in HCl/MeOH(4 M, 4 mL) was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to afford l-(5-(aminomethyl)pyridin-2-yl)-lH-pyrazole-4-carbonitrile (120 mg, 96% yield), m/z = 200.78 (M+H)+, as an off-white solid. The structure was confirmed by LC-MS.
Synthesis of ( -(3-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
Figure imgf000042_0001
6-(3-formyl-lH-pyrazol-l-yl)nicotinonitrile
To a solution of lH-pyrazole-5-carbaldehyde (72 mg, 0.75 mmol) and 6- chloronicotinonitrile ( 75 mg, 0.5mmol ) in 2 mL i-PrOH was added Cs2CO3(100 mg, 0.3mmol). The resulting mixture was stirred at 100°C for 2h. The resulting mixture was concentrated and crude was purified by column flash to give the 6-(3-formyl-lH-pyrazol-l- yl)nicotinonitrile (1.26 g). The structure was confirmed by LC-MS.
6-(3-(difluoromethyl)-lH-pyrazol-l-yl)nicotinonitrile
To a solution of 6-(3-formyl-lH-pyrazol-l-yl)nicotinonitrile (1.26 g, 6.36 mmol) in 120 mL DCM was added DAST (20.0eq) at -78 °C. The reaction mixture was warmed to room temperature overnight, then sat NaHC03 was added to the mixture until the mixture reached a pH of 7. The reaction mixture was washed with water 3 times. The resulting organic phase was separated and dried over Na2S04. The crude product was purified by flash column
chromatography to obtain 6-(3-(difluoromethyl)-lH-pyrazol-l-yl)nicotinonitrile (745mg).
The structure was confirmed by LC-MS.
tert-butyl ((6-(3-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
To a solution of 6-(3-(difluoromethyl)-lH-pyrazol-l-yl)nicotinonitrile (745 mg, 3.39 mmol) and (Boc)20 (1.1 g, 5.0) in 20 mL MeOH was added NaBH4 ( 7.0eq) at 0°C. The mixture was stirred at room temperature for 30 minutes. The resulting mixture was filtered and concentrated, and the crude product was purified by flash column chromatography to obtain 745mg of tert-butyl ((6-(3-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate. The structure was confirmed by LC-MS.
(6-(3-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)methanamine
A mixture of tert-butyl ((6-(3-(difluoromethyl)-lH-pyrazol-l-yl)pyridin-3- yl)methyl)carbamate (324 mg, lmmol) in 5 mL of HCl/MeOH (6 M) was stirred for 30 minutes at room temperature. The resulting mixture was concentrated to give (6-(3-(difluoromethyl)-lH- pyrazol-l-yl)pyridin-3-yl)methanamine, which was used without further purification. The structure was confirmed by LC-MS.
Synthesis of (5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)methanamine
Figure imgf000043_0001
5-(4-fluoro-lH-pyrazol-l-yl)pyrazine-2-carbonitrile To a solution of 5-chloropyrazine-2-carbonitrile (280 mg, 2.0 mmoL) in DMF was added 4-fluoro-lH-pyrazole (170 mg,2.0 mmoL), and potassium acetate (395 mg, 4.0 mmoL). The mixture was stirred at the 100°C for 4 hours. The reaction mixture was cooled to 20°C, poured into brine (25 mL), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (hexane: ethyl acetate = 5: 1) to give 5-(4-fluoro-lH-pyrazol-l-yl)pyrazine-2-carbonitrile (310 mg, Yield 82%). The structure was confirmed by LC-MS.
(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)methanamine
A mixture of 5-(4-fluoro-lH-pyrazol-l-yl)pyrazine-2-carbonitrile (190 mg, 1.0 mmoL) and NiCl2 (12 mg, 0.1 mmoL) in MeOH (5 mL) was added NaBH4 (380 mg, 10 mmoL) at 0 °C. The mixture was stirred at 0 °C for 2 hours, quenched with aqueous NH4C1 and purified by HPLC to give (5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)methanamine (160 mg, Yield 82%). The structure was confirmed by LC-MS.
The synthetic protocols that can be used to prepare the compounds disclosed herein are indicated below. The NMR and LC MS data obtained for compounds disclosed herein are also shown below.
