WO2017079140A1 - Inhibitors of ret - Google Patents

Inhibitors of ret Download PDF

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Publication number
WO2017079140A1
WO2017079140A1 PCT/US2016/059879 US2016059879W WO2017079140A1 WO 2017079140 A1 WO2017079140 A1 WO 2017079140A1 US 2016059879 W US2016059879 W US 2016059879W WO 2017079140 A1 WO2017079140 A1 WO 2017079140A1
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Prior art keywords
alkyl
compound
hydrogen
methyl
occurrences
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PCT/US2016/059879
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French (fr)
Inventor
Jason D. Brubaker
Joseph L. Kim
Kevin J. Wilson
Douglas Wilson
Lucian V. Dipietro
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Blueprint Medicines Corporation
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Priority to JP2018521916A priority Critical patent/JP6807385B2/en
Priority to PL16794885.0T priority patent/PL3371171T3/en
Priority to DK16794885.0T priority patent/DK3371171T3/en
Priority to CN202010391097.9A priority patent/CN111423416B/en
Application filed by Blueprint Medicines Corporation filed Critical Blueprint Medicines Corporation
Priority to SG11201803653QA priority patent/SG11201803653QA/en
Priority to CA3003721A priority patent/CA3003721C/en
Priority to BR112018008877-3A priority patent/BR112018008877B1/en
Priority to CN201680076816.XA priority patent/CN108473468B/en
Priority to FIEP16794885.0T priority patent/FI3371171T3/en
Priority to RS20240044A priority patent/RS65069B1/en
Priority to SI201631796T priority patent/SI3371171T1/en
Priority to EA201891087A priority patent/EA038890B1/en
Priority to MYPI2018701728A priority patent/MY194262A/en
Priority to EP23201915.8A priority patent/EP4292594A3/en
Priority to NZ742351A priority patent/NZ742351A/en
Priority to IL302209A priority patent/IL302209B2/en
Priority to AU2016348402A priority patent/AU2016348402B2/en
Priority to IL288519A priority patent/IL288519B2/en
Priority to EP23201930.7A priority patent/EP4331585A3/en
Priority to KR1020187015706A priority patent/KR20180073689A/en
Priority to MX2018005528A priority patent/MX2018005528A/en
Priority to MA43165A priority patent/MA43165B1/en
Priority to LTEPPCT/US2016/059879T priority patent/LT3371171T/en
Priority to EP16794885.0A priority patent/EP3371171B1/en
Priority to HRP20231681TT priority patent/HRP20231681T1/en
Priority to ES16794885T priority patent/ES2969185T3/en
Publication of WO2017079140A1 publication Critical patent/WO2017079140A1/en
Priority to IL258902A priority patent/IL258902B/en
Priority to PH12018500907A priority patent/PH12018500907A1/en
Priority to SA518391496A priority patent/SA518391496B1/en
Priority to ZA2018/03050A priority patent/ZA201803050B/en
Priority to HK19101648.3A priority patent/HK1259287A1/en
Priority to FR24C1016C priority patent/FR24C1016I1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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

Definitions

  • This invention relates to inhibitors of RET that are active against wild-type RET and its resistant mutants.
  • RET (rearranged during transfection) is a receptor tyrosine kinase that activates multiple downstream pathways involved in cell proliferation and survival. RET fusions are implicated in several cancers including papillary thyroid carcinoma and non-small ceil 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 present invention provides inhibitors of RET and RET mutants, e.g. , RET resistant mutants (as defined herein), for example, inhibitors of structural formula (I) and
  • the present invention further provides methods of using the compounds of the invention, and pharmaceutically acceptable salts and compositions thereof, to inhibit the activity of RET or RET mutants in a cell or patient.
  • the present invention still further provides methods for using the compounds of the invention, and pharmaceutically acceptable salts and compositions thereof, to treat a subject suffering from a condition mediated by aberrant RET activity, e.g. , cancer.
  • the invention features a compound of structural formula (A) or a pharmaceutically acceptable salt thereof:
  • the present invention provides pharmaceutical compositions comprising a compound of structural formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention provides a method for inhibiting RET activity in a cell or in a patient.
  • said method comprises the step of contacting the cell or administering to the patient a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
  • the present invention provides a method for treating a subject suffering from a condition mediated by aberrant RET activity.
  • said method comprises administering to the subject a therapeutically effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
  • the present invention provides a method for treating a subject who has developed resistance to a cancer treatment.
  • said method comprises administering to the subject a therapeutically effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
  • the present invention features a compound having the structural formula
  • ring A is an aryl or heteroaryl ring
  • each of X 1 and X 2 is independently selected from N and C(R 6 );
  • each of Y 1 and Y 2 is independently selected from -CH 2 - and -0-, wherein no more than one of Y 1 or Y 2 is -0-;
  • each R and each R is independently selected from selected from Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, Ci-C 6 alkoxy, halo, Ci-C 6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(0)R, -OC(0)R, - C(0)OR, -(Ci-Ce alkylene)-C(0)R, -SR, -S(0) 2 R, -S(0) 2 -N(R)(R), -(Ci-C 6 alkylene)- S(0) 2 R, -(Ci-Ce alkylene)-S(0) 2 -N(R)(R) , -N(R)(R), -C(0)-N(R)(R), -N(R)-C(0)R, -N(R)- C
  • each of R 2 when present, R 3a , R 3b , R 4 , R 8a and R 8b , when present is independently selected from hydrogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, halo, hydroxyl, Ci-C 6 heteroalkyl, and - N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;
  • each of R 5 and R 9 is independently selected from hydrogen, Ci-C 6 alkyl, and Ci-C 6 heteroalkyl; wherein each alkyl and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;
  • each R 6 is independently selected from hydrogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, halo, Ci-C 6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;
  • each R is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C 6 alkyl, Ci-C 6 thioalkyl, Ci-C 6 alkoxy, Ci-C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , 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
  • each R a and each R b is independently selected from Ci-C 6 alkyl, halo, hydroxyl, Ci-C 6 heteroalkyl, Ci-C 6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R'; each R' is independently selected from Ci-C 6 alkyl, Ci-C 6 heteroalkyl, halo, hydroxyl, 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, or 2;
  • n 0, 1, 2, or 3;
  • the compound is a compound having formula (I):
  • each of ring A, X 1 , X 2 , R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , R, R a , R b , R', m, and n is as described for a compound of Formula A.
  • represents a double bond and the compound has formula lb:
  • each of ring A, X 1 , X 2 , R 1 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 9 , R, R a , R b , R', m, and n is as described for a compound of Formula A.
  • R 1 is located at the 5-position. In some embodiments, R 1 is located at the 4-position. In some embodiments, R 1 is Ci-C 4 alkyl optionally substituted with 0-3 occurrences of R a . In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 1; R 1 is located at the 5-position; and R 1 is Q- C 4 alkyl optionally substituted with 0-3 occurrences of R a . In some embodiments, R 1 is -CH 3 .
  • R is selected from hydrogen, hydroxyl, halo and 0-Ci-C 4 alkyl. In some embodiments, R is selected from hydrogen, hydroxyl, fluoro and -OCH 3 .
  • any of Formulae A, I, la or lb each of R 3a , R 3b , R 8a and R 8b (which is only present in Formulae I or la) is independently selected from hydrogen and Ci-C 4 alkyl optionally substituted with 0-3 occurrences of R a .
  • each of R 3a , R 3b , R 8a and R 8b is independently selected from hydrogen and -CH 3 .
  • at least one pair of R 3a and R 3b or R 8a and R 8b is simultaneously hydrogen.
  • R 4 is selected from hydrogen, Ci-C 4 alkyl, and 0-Ci-C 4 alkyl, wherein each alkyl portion of R 4 is optionally substituted with 0-3 occurrences of R a .
  • R 4 is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -OCH 3 and -OCH 2 CH 3 .
  • any of Formulae A, I, la or lb, R 5 is selected from hydrogen and Ci-C 4 alkyl optionally substituted with 0-3 occurrences of R a . In some embodiments, R 5 is selected from hydrogen and -CH 3 . In some embodiments any of Formulae A, I, la or lb, each R 6 is independently selected from hydrogen, halo, and Ci-C 4 alkyl optionally substituted with 0-3 occurrences of R a . In some embodiments, each R 6 is independently selected from hydrogen, chloro, and -CH 3 . In some embodiments, no more than one R 6 is other than hydrogen.
  • ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom. In some embodiments, ring A is selected
  • R is heteroaryl optionally substituted with 0-3 occurrences of R b .
  • R 7 is selected from 4- fluoropyrazol-l-yl, 4-chloropyrazol-l-yl, pyrazol-l-yl, and 3,5-dimethylpyrazol-l-yl optionally substituted with 0-3 occurrences of R b .
  • R 7 is pyrazol-l-yl optionally substituted with 0-3 occurrences of R b .
  • n is 1. In some embodiments, n is 1; and R 7 is pyrazol-l-yl an optionally substituted with 0-3 occurrences of R b .
  • R 9 is selected from hydrogen and Ci-C 4 alkyl optionally substituted with 0-3 occurrences of R a .
  • R 9 is hydrogen.
  • R 9 is Ci-C 4 alkyl.
  • R 5 and R 9 are both hydrogen.
  • the compound is a compound having the structural formula (Ic):
  • the compound is a compound having the structural formula (Id):
  • the compound is a compound having the structural formula Ie:
  • wwhheeirein ring A X 1 , X 2 , R 1 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 9 , m and n are as defined for Formula (A).
  • the compound is a compound having the structural formula (If)
  • the present invention features a compound having the structural formula (II):
  • X 1 is selected from N, CH and C(halo);
  • X is selected from N and CH;
  • X is selected from N and CH;
  • R 12 is selected from hydrogen, hydroxyl, halo and 0-Ci-C 4 alkyl
  • each of R 13a , R 13b , R 18a and R 18b is independently selected from hydrogen and Ci-C 4 alkyl;
  • R 14 is selected from hydrogen, -Ci-C 4 alkyl and -0-Ci-C 4 alkyl; R is selected from hydrogen and -Ci-C 4 alkyl;
  • R 16 is selected from hydrogen and -Ci-C 4 alkyl
  • R 17b is selected from hydrogen and halo
  • R 17a and R 17c are independently selected from hydrogen and -Ci-C 4 alkyl.
  • R 12 is selected from hydrogen, hydroxyl, fluoro and -O-CH 3 ; each of R 13a , R 13b , R 18a and R 18b is independently selected from hydrogen, methyl and ethyl; and wherein at least one pair of R 13a and R 13b or R 18a and R 18b is simultaneously hydrogen;
  • R 14 is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -OCH 3 and -OCH 2 CH 3 ;
  • R 15 is selected from hydrogen and -CH 3 ;
  • R 16 is selected from hydrogen and -CH 3 ;
  • R 17b is selected from hydrogen, chloro and fluoro;
  • R 17a and R 17c are simultaneously hydrogen or -CH 3 , wherein when R 17a and R 17c are simultaneously -CH 3 , R 17b is hydrogen.
  • the compound is a compound having the structural formula (Ila):
  • X 1 , X 2 , X 3 , R 12 , R 13a , R 13b , R 14 , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , and R 18b are as defined as for Formula (II).
  • the compound is a compound having the structural formula (lib):
  • X 1 , X 2 , X 3 , R 12 , R 13a , R 13b , R 14 , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , and R 18b are as defined as for Formula (II).
  • the invention provides a compound of Formula Ilia or Formula
  • the compound has the Formula IIIb-2:
  • each of X 1 and X 2 is C(R 6 ). In one aspect of these embodiments, each of X 1 and X 2 is CH. In some embodiments of Formula Illb the compound has the Formula IIIb-3 or IIIb-4:
  • R , R 1 , R , R , R 1 /a , R , R 17c , R 18a and R 18b are as defined for Formula II, including the more specific embodiments and aspects of each of the above variables.
  • the present invention features a compound selected from any compound in Table 1.