Figure imgf000044_0001
Compound Synthetic MS
IH NMR
Number Protocol (M+l)
1H NMR (301 MHz, DMSO) δ 10.68 (s, IH), 9.70 (s,
IH), 9.47 (s, IH), 9.04 (s, IH), 8.81 (d, 7 = 8.2 Hz, IH),
3 1 407
8.31 (d, 7 = 8.2 Hz, IH), 7.90 (s, IH), 4.79 (d, 7 = 6.1
Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H).
10.52 (br s, IH) 9.52 (s, IH) 8.78 (d, IH) 8.09 (d, IH)
4 1 7.48 (m, IH) 7.37 (m, 3H) 7.25 (br s, IH) 5.18 (s, 2H) 412
5.00 (s, 2H) 2.56 (s, 3H) 2.33 (s, 3H)
1H NMR (301 MHz, DMSO) δ 12.10 (s, IH), 9.95 (s,
IH), 9.54 (s, IH), 9.43 (s, IH), 8.84 (dd, 7 = 8.1, 1.4 Hz,
5 1 IH), 8.24 (d, 7 = 8.2 Hz, IH), 7.30 (d, 7 = 7.8 Hz, 2H), 414
7.18 (d, 7 = 7.8 Hz, 2H), 4.53 (d, 7 = 6.1 Hz, 2H), 2.45
(s, 3H), 2.31 (s, 3H).
1H NMR (301 MHz, DMSO) δ 10.38 (s, IH), 9.52 (s,
IH), 9.24 (d, 7 = 8.5 Hz, IH), 8.82 (dd, 7 = 8.1, 1.5 Hz,
6 1 IH), 8.25 (d, 7 = 8.2 Hz, IH), 7.51 (d, 7 = 7.5 Hz, 2H), 414
7.39 (t, 7 = 7.4 Hz, 2H), 7.30 (s, IH), 5.32 - 5.23 (m,
IH), 2.50 (s, 3H), 2.33 (s, 3H), 1.62 (d, 7 = 7.0 Hz, 3H).
12.03 (s, IH) 9.9 (s, IH) 9.5 (s, IH) 9.43 (m, IH) 8.78
7 1 (d, IH) 8.36 (s, IH) 8.19(d, IH) 7.56 (d, IH) 7.24 (d, 415
IH) 4.59 (d, 2H) 2.39 (s, 3H) 2.25 (s, 3H) 2.24 (s, 3H)
1H NMR (301 MHz, DMSO) δ 10.36 (s, IH), 9.62 (s,
IH), 9.52 (s, IH), 8.83 (dd, 7 = 8.2, 1.8 Hz, IH), 8.28 (d,
8 1 7 = 8.2 Hz, IH), 7.43 (d, 7 = 6.3 Hz, IH), 7.24 (t, 7 = 9.4 418
Hz, 2H), 7.15 (d, 7 = 9.0 Hz, IH), 4.60 (d, 7 = 6.3 Hz,
2H), 2.50 (s, 3H), 2.32 (s, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
1H NMR (301 MHz, DMSO) δ 10.37 (s, IH), 9.54 (d,
= 17.7 Hz, 2H), 8.82 (d, = 8.2 Hz, IH), 8.28 (d, = 8.2
9 1 418
Hz, IH), 7.50 - 7.41 (m, 2H), 7.20 (t, = 8.8 Hz, 2H),
4.56 (d, J = 6.2 Hz, 2H), 2.50 (s, 3H), 2.32 (s, 3H).
1H NMR (301 MHz, DMSO) δ 10.35 (s, IH), 9.50 (s,
IH), 9.43 (s, IH), 8.82 (dd, / = 8.2, 1.7 Hz, IH), 8.27 (d,
10 1 = 8.2 Hz, IH), 7.35 (d, = 8.5 Hz, 2H), 6.94 (d, = 430
8.5 Hz, 2H), 4.51 (d, = 6.2 Hz, 2H), 3.78 (s, 3H), 2.49
(s, 3H), 2.32 (s, 3H).