  • the present invention features a pharmaceutical composition
  • the present invention features a method for inhibiting RET activity in a cell or in a patient comprising the step of contacting the cell or administering to the patient a compound described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound described herein e.g. , a compound in Table 1
  • the present invention features 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 described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound described herein e.g. , a compound in Table 1
  • the present invention features 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 described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a compound described herein e.g. , a compound in Table 1
  • 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.
  • 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. For example,
  • 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.
  • “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.
  • 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,
  • benzthiazolyl quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3-b]- l,4-oxazin-3-
  • 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 that ring 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. , tetrahydrofuranyl, 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. ,
  • Heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group.
  • Cyano refers to a -CN radical.
  • Niro refers to -N0 2 .
  • 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.
  • 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.
  • 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 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.
  • 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.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at 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.
  • “Pharmaceutically acceptable salt” refers to any salt of a compound of the invention which retains its biological properties 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, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthaiic, lauric, methanesulfonic, ethane sulfonic, 1 ,2-ethane-disuifonic, 2- hydroxyethanesulfonic, benzenesulionic, 4-chlorobenzenesulfonic, 2-nap t alenesulfonic
  • 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, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N- methylglucamine piperazine, tris(3 ⁇ 4ydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
  • an organic base such as
  • Pharmaceutically acceptable salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hvdrobromide, tartrate, mesylate, besylate, acetate, maleate, oxalate and the like.
  • non-toxic organic or inorganic acids such as hydrochloride, hvdrobromide, 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.
  • 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. Dosages
  • 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 mutants of RET, e.g. , mutants of RET that are resistant to current standard of care treatments ("RET resistant mutants").
  • 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.
  • 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, RET resistant mutants 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
  • pancreatic ductal adenocarcinoma pancreatic ductal adenocarcinoma
  • 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.
  • 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.
  • An aryl dihalide may be treated with an organolithium or organomagnesium halide reagent, such as n-BuLi or z ' -PrMgCl, and the arylmetal reagent may then undergo addition to an ester substituted cyclohexanone (either commercially available or prepared as described in "Synthesis of Ketone and Boronate Intermediates").
  • the remaining halide can then undergo a coupling reaction with an arylamine under SnAr conditions or metal-catalyzed coupling conditions to give a tricyclic ester intermediate.
  • the ester can then be hydrolyzed under basic conditions to give an acid, which can then undergo an amide coupling reaction with an amine (either commercially available or prepared as described in "Synthesis of Amine Intermediates").
  • the amides are examples of RET inhibitors described herein, but can also be further modified.
  • the tertiary alcohol can be treated with a fluorinating reagent such as DAST to give a mixture of deoxyfluorinated products and dehydrated products.
  • the dehydrated products can be reduced under typical hydrogenation conditions such as Pd and H 2 , or Pd and ammonium formate to give the reduced products which are also examples of RET inhibitors.
  • the heteroaryl dihalide can be coupled to an amino pyrazole 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 bicyclic heteroaryl halide can then be coupled to a to a boron, tin or zinc alkenyl or alkyl reagent via a Palladium-mediated coupling reaction, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system.
  • the carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate.
  • the carboxylic acid intermediate can then be coupled to a variety of amine intermediates, such as those described in Example 9 to provide the amide final product.
  • a substituted cycloalkyl iodide (either commercially available or prepared as described in "Synthesis of Iodide Intermediates") was treated with activated zinc.
  • the zinc was then activated by a variety methods, including but not limited to the method of Reike or treatment with TMS-Cl and 1,2-dibromoethane.
  • the cycloalkyl zinc reagent can then be coupled to a heteroaryl halide with palladium catalysis under Negishi coupling conditions.
  • the thiomethyl group of the resulting product can then be converted to a chloride via oxidation to the sulfone, hydrolysis under acidic conditions, and chlorination with POCI 3 or oxalyl chloride.
  • the heteroaryl chloride can then undergo displacement with an aryl amine under either SnAr conditions or palladium mediated coupling conditions.
  • the tricyclic carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate.
  • the carboxylic acid intermediate can then be coupled to a variety of amines intermediates, such as those described in Example 9 to provide the amide final product.
  • a substituted cycloalkyl iodide (either commercially available or prepared as described in "Synthesis of Iodide Intermediates") was treated with activated zinc.
  • the zinc could be activated by a variety methods, including but not limited to the method of Reike or treatment with TMS-Cl and 1,2-dibromoethane.
  • the cycloalkyl zinc reagent can then be coupled to a heteroaryl dihalide with palladium catalysis under Negishi coupling conditions.
  • the remaining halide group of the resulting product can then undergo displacement with an aryl amine under either SnAr conditions or palladium mediated coupling conditions.
  • the aryl amine can either be unprotected or the pyrazole N-H can be protected with a variety of groups, such as Boc.
  • the tricyclic carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate, which also removes the protecting group from the pyrazole.
  • the carboxylic acid intermediate can then be coupled to a variety of amines intermediates, such as those described in "Synthesis of Amine Intermediates" to provide the amide final product.
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the
  • 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, 5th ed., John Wiley & Sons: New Jersey, (2014), 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, 2.7 um 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.
  • Step 1 Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4- methyl-6-( 5-methyl-lH-pyrazol-3-ylamino )pyridin-2-yl)cyclohexanecarboxamide ( Compound 109) and (lS,4R)-N-((S)-l-(6-(4-fluoro-lH yrazol-l-yl)pyridin-3-yl)e ⁇
  • Step 1 Synthesis of2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine.
  • Step 2 Synthesis of ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohex-3
  • the reaction mixture was heated in a microwave reactor at 125 °C for 80 min, then cooled to ambient temperature and partitioned between 5: 1 DCM/IPA and water. The aqueous layer was further extracted with 5: 1 DCM/IPA. The organic layers were combined and dried over sodium sulfate. The dried solution was filtered,
  • Step 3 Synthesis of ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexane-l-carboxylate.
  • Step 4 Synthesis of 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexane-l -carboxylic acid.
  • Lithium hydroxide monohydrate (0.029 g, 0.70 mmol) was added to a solution of ethyl 4- (4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (0.12 g, 0.35 mmol) in THF (2.8 mL), EtOH (2.8 mL), and water at ambient temperature.
  • the reaction mixture was stirred for 6 h, then concentrated aqueous HC1 (37%, 0.072 ml, 0.87 mmol) was added. The reaction mixture was concentrated and carried forward in the next step.
  • Step 5 Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4- methyl-6-((5-methyl-lH ⁇ yrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-l-carboxamide
  • Step 1 Synthesis of (lS,4S)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane- carboxylate and (lR,4R)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane- carboxylate.
  • Step 2 Synthesis of (lS,4S)-ethyl 4-hydroxy-4-(4-methyl-6-(5-methyl-lH-pyrazol-3- ylamino)pyridin-2-yl)cyclohexanecarboxylate.
  • Step 3 Synthesis of (lS,4S)-4-hydroxy-4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin- 2 -yl )cyclohexanecarboxylic acid.
  • Step 4 Synthesis of (ls,4R )-N-( (S)-l-( 6-(4-fluoro-lH-pyrazol-l -yl)pyridin-3-yl)ethyl)-4-hydroxy- 4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
  • Step 1 Synthesis of (ls,4R )-4-fluoro-N-( (S)-l-(6-( 4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl )ethyl)- 4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
  • Step 1 Synthesis of2-chloro-4-methyl-6-(methylthio)pyrimidine.
  • Step 2 Synthesis of Methyl l-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl)cyclohexane-l- carboxylate.
  • Methyl 4-iodo-l-methoxycyclohexanecarboxylate (1.35 g, 4.53 mmol) was dissolved in dimethylacetamide (10 mL) in a pressure vessel under a stream of N 2 .
  • Rieke Zinc (5.7 mL of a 50mg/mL suspension in THF, 4.34 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes.
  • the vessel was opened under a stream of N 2 and 2-chloro-4-methyl-6-(methylthio)pyrimidine (659 mg, 3.8 mmol) was added followed by PdCl 2 dppf (138 mg, 0.19 mmol).
  • the vessel was capped and heated to 80 °C for one hour, then cooled to room temperature.
  • the reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H 2 0 (3x), brine, dried over sodium sulfate, filtered, and concentrated.
  • the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% EtOAc-hexanes) to give methyl l-methoxy-4-(4-methyl-6- (methylthio)pyrimidin-2-yl)cyclohexanecarboxylate (828 mg, 70%) as a colorless oil.
  • Methyl l-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl)cyclohexanecarboxylate 825 mg, 2.66 mmol was dissolved in DCM (12 mL) followed by the addition of mCPBA (1.10 g, 6.38 mmol) at ambient temperature. The reaction mixture was stirred for 16 h, then an additional portion of mCPBA was added (200 mg). After stirring for an additional 4 h, the reaction mixture was diluted with DCM and then washed with saturated sodium bicarbonate solution.
  • Step 4 Synthesis of Methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)-l -methoxycyclohexane-1 - carboxylate.
  • Methyl l-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2-yl)cyclohexane- carboxylate (600 mg, 1.75 mmol) was dissolved in acetic acid (5 mL) and heated to 80 °C for 1 h. The reaction mixture was then cooled to ambient temperature, concentrated under reduced pressure, triturated with H 2 0, and filtered. The solids were washed with additional H 2 0 and then dried under reduced pressure to afford the title compound, methyl 4-(4-hydroxy-6- methylpyrimidin-2-yl)-l-methoxycyclohexanecarboxylate (390 mg, 79%), as a pale yellow solid.
  • MS (ES+) Ci 4 H 20 N 2 O 4 requires: 280, found: 281 [M+H] + .
  • Step 5 Synthesis of Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-l -methoxycyclohexane-1 - carboxylate.
  • Methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)- 1-methoxycyclohexanecarboxylate (380 mg, 1.36 mmol) was suspended in POCl 3 (3.2 mL, 33.9 mmol) and heated to 100 °C for 2 h. The reaction mixture was then cooled to ambient temperature, concentrated, and the residue was treated with crushed ice. The resulting suspension was partitioned with DCM, and the organic layer was extracted with saturated sodium bicarbonate solution and dried over sodium sulfate.
  • Step 6 Synthesis of Methyl 1 -methoxy-4-(4-methyl-6-((5-methyl-l H-pyrazol-3- yl)amino )pyrimidin-2-yl)cyclohexane-l -carboxylate.
  • Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)- 1-methoxycyclohexanecarboxylate 300 mg, 1.00 mmol
  • 3-methyl-l-pyrazol-5-amine 146 mg, 1.51 mmol
  • di-tert-butyl(2',4',6'- triisopropyl-[l,l'-biphenyl]-2-yl)phosphine 85 mg, 0.2 equiv.
  • Pd 2 (dba)3 92 mg, 0.1 equiv.
  • potassium acetate 394 mg, 4.02 mmol
  • Step 7 Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane- carboxamide (Compound 129) and (lS,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)-l-methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexanecarboxamide (Compound 130).
  • the title compounds were prepared from methyl l-methoxy-4-(4-methyl-6-((5-methyl- lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU.
  • the products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21 x 250 mm, 40% MeOH containing 0.25% DEA in C0 2 , 2.5 mL injections, 70 mL/min).
  • Peak 1 was concentrated to give (lR,4S)-N-((S)-l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l-methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid.
  • Peak 2 was concentrated to give (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane- carboxamide (130 mg, 46%) as a white solid.
  • Step 1 Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-l -methoxycyclohexane-1 - carboxylate.
  • Methyl 4-iodo-l-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N 2 .
  • Rieke Zinc (17.7 mL of a 50mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes.
  • the vessel was opened under a stream of N 2 and 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl 2 dppf (826 mg, 1.13 mmol).
  • the vessel was capped and heated to 80 °C for one hour, then cooled to room temperature.
  • the reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H 2 0 (3x), brine, dried over sodium sulfate, filtered, and concentrated.
  • the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4- yl)-l -methoxycyclohexane-1 -carboxylate (74 mg, 2.2%) as a colorless oil.
  • Ci 4 Hi 9 ClN 2 0 3 requires: 298, found: 299 [M+H] + .