1H NMR (301 MHz, DMSO) δ 10.34 (s, IH), 9.60 (s,
IH), 9.52 (s, IH), 8.83 (d, = 8.1 Hz, IH), 8.27 (d, =
11 1 434
8.2 Hz, IH), 7.44 (s, 4H), 4.57 (d, = 6.3 Hz, 2H), 2.49
(s, 3H), 2.32 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.49 (s, IH), 9.42 (d,
= 7.0 Hz, 2H), 8.76 (dd, / = 8.2, 2.0 Hz, IH), 8.24 (d,
12 1 = 8.2 Hz, IH), 7.28 (d, = 8.7 Hz, 2H), 6.89 - 6.85 (m, 444
2H), 4.45 (d, = 6.3 Hz, 2H), 3.99 (d, = 7.0 Hz, 2H),
2.45 (s, 3H), 2.27 (s, 3H), 1.31 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.54 (s, IH), 9.26 - 9.14 (m, 2H), 8.49 (d, J = 1.3 Hz, IH), 7.28 (d, J = 8.6
13 2 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.27 (s, IH), 4.41 (d, J 458
= 6.2 Hz, 2H), 4.00 (q, J = 7.0 Hz, 2H), 2.63 (s, 3H),
2.46 (s, 3H), 2.26 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
1H NMR (400 MHz, DMSO) δ 10.52 (s, IH), 9.44 - 9.37 (m, 2H), 8.76 (dd, J = 8.2, 2.1 Hz, IH), 8.24 (d, / =
14 1 458
8.2 Hz, IH), 7.27 (d, / = 8.7 Hz, 2H), 6.86 (d, / = 8.7
Hz, 2H), 4.60 - 4.54 (m, IH), 4.45 (d, J = 6.3 Hz, 2H),
2.46 (s, 3H), 2.27 (s, 3H), 1.24 (d, J = 6.0 Hz, 6H).
1H NMR (400 MHz, DMSO) δ 10.39 (s, IH), 9.55 (t,
= 6.4 Hz, IH), 9.45 (d, 7 = 1.6 Hz, IH), 8.77 (dd, J =
15 1 8.2, 2.1 Hz, IH), 8.23 (d, J = 8.3 Hz, IH), 7.41 (d, J = 466
8.7 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 4.51 (d, J = 6.3
Hz, 2H), 2.45 (s, 3H), 2.27 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.77 (s, IH), 9.21 (s,
IH), 8.98 (d, J = 8.5 Hz, IH), 8.47 (d, J = 1.8 Hz, IH),
7.34 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.15 -
16 2 472
5.10 (m, IH), 4.00 (q, J = 7.0 Hz, 2H), 2.56 (s, 3H), 2.48
(s, 3H), 2.27 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.32 (t, J
= 7.0 Hz, 3H).
1H NMR (400 MHz, DMSO) δ 10.65 (s, IH), 9.21 (s,
IH), 8.97 (d, J = 8.5 Hz, IH), 8.47 (d, J = 1.4 Hz, IH),
7.34 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.12
17 2 472
(d, J = 7.7 Hz, IH), 4.00 (q, J = 7.0 Hz, 2H), 2.56 (s,
3H), 2.47 (s, 3H), 2.27 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H),
1.31 (t, J = 7.0 Hz, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
IH NMR (301 MHz, DMSO) δ 10.48 (s, IH), 9.63 (s,
IH), 9.45 (s, IH), 8.76 (d, J = 6.6 Hz, IH), 8.43 (s, IH),
8.36 (s, IH), 8.24 (d, J = 8.2 Hz, IH), 7.94 (d, J = 7.4
18 1 481
Hz, IH), 7.84 (d, J = 8.4 Hz, IH), 7.61 (s, IH), 7.21 - 6.89 (m, IH), 6.42 - 6.11 (m, IH), 4.57 (d, J = 6.2 Hz,
2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.49 (s, IH), 9.44 (s,
IH), 9.25 (s, IH), 8.61 (d, J = 2.2 Hz, IH), 8.51 (d, J =
1.3 Hz, IH), 8.47 (d, J = 1.6 Hz, IH), 7.98 (dd, J = 8.5,
19 2 2.1 Hz, IH), 7.92 (d, J = 8.4 Hz, IH), 7.81 (d, J = 1.0 481
Hz, IH), 7.11 (s, IH), 6.59 - 6.55 (m, IH), 6.28 (s, IH),
4.55 (d, J = 6.1 Hz, 2H), 2.65 (s, 3H), 2.45 (s, 3H), 2.26
(s, 3H).