  • Step 2 Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6- methylpyrimidin-2-yl)amino)-5-methyl-lH-pyrazole-l -carboxylate.
  • Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)- 1-methoxycyclohexane- 1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2',4',6'-triisopropyl-[l, -biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd 2 (dba) 3 (21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added.
  • Step 3 Synthesis of l-Methoxy-4-( 6-methyl-2-( ( 5 -methyl- lH-pyrazol-3-yl)amino )pyrimidin-4- yl)cyclohexane-l -carboxylic acid.
  • Lithium hydroxide monohydrate 13 mg, 0.31 mmol was added to a solution of tert- butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5- methyl-lH-pyrazole- 1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H 2 0 (17: 1: 1, 1.8 mL) The reaction mixture was heated to 60 °C and stirred for 16 h.
  • Step 4 Synthesis of (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-( 6-methyl-2-( ( 5 -methyl- lH-pyrazol-3-yl)amino )pyrimidin-4-yl)cyclohexane-l - carboxamide ( mpound 149).
  • the title compound was prepared from l-methoxy-4-(6-methyl-2-((5-methyl-lH-pyrazol- 3-yl)amino)pyrimidin-4-yl)cyclohexane-l-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU.
  • Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l-methoxy-4-(6-methyl-2-((5- methyl-lH-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-l-carboxamide (13.4 mg, 24%) as a white solid.
  • Step 1 Synthesis of ethyl 8-ethoxy-l ,4-dioxaspiro[4.5] decane-8-carboxylate.
  • Step 2 Synthesis of ethyl 1 -ethoxy-4-oxocyclohexane-l -carboxylate.
  • Step 1 Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-l-carboxylate.
  • a solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C and then cooled to -78 °C. The solution of ethyl 2-methyl- 4-oxocyclohex-2-ene-l-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between -40 °C to -20 °C for 2h, then was warmed to ambient temperature for 16 h.
  • Step 2 Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-l- carboxylate.
  • Ethyl 2,2-dimethyl-4-oxocyclohexane-l-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45 °C for 10 minutes.
  • Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45 °C for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2 x 40 mL).
  • Step 3 Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex- 3-ene-l-carboxylate.
  • reaction mixture was flushed with nitrogen, then heated to 100 °C for 2 h.
  • the mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate (618 mg).
  • Ethyl 6-methyl-4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 - carboxylate was prepared using the same synthetic protocol as described above using ethyl 2- methyl-4-oxocyclohexane-l-carboxylate as the starting material.
  • Step 1 Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate
  • Step 2 Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in
  • Step 3 Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate
  • Step 1 Synthesis of methyl 1 -methoxy-4-hydroxycyclohexane-l -carboxylate.
  • Methyl l-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved methanol (100 mL) and the solution was cooled to 0 °C.
  • Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH 4 C1 solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3 x).
  • Step 2 Synthesis of methyl 1 -methoxy-4-iodocyclohexane-l -carboxylate.
  • Methyl l-methoxy-4-hydroxycyclohexane-l -carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0 °C, and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc.
  • Step 1 Synthesis of 1 -(6-(4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl)ethan-l -one.
  • Step 2 Synthesis of (R)-N-((S)-1 -(6-(4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl)ethyl)-2- methylpropane-2-sulfinamide.
  • Step 3 Synthesis of (S)-l -(6-(4-fluoro-lH-pyrazol-l -yl)pyridin-3-yl)ethan-l -amine.
  • Step 1 Synthesis of 1 -(5-(4-fluoro-l H-pyrazol-1 -yl)pyrazin-2-yl)ethan-l -one.
  • Step 2 Synthesis of (R)-N-((S)-1 -(5-(4-fluoro-l H-pyrazol-1 -yl)pyrazin-2-yl)ethyl)-2- methylpropane-2-sulfinamide.
  • Step 3 Synthesis of (S)-l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethan-l -amine.
  • Step 1 Synthesis of 5-(4-fluoro-lH-pyrazol-l-yl)pyrazine-2-carbonitrile.
  • Step 1 Synthesis of ' 6-( 3, 5 -dimethyl- IH-pyrazol-l -yl)nicotinonitrile.
  • Step 2 Synthesis of tert-Butyl ((6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate.
  • 6-(3,5-dimethyl-lH-pyrazol-l-yl)nicotinonitrile 300 mg, 1.5 mmol
  • MeOH MeOH
  • Boc 2 0 (Boc) 2 0 (654 mg, 3.0 mmol)
  • NaBH 4 142 mg, 3.8 mmol
  • the aqueous suspension was partitioned with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution (2 x 50mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 450 mg target compound which was used in the next step without further purification.
  • Step 3 Synthesis of ' (6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine.
  • Step 1 Synthesis of 6-(4-Chloro-l H-pyrazol-1 -yl)nicotinonitrile
  • Step 3 Synthesis of (6-(4-chloro-lH-pyrazol-l -yl)pyridin-3-yl)methanamine
  • the Caliper LifeSciences electrophoretic mobility shift technology platform was used. Fluorescently labeled substrate peptide was incubated in the presence of kinase and ATP so that a reflective proportion of the peptide was phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides were 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.
  • 7.5 nM - 10 nM of wild type RET (ProQinase 1090- 0000-1) was incubated in a total of 12.5 of buffer (100 mM HEPES pH 7.5, 0.015% Bri/ 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% Bri/ 35, 10 mM MgCl 2 , ImM DTT
  • 1 ⁇ CSKtide FITC-AHA-KKKKD DIYFFFG-NH2
  • the reaction was 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 was then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data was 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) was incubated in a total of 12.5 ⁇ , of buffer (100 mM HEPES pH 7.5, 0.015% Bri/ 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% Bri/ 35, 10 mM MgC12, ImM DTT
  • 1 ⁇ CSKtide FITC-AHA-KKKKDDIYFFFG-NH2
  • the reaction was 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 was then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data was 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

Inhibitors of wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

Description

INHIBITORS OF RET
This invention relates to inhibitors of RET that are active against wild-type RET and its resistant mutants.