IH NMR (400 MHz, DMSO) δ 10.42 (s, IH), 9.61 (t, J
= 6.4 Hz, IH), 9.46 (d, J = 1.9 Hz, IH), 8.77 (dd, J =
20 1 8.2, 2.1 Hz, IH), 8.23 (d, J = 8.2 Hz, IH), 7.48 (d, J = 483
8.7 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.55 (d, J = 6.4
Hz, 2H), 2.45 (s, 3H), 2.27 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.00 (s, IH), 9.60 (s,
IH), 9.52 (s, IH), 9.15 (s, IH), 8.81 (d, = 10.0 Hz,
21 1 IH), 8.73 (s, IH), 8.55 (s, IH), 8.21 (d, = 8.1 Hz, IH), 486
8.04 (d, = 4.2 Hz, IH), 4.75 (d, = 6.1 Hz, 3H), 2.42
(s, 2H), 2.26 (s, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
IH NMR (400 MHz, DMSO) δ 10.39 (s, IH), 9.70 (t, J
= 6.3 Hz, IH), 9.47 (d, J = 1.5 Hz, IH), 9.43 - 9.36 (m,
IH), 8.78 (dd, J = 8.2, 2.1 Hz, IH), 8.54 (d, J = 1.8 Hz,
22 1 IH), 8.43 - 8.38 (m, IH), 8.24 (d, J = 8.1 Hz, IH), 8.05 492
(dd, J = 8.5, 2.2 Hz, IH), 7.96 (d, J = 8.4 Hz, IH), 7.14
(s, IH), 6.31 (s, IH), 4.61 (d, J = 6.2 Hz, 2H), 2.45 (s,
3H), 2.27 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.36 (s, IH), 9.30 - 9.19 (m, 2H), 8.61 (d, J = 2.5 Hz, IH), 8.54 (d, J = 2.0
Hz, IH), 8.50 (s, IH), 8.10 - 8.03 (m, IH), 7.92 (d, J =
23 2 495
8.5 Hz, IH), 7.81 (s, IH), 6.60 - 6.54 (m, IH), 5.25 (d, J
= 7.4 Hz, IH), 2.56 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H),
1.58 (d, J = 7.0 Hz, 3H).
1H NMR (400 MHz, DMSO) δ 10.53 (s, IH), 9.65 (t, J
= 6.3 Hz, IH), 9.45 (d, J = 1.4 Hz, IH), 8.77 (dd, J =
8.2, 2.1 Hz, IH), 8.44 (s, IH), 8.26 (d, J = 8.2 Hz, IH),
24 1 495
7.92 (d, J = 8.5 Hz, IH), 7.77 (d, J = 8.4 Hz, IH), 6.10
(s, IH), 4.58 (d, J = 6.2 Hz, 2H), 2.56 (s, 3H), 2.46 (s,
3H), 2.27 (s, 3H), 2.19 (s, 3H).
(400 MHz, DMSO-d6) δ 12.03 (s, IH), 9.90 (s, IH),
9.51 (d, J = 2.0 Hz, IH), 9.39 (d, J = 8.3 Hz, IH), 8.77
(dd, J = 8.2, 2.1 Hz, IH), 8.66 (d, J = 4.5 Hz, IH), 8.53
25 1 (d, J = 2.2 Hz, IH), 8.15 (d, J = 8.2 Hz, IH), 8.09 (dd, J 499
= 8.6, 2.3 Hz, IH), 7.92 - 7.86 (m, 2H), 5.30 (p, J = 7.1
Hz, IH), 2.39 (s, 3H), 2.25 (s, 3H), 1.61 (d, J = 7.0 Hz,
3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
IH NMR (400 MHz, DMSO) δ 10.44 (s, IH), 9.65 (s,
IH), 9.46 (d, J = 1.6 Hz, IH), 8.77 (s, IH), 8.43 (dd, J =
7.7, 2.2 Hz, 2H), 8.24 (d, J = 8.2 Hz, IH), 7.92 (d, J =
26 1 2.2 Hz, IH), 7.81 (d, J = 8.4 Hz, IH), 6.26 (d, J = 2.6 507
Hz, IH), 4.56 (d, J = 6.2 Hz, 2H), 2.27 (s, 3H), 2.04 - 1.93 (m, IH), 0.94 (dd, J = 8.4, 2.4 Hz, 2H), 0.75 (dd, J
= 4.9, 2.3 Hz, 2H).
1H NMR (400 MHz, DMSO) δ 10.40 (s, IH), 9.65 (t,
= 6.2 Hz, IH), 9.46 (d, = 1.6 Hz, IH), 8.78 (dd, =
8.2, 2.1 Hz, IH), 8.43 (d, = 1.8 Hz, IH), 8.35 (s, IH),
27 1 8.24 (d, = 8.2 Hz, IH), 7.94 (dd, = 8.5, 2.2 Hz, IH), 507
7.84 (d, = 8.4 Hz, IH), 7.62 (s, IH), 4.57 (d, = 6.3
Hz, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 0.90 - 0.85 (m, 2H),
0.64 - 0.59 (m, 2H).
1H NMR (400 MHz, DMSO) δ 12.06 (s, IH), 9.93 (s,
IH), 9.62 (t, J = 6.3 Hz, IH), 9.50 (d, J = 1.4 Hz, IH),
8.80 (dd, J = 8.2, 2.1 Hz, IH), 8.46 - 8.39 (m, 2H), 8.20
28 1 (d, J = 8.6 Hz, IH), 7.94 (dd, J = 8.5, 2.2 Hz, IH), 7.85 511
(d, J = 8.5 Hz, IH), 7.66 (s, IH), 4.71 (t, J = 5.2 Hz,
IH), 4.57 (d, J = 6.2 Hz, 2H), 3.62 - 3.57 (m, 2H), 2.64
(t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.26 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.73 (s, IH), 9.25 (dd, J
= 12.9, 5.0 Hz, 2H), 8.69 (dd, J = 4.6, 0.8 Hz, IH), 8.54
(d, J = 2.2 Hz, IH), 8.49 (d, J = 1.4 Hz, IH), 8.08 (dd, J
29 3 = 8.6, 2.3 Hz, IH), 7.92 (dd, J = 4.6, 3.8 Hz, 2H), 7.21 - 513
7.05 (m, IH), 6.38 - 6.19 (m, IH), 5.31 - 5.23 (m, IH),
2.56 (s, 3H), 2.48 (s, 3H), 2.27 (s, 3H), 1.58 (d, J = 7.1
Hz, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
(400 MHz, DMSO-d6) δ 12.06 (s, IH), 9.97 (s, IH),
9.35 (d, J = 8.1 Hz, IH), 9.31 (s, IH), 8.69 (d, J = 4.5
Hz, IH), 8.52 (d, J = 2.3 Hz, IH), 8.42 (d, J = 11.4 Hz,
30 3 517
IH), 8.06 (dd, J = 8.4, 2.3 Hz, IH), 7.95 - 7.86 (m, 2H),
5.26 (p, J = 7.1 Hz, IH), 2.39 (s, 3H), 2.24 (s, 3H), 1.56
(d, J = 7.0 Hz, 3H).
1H NMR (400 MHz, DMSO) δ 10.41 (s, IH), 9.68 (t, 7
= 6.3 Hz, IH), 9.46 (d, 7 = 1.5 Hz, IH), 8.91 (s, IH),
8.78 (dd, 7 = 8.2, 2.1 Hz, IH), 8.51 (d, 7 = 1.8 Hz, IH),
31 1 8.24 (d, 7 = 8.1 Hz, IH), 8.08 (s, IH), 8.02 (dd, 7 = 8.5, 517
2.2 Hz, IH), 7.94 (d, 7 = 8.4 Hz, IH), 7.14 (t, 7 = 55.8
Hz, IH), 4.60 (d, 7 = 6.3 Hz, 2H), 2.51 (dt, 7 = 3.5, 1.7
Hz, 14H), 2.45 (s, 3H), 2.27 (s, 3H).