CLAIM OF PRIORITY
This application claims priority from U.S. S.N. 62/249,784, filed November 2, 2105, and U.S. S.N. 62/367,960, filed July 28, 2016, each of which is incorporated herein in its entirety.
BACKGROUND
RET (rearranged during transfection) is a receptor tyrosine kinase that activates multiple downstream pathways involved in cell proliferation and survival. RET fusions are implicated in several cancers including papillary thyroid carcinoma and non-small ceil 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
The present invention provides inhibitors of RET and RET mutants, e.g. , RET resistant mutants (as defined herein), for example, inhibitors of structural formula (I) and
pharmaceutically acceptable salts and compositions thereof. The present invention further provides methods of using the compounds of the invention, and pharmaceutically acceptable salts and compositions thereof, to inhibit the activity of RET or RET mutants in a cell or patient. The present invention still further provides methods for using the compounds of the invention, and pharmaceutically acceptable salts and compositions thereof, to treat a subject suffering from a condition mediated by aberrant RET activity, e.g. , cancer.
In one aspect, the invention features a compound of structural formula (A) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
(A)
wherein each of ring A, X1, X2, Y1, Y2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, m, n, o and
is defined as described herein.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of structural formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method for inhibiting RET activity in a cell or in a patient. In some embodiments, said method comprises the step of contacting the cell or administering to the patient a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
In another aspect, the present invention provides a method for treating a subject suffering from a condition mediated by aberrant RET activity. In some embodiments, said method comprises administering to the subject a therapeutically effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
In another aspect, the present invention provides a method for treating a subject who has developed resistance to a cancer treatment. In some embodiments, said method comprises administering to the subject a therapeutically effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt or composition thereof.
EMBODIMENTS OF THE INVENTION
Compounds
In one aspect, the present invention features a compound having the structural formula
(A
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
ring A is an aryl or heteroaryl ring;
each of X1 and X2 is independently selected from N and C(R6);
each of Y 1 and Y 2 is independently selected from -CH2- and -0-, wherein no more than one of Y1 or Y2 is -0-;
1 7
each R and each R is independently selected from selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(0)R, -OC(0)R, - C(0)OR, -(Ci-Ce alkylene)-C(0)R, -SR, -S(0)2R, -S(0)2-N(R)(R), -(Ci-C6 alkylene)- S(0)2R, -(Ci-Ce alkylene)-S(0)2-N(R)(R), -N(R)(R), -C(0)-N(R)(R), -N(R)-C(0)R, -N(R)- C(0)OR, -(Ci-C6 alkylene)-N(R)-C(0)R, -N(R)S(0)2R, and -P(0)(R)(R); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or two R1 or two R are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;
each of R2 when present, R3a, R3b, R4, R8a and R8b, when present is independently selected from hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, halo, hydroxyl, Ci-C6 heteroalkyl, and - N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;
each of R5 and R9 is independently selected from hydrogen, Ci-C6 alkyl, and Ci-C6 heteroalkyl; wherein each alkyl and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;
each R6 is independently selected from hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;
each R is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C6 alkyl, Ci-C6 thioalkyl, Ci-C6 alkoxy, Ci-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra, 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 each Rb is independently selected from Ci-C6 alkyl, halo, hydroxyl, Ci-C6 heteroalkyl, Ci-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R'; each R' is independently selected from Ci-C6 alkyl, Ci-C6 heteroalkyl, halo, hydroxyl, 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, or 2;
n is 0, 1, 2, or 3;
= represents a single or double bond;
each o is 0 when = is a double bond; and
each o is 1 when = is a single bond. , the compound is a compound having formula (I):
Figure imgf000007_0001
(I), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A.
In some embodiments, = represents a single bond and the compound has formula la:
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A.
In some embodiments, = represents a double bond and the compound has formula lb:
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R3a, R3b, R4, R5, R6, R7, R8a, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A.
In some embodiments of any of Formulae A, I, la or lb, R1 is located at the 5-position. In some embodiments, R1 is located at the 4-position. In some embodiments, R1 is Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 1; R1 is located at the 5-position; and R1 is Q- C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, R1 is -CH3.
In some embodiments of Formulae I or la, R is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl. In some embodiments, R is selected from hydrogen, hydroxyl, fluoro and -OCH3.
In some embodiments any of Formulae A, I, la or lb, each of R3a, R3b, R8a and R8b (which is only present in Formulae I or la) is independently selected from hydrogen and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, each of R3a, R3b, R8a and R 8b is independently selected from hydrogen and -CH3. In some embodiments, at least one pair of R3a and R3b or R8a and R8b is simultaneously hydrogen.
In some embodiments any of Formulae A, I, la or lb, R4 is selected from hydrogen, Ci-C4 alkyl, and 0-Ci-C4 alkyl, wherein each alkyl portion of R4 is optionally substituted with 0-3 occurrences of Ra. In some embodiments, R4 is selected from hydrogen, -CH3, -CH2CH3, -OCH3 and -OCH2CH3.
In some embodiments any of Formulae A, I, la or lb, R5 is selected from hydrogen and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, R5 is selected from hydrogen and -CH3. In some embodiments any of Formulae A, I, la or lb, each R6 is independently selected from hydrogen, halo, and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, each R6 is independently selected from hydrogen, chloro, and -CH3. In some embodiments, no more than one R6 is other than hydrogen.
In some embodiments any of Formulae A, I, la or lb, ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom. In some embodiments, ring A is selected
Figure imgf000009_0001
from and
In some embodiments any of Formulae A, I, la or lb, R is heteroaryl optionally substituted with 0-3 occurrences of Rb. In some embodiments, R7 is selected from 4- fluoropyrazol-l-yl, 4-chloropyrazol-l-yl, pyrazol-l-yl, and 3,5-dimethylpyrazol-l-yl optionally substituted with 0-3 occurrences of Rb. In some embodiments, R7 is pyrazol-l-yl optionally substituted with 0-3 occurrences of Rb. In some embodiments, n is 1. In some embodiments, n is 1; and R7 is pyrazol-l-yl an optionally substituted with 0-3 occurrences of Rb.