1H NMR (400 MHz, DMSO) δ 10.22 (s, IH), 9.66 (t, J
= 6.2 Hz, IH), 9.48 (d, J = 1.7 Hz, IH), 8.79 (dd, J =
9.9, 1.7 Hz, 2H), 8.48 (d, J = 2.0 Hz, IH), 8.23 (d, J =
32 1 8.2 Hz, IH), 7.98 (dd, J = 8.5, 2.2 Hz, IH), 7.87 (d, J = 531
8.4 Hz, IH), 7.26 (s, 0.2H), 7.12 (s, 0.5H), 6.98 (s,
0.3H), 4.58 (d, J = 6.3 Hz, 2H), 2.43 (s, 3H), 2.36 (s,
3H), 2.26 (s, 3H).
1H NMR (400 MHz, DMSO- 6) δ 12.03 (s, IH), 9.91 (s,
IH), 9.51 (d, 7 = 2.0 Hz, IH), 9.30 (d, 7 = 8.0 Hz, IH),
9.17 (d, 7 = 1.4 Hz, IH), 8.79 (dd, 7 = 8.2, 2.2 Hz, IH),
33 1 8.72 (d, 7 = 4.5 Hz, IH), 8.65 (d, 7 = 1.5 Hz, IH), 8.17 500
(d, 7 = 8.2 Hz, IH), 8.03 (d, 7 = 4.2 Hz, IH), 5.41 (p, 7 =
7.1 Hz, IH), 2.39 (s, 3H), 2.25 (s, 3H), 1.62 (d, 7 = 7.0
Hz, 3H) Compound Synthetic MS
1H NMR
Number Protocol (M+l)
1H NMR (400 MHz, DMSO- 6) δ 12.03 (s, 1H), 9.90 (s,
1H), 9.51 (d, 7 = 2.1 Hz, 1H), 9.39 (d, 7 = 8.7 Hz, 1H),
8.77 (dd, 7 = 8.2, 2.1 Hz, 1H), 8.66 (d, 7 = 4.5 Hz, 1H),
34 1 8.53 (d, 7 = 2.2 Hz, 1H), 8.17 - 8.08 (m, 2H), 7.93 - 513
7.85 (m, 2H), 5.04 (q, 7 = 8.3 Hz, 1H), 2.38 (s, 3H),
2.25 (s, 3H), 2.07 (dt, 7 = 15.6, 7.7 Hz, 1H), 1.93 (dt, 7
= 13.7, 6.9 Hz, 1H), 0.91 (t, 7 = 7.2 Hz, 3H)
1H NMR (400 MHz, DMSO- 6) δ 12.03 (s, 1H), 9.90 (s,
1H), 9.54 - 9.47 (m, 1H), 9.40 (d, 7 = 8.4 Hz, 1H), 8.77
(dd, 7 = 8.2, 2.1 Hz, 1H), 8.66 (d, 7 = 4.5 Hz, 1H), 8.53
35 1 (d, 7 = 2.3 Hz, 1H), 8.14 (d, 7 = 8.2 Hz, 1H), 8.09 (dd, 7 499
= 8.6, 2.3 Hz, 1H), 7.93 - 7.83 (m, 2H), 5.30 (p, 7 = 7.1
Hz, 1H), 2.39 (s, 3H), 2.25 (s, 3H), 1.61 (d, 7 = 7.1 Hz,
3H).
Example 4: Measurement of Biochemical Activity of Compounds
In order to assess the activity of chemical compounds against the relevant kinase of interest, the Caliper LifeSciences electrophoretic mobility shift technology platform is used. Fluorescently labeled substrate peptide is incubated in the presence of kinase and ATP so that a reflective proportion of the peptide is phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides are passed through the microfluidic system of the Caliper EZ Reader 2, under an applied potential difference. The presence of the phosphate group on the product peptide provides a difference in mass and charge between those of the substrate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass a LEDS within the instrument, these pools are detected and resolved as separate peaks. The ratio between these peaks therefore reflects the activity of the chemical matter at that concentration in that well, under those conditions. RET wild type assay at KM
In each well of a 384-well plate, 7.5 nM - 10 nM of wild type RET (ProQinase 1090- 0000-1) is incubated in a total of 12.5 of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, ImM DTT) with 1 μΜ CSKtide (FITC - AHA- KKKKD DIYFFFG-NH2) and 25 μΜ ATP at 25°C for 120 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The reaction is stopped by the addition of 70 μΐ^ of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plate is then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data is normalized to 0% and 100% inhibition controls and the IC50 calculated using a 4-parameter fit in the CORE LIMS.
RET V804L Gatekeeper mutant assay at KM
In each well of a 384-well plate, 7.5 nM - 10 nM of mutant RET (ProQinase 1096-0000- 1) is incubated in a total of 12.5 μΐ, of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgC12, ImM DTT) with 1 μΜ CSKtide (FITC-AHA-KKKKDDIYFFFG-NH2) and 10 μΜ ATP at 25°C for 120 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The reaction is stopped by the addition of 70 μΐ^ of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plate is then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data is normalized to 0% and 100% inhibition controls and the IC50 calculated using a 4-parameter fit in the CORE LIMS.
In the Table below, the following designations are used: < 10.00 nM = A; 10.01-100.0 nM = B; >100 nM = C; and ND = not determined.
Figure imgf000053_0001
Figure imgf000053_0002
Compound Wild-type V804L Compound Wild-type V804L Number RET Mutant Number RET Mutant
5 B B 21 A A
6 C B 22 B B
7 B B 23 A A
8 C B 24 A A
9 B B 25 A A
10 B B 26 A A
11 B A 27 B C
12 B B 28 B A
13 B ND 29 A A
14 B B 30 A A
15 B B 31 B B
16 C ND 32 B B
17 C ND 33 A C
18 A A 34 A C
19 A A 35 A C
20 C C
Incorporation by Reference
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

Claims:
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000055_0001
(I)
rings A and B are each independently selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;
1 2
each L and L is independently selected from -(Ci-C6 alkylene)-, -(C2-C6 alkenylene)-, - (C2-C6 alkynylene)-, -(Ci-C6 haloalkylene)-, -(Ci-C6 heteroalkylene)-, -C(O)-, -0-, -S-, -S(O), - S(0)2-, -NCR1)-, -0-(Ci-C6 alkylene)-, -(Ci-C6 alkylene)-0-, -NCR^-CCO)-, -C(0)-N(R1)-, -(d- C6 alkylene)-N(R1)-,
Figure imgf000055_0002
alkylene)-, -N(R1)-C(0)-(d-C6 alkylene)-, -(Ci-C6 alkylene)-N(R1)-C(0)-, -C(0)-N(R1)-(d-C6 alkylene)-, -(Ci-C6 alkylene)-C(0)-N(R1)-,
-N(R')-S(0)2-, -SCO NCR1)-,
Figure imgf000055_0003
alkylene)-, and
alkylene)-; wherein each alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene is independently substituted with 0-5 occurrences of R' ;
A B
each R and R is independently selected from Ci-C6 alkyl, Q-C6 alkoxy, halo, Q-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, and -N^R^R1); wherein each alkyl, alkoxy, haloalkyl, hydroxyalkyl, and hydroxyalkyl is independently substituted with 0-5 occurrences of
Ra;
C D
each R and R is independently selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC6 alkoxy, halo, Ci-C6 heteroalkyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, Ci-C6 hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, - C(0)R1, -OC(0)R1, -C(0)OR1, -(Ci-C6 alkylene)-C(0)R1, -SR1, -SCO^R1, -S(0)2-N(R1)(R1), -(Ci-C6 alkylene)-S(0)2R1, -(Ci-C6 alkylene)-S(0)2-N(R1)(R1), -NCR^R1), -C(0)-N(R1)(R1), - N(R1)-C(0)R1, -N(R1)-C(0)OR1, -(Ci-C6 alkylene)-N(R1)-C(0)R1, -NCR^SCO^R1, and - P(0)(R1)(R1); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl,
haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or 2 Rc or 2 RD together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Ra;
each R1 is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C6 alkyl, Q- C6 thioalkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Rb, or 2 R1 together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;
each Ra and Rb is independently Ci-C6 alkyl, halo, hydroxyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, Ci-C6 hydroxyalkyl, Ci-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl is
independently substituted with 0-5 occurrences of R' ;
each R' is Ci-C6 alkyl, Ci-C6 heteroalkyl, halo, hydroxyl, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, cycloalkyl or cyano; or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
m is 0, 1, 2, or 3;
n is 0, 1, or 2; and
and q are each independently 0, 1, 2, 3, or 4, wherein the compound is other than:
Figure imgf000056_0001
Figure imgf000057_0001
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is heteroaryl.