In some embodiments any of Formulae A, I, la or lb, R9 is selected from hydrogen and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra. In some embodiments, R9 is hydrogen. In some embodiments, R9 is Ci-C4 alkyl. In some embodiments, R5 and R9 are both hydrogen.
In some embodiments, the compound is a compound having the structural formula (Ic):
Figure imgf000009_0002
or a pharmaceutically acceptable salt thereof, wherein ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, m and n are as defined for Formula (A).
In some embodiments, the compound is a compound having the structural formula (Id):
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof,
wherein ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, m and n are as defined for Formula (A).
In some embodiments, the compound is a compound having the structural formula Ie:
Figure imgf000010_0002
or a pharmaceutically acceptable salt thereof,
wwhheeirein ring A, X1, X2, R1, R3a, R3b, R4, R5, R6, R7, R8a, R9, m and n are as defined for Formula (A).
some embodiments, the compound is a compound having the structural formula (If)
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof,
wherein ring A, X1, X2, R1, R3a, R3b, R4, R5, R6, R7, R8a, R9, m and n are as defined for Formula
(A).
In another aspect, the present invention features a compound having the structural formula (II):
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof, wherein:
X1 is selected from N, CH and C(halo);
X is selected from N and CH;
X is selected from N and CH;
R 12 is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl;
each of R13a, R13b, R18a and R18b is independently selected from hydrogen and Ci-C4 alkyl;
R14 is selected from hydrogen, -Ci-C4 alkyl and -0-Ci-C4 alkyl; R is selected from hydrogen and -Ci-C4 alkyl;
R16 is selected from hydrogen and -Ci-C4 alkyl;
R17b is selected from hydrogen and halo; and
R17a and R17c are independently selected from hydrogen and -Ci-C4 alkyl.
In some embodiments, X 1 is selected from N, CH and C(C1); X 2 is selected from
CH; X 3 is selected from N and CH; R 12 is selected from hydrogen, hydroxyl, fluoro and -O-CH3; each of R13a, R13b, R18a and R18b is independently selected from hydrogen, methyl and ethyl; and wherein at least one pair of R13a and R13b or R18a and R18b is simultaneously hydrogen; R14 is selected from hydrogen, -CH3, -CH2CH3, -OCH3 and -OCH2CH3; R15 is selected from hydrogen and -CH3; R16 is selected from hydrogen and -CH3; R17b is selected from hydrogen, chloro and fluoro; R17a and R17c are simultaneously hydrogen or -CH3, wherein when R17a and R17c are simultaneously -CH3, R17b is hydrogen.
In some embodiments, the compound is a compound having the structural formula (Ila):
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof,
wherein X1, X2, X3, R12, R13a, R13b, R14, R15, R16, R17a, R17b, R17c, R18a, and R18b are as defined as for Formula (II).
In some embodiments, the compound is a compound having the structural formula (lib):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof,
wherein X1, X2, X3, R12, R13a, R13b, R14, R15, R16, R17a, R17b, R17c, R18a, and R18b are as defined as for Formula (II).
In some embodiments, the invention provides a compound of Formula Ilia or Formula
Illb:
Figure imgf000013_0002
(Mb), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A, including the more specific embodiments and aspects of each of the above variables. nts of Formula Illb, the compound has the Formula IIIb-1:
Figure imgf000014_0001
(IIIb-1), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A, including the more specific embodiments and aspects of each of the above variables.
In some embodiments of Formula Illb, the compound has the Formula IIIb-2:
Figure imgf000014_0002
(IIIb-2), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as described for a compound of Formula A, including the more specific embodiments and aspects of each of the above variables.
In some embodiments of Formulae Ilia, Illb, IIIb-1 and IIIb-2, each of X 1 and X 2 is C(R6). In one aspect of these embodiments, each of X1 and X2 is CH. In some embodiments of Formula Illb the compound has the Formula IIIb-3 or IIIb-4:
Figure imgf000015_0001
pharmaceutically acceptable salt thereof, wherein each of R , R , R1 , R , R , R , R1 /a, R , R17c, R18a and R18b are as defined for Formula II, including the more specific embodiments and aspects of each of the above variables.
In some embodiments, the present invention features a compound selected from any compound in Table 1.
In another aspect, the present invention features a pharmaceutical composition
comprising a compound of Formula A, I, la, lb, Ic, Id, II, Ila, lib, Ilia, Illb, Illb- 1 , IIIb-2, IIIb-3, or IIIb-4 described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present invention features a method for inhibiting RET activity in a cell or in a patient comprising the step of contacting the cell or administering to the patient a compound described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present invention features 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 described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the present invention features 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 described herein (e.g. , a compound in Table 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
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 "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- l -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. "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.
"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 that ring 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. , tetrahydrofuranyl, 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. ,
3,4-dihydro- lH-pyrano[4,3-c]pyridine, and l,2,3,4-tetrahydro-2,6-naphthyridine.
"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.
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.)
As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at 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.
Suitable substituents for an optionally substituted alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl group and heteroaryl group include halogen, =0, - CN, -ORc, -NRdRe, -S(0)kRc, -NRcS(0)2Rc, -S(0)2NRdRe, -C(=0)ORc, -OC(=0)ORc,- OC(=0)Rc, - OC(=S)ORc, -C(=S)ORc, -0(C=S)Rc, -C(=0)NRdRe, -NRcC(=0)Rc, -C(=S)NRdRe, -NRCC(=S)RC , -NRc(C=0)ORc, -0(C=0)NRdRe, -NRc(C=S)ORc, -0(C=S)NRdRe, -NRc(C=0)NRdRe, -NRC(C= S)NRdRe, -C(=S)RC, -C(=0)Rc, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, carbocyclyl, (Ci-C6-alkylene)-carbocyclyl, (Ci-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (Ci-C6- alkylene)-heterocyclyl, (Ci-C6-heteroalkylene)-heterocyclyl, aryl, (Ci-C6-alkylene)-aryl, (Ci-C6- heteroalkylene)-aryl, heteroaryl, (Ci-C6-alkylene)-heteroaryl, or (Ci-C6-heteroalkylene)- heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more of halogen,
ORc, -N02, -CN, -NRcC(=0)Rc, -NRdRe, -S(0)kRc, -C(=0)ORc, -C(=0)NRdRe, -C(=0)Rc, Ci-C6 alkyl, Ci-C6 haloalkyl, or Ci-C6 heteroalkyl, and wherein Rc is hydrogen, hydroxy, Ci-C6 alkyl, CrC6 heteroalkyl, carbocyclyl, (Ci-C6-alkylene)-carbocyclyl, (Ci-C6-heteroalkylene)- carbocyclyl, heterocyclyl, (Ci-C6-alkylene)-heterocyclyl, (Ci-C6-heteroalkylene)-heterocyclyl, aryl, (Ci-C6-alkylene)-aryl, (Ci-C6-heteroalkylene)-aryl, heteroaryl, (Ci-C6-alkylene)-heteroaryl, or (Ci-C6-heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Rd and Re are each independently selected from hydrogen, Ci-C6 alkyl, or Ci- C6 heteroalkyl; and k is 0, 1 or 2. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
Table 1. Exemplary Compounds of the Invention.