3. The compound of claim 2, wherein ring A is lH-pyrazol-3-yl.
The compound of claim 3, wherein the portion of the compound represented by: (Rc^
is 5-methyl-lH-pyrazol-l-yl.
5. The compound of any one of claims 1-4, wherein L1 is selected from -NCR1)-,
Figure imgf000057_0002
alkylene)-†, and -N(R1)-C(0)-(Ci-C6 alkylene)-†, wherein "†" represents a portion of L1 bound to ring A.
6. The compound of claim 5, wherein L1 is -NH-.
7. The compound of any one of claims 1-6, wherein L is selected from *-C(0)-,
*-Ν^)-ΰ;θ)- and *-(Ci-C6 alkylene)-N(R1)-C(0)-, wherein the Ci-C6 alkylene portion of L2 is substituted with 0-5 occurrences of R', and wherein "*" represents a portion of L bound to ring B. 2
8. The compound of claim 7, wherein L is selected from *-C(0)- and *-(Ci-C6
1 2
alkylene)-N(R )-C(0)-, wherein the Ci-C6 alkylene portion of L is substituted with 0-5 occurrences of R' .
9. The compound of claim 1 having structural Formula 1(b):
Figure imgf000058_0001
1(b),
2 1
or a pharmaceutically acceptable salt therof, wherein L is -C(0)-N(R )-(Ci-C6 alkylene)-, and wherein Ci-C6 alkylene is substituted with 0-5 occurrences of R' .
10. The compound of claim 9, wherein L is selected from *-C(0)-, *-CH2-NH-C(0)-, *-CH(CH3)-NH-C(0)-, and *-CH(CH2CH3)-NH-C(0)-.
The compound of claim 9 having structural Formula 1(c):
Figure imgf000058_0002
1(c),
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11, having structural Formula 1(d):
Figure imgf000058_0003
(Id),
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 11, having structural Formula 1(e):
Figure imgf000059_0001
(Ie),
or a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1-13, wherein R1 is hydrogen.
15. The compound of any one of claim 1-14, wherein n is 0 or 1.
16. The compound of claim 15, wherein n is 1 and R is methyl.
17. The compound of any one of claims 1-16, wherein m is 0 or 1.
18. The compound of claim 17, wherein m is 0, or m is 1 and RA is methyl or fluoro.
19. The compound of any one of claims 1-18, wherein ring B is selected from aryl, heteroaryl and heterocyclyl.
20. The compound of claim 19, wherein ring B is selected from phenyl, furan-3-yl, thiazol-5- yl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl and, when L is -C(O)-, ring B is additionally selected from isoindolin-l-yl.
21. The compound of any one of claims 1-20, wherein q is 0, 1, or 2.
22. The compound of claim 21, wherein q is 1 or 2 and each q is independently selected from fluoro, chloro, methyl, -0-CH3, -0-CH2CH3, -0-CH(CH3)2, -0-CHF2, -0-CF3, and optionally substituted lH-pyrazol-l-yl.
23. The compound of claim 22, wherein each q is independently selected from fluoro, chloro, methyl, -0-CH3, -0-CH2CH3, -0-CH(CH3)2, -0-CHF2, -0-CF3, 4-methyl-l H-pyrazol- 1-yl, 1H- pyrazol-l-yl, 4-fluoro-lH-pyrazol-l-yl, 4-cyano-l H-pyrazol- 1-yl, 3,5-dimethyl-lH-pyrazol-l-yl, 3 -cyclopropyl- 1 H-pyrazol- 1-yl, 4-cyclopropyl- 1 H-pyrazol- 1-yl, 4-(l -hydroxyethyl)- 1 H-pyrazol- 1-yl, 4-difluoromethyl-l H-pyrazol- 1-yl, and 3-methyl-4-difluoromethyl-lH-pyrazol-l-yl.
24. A pharmaceutical composition comprising a compound of any one of claims 1-23; and a pharmaceutically acceptable carrier.
25. A method for treating a subject suffering from a condition mediated by aberrant RET activity, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-23, or a composition of claim 24.
26. A method for treating a subject who has developed resistance to a cancer treatment, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-23, or a composition of claim 24.
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