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_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 properties 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, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthaiic, lauric, methanesulfonic, ethane sulfonic, 1 ,2-ethane-disuifonic, 2- hydroxyethanesulfonic, benzenesulionic, 4-chlorobenzenesulfonic, 2-nap t alenesulfonic, 4- toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydro xynaphthoic, salicylic, stearic, cyclohexylsuifamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton present 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, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N- methylglucamine piperazine, tris(¾ydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like. Pharmaceutically acceptable salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hvdrobromide, 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. 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 imgf000035_0001
The invention provides compounds that inhibit both wild-type RET and mutants of RET, e.g. , mutants of RET that are resistant to current standard of care treatments ("RET resistant mutants"). 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.
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, RET resistant mutants 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. Ei 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.
EXAMPLES
The following examples are intended to be illustrative, and are not meant in any way to be limiting.
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 Synthetic Protocols below and in the Examples. 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 imgf000038_0001
An aryl dihalide may be treated with an organolithium or organomagnesium halide reagent, such as n-BuLi or z'-PrMgCl, and the arylmetal reagent may then undergo addition to an ester substituted cyclohexanone (either commercially available or prepared as described in "Synthesis of Ketone and Boronate Intermediates"). The remaining halide can then undergo a coupling reaction with an arylamine under SnAr conditions or metal-catalyzed coupling conditions to give a tricyclic ester intermediate. The ester can then be hydrolyzed under basic conditions to give an acid, which can then undergo an amide coupling reaction with an amine (either commercially available or prepared as described in "Synthesis of Amine Intermediates"). The amides are examples of RET inhibitors described herein, but can also be further modified. For example, the tertiary alcohol can be treated with a fluorinating reagent such as DAST to give a mixture of deoxyfluorinated products and dehydrated products. The dehydrated products can be reduced under typical hydrogenation conditions such as Pd and H2, or Pd and ammonium formate to give the reduced products which are also examples of RET inhibitors.
Synthetic Protocol 2:
Figure imgf000039_0001
Figure imgf000039_0002
The heteroaryl dihalide can be coupled to an amino pyrazole 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 bicyclic heteroaryl halide can then be coupled to a to a boron, tin or zinc alkenyl or alkyl reagent via a Palladium-mediated coupling reaction, e.g. , Suzuki, Stille, Negishi coupling, to provide the tricyclic ring system. For example, in Synthetic Protocol 2, the bicyclic heteroaryl halide of the can be coupled to a variety of ester substituted cyclohexenyl boronic esters (commercially available or those described under the heading "Synthesis of Vinyl Boronates") under Suzuki coupling reaction conditions (X = halo, e.g. , chloro; and M = B(OR)2) to provide the tricyclic carboxylic ester intermediate. The carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate. The carboxylic acid intermediate can then be coupled to a variety of amine intermediates, such as those described in Example 9 to provide the amide final product.
Synthetic Protocol 3:
Figure imgf000040_0001
PdCI2dppf
Figure imgf000040_0002
A substituted cycloalkyl iodide (either commercially available or prepared as described in "Synthesis of Iodide Intermediates") was treated with activated zinc. The zinc was then activated by a variety methods, including but not limited to the method of Reike or treatment with TMS-Cl and 1,2-dibromoethane. The cycloalkyl zinc reagent can then be coupled to a heteroaryl halide with palladium catalysis under Negishi coupling conditions. The thiomethyl group of the resulting product can then be converted to a chloride via oxidation to the sulfone, hydrolysis under acidic conditions, and chlorination with POCI3 or oxalyl chloride. The heteroaryl chloride can then undergo displacement with an aryl amine under either SnAr conditions or palladium mediated coupling conditions. The tricyclic carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate. The carboxylic acid intermediate can then be coupled to a variety of amines intermediates, such as those described in Example 9 to provide the amide final product. Synthetic Protocol 4:
Figure imgf000041_0001
PdCI2dppf
Figure imgf000041_0002
A substituted cycloalkyl iodide (either commercially available or prepared as described in "Synthesis of Iodide Intermediates") was treated with activated zinc. The zinc could be activated by a variety methods, including but not limited to the method of Reike or treatment with TMS-Cl and 1,2-dibromoethane. The cycloalkyl zinc reagent can then be coupled to a heteroaryl dihalide with palladium catalysis under Negishi coupling conditions. The remaining halide group of the resulting product can then undergo displacement with an aryl amine under either SnAr conditions or palladium mediated coupling conditions. The aryl amine can either be unprotected or the pyrazole N-H can be protected with a variety of groups, such as Boc. The tricyclic carboxylic ester can then be hydrolyzed under acidic or basic conditions to provide a carboxylic acid intermediate, which also removes the protecting group from the pyrazole. The carboxylic acid intermediate can then be coupled to a variety of amines intermediates, such as those described in "Synthesis of Amine Intermediates" to provide the amide final product.
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, 5th ed., John Wiley & Sons: New Jersey, (2014), 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, 2.7 um 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 OMSO-d6 solvent as parts-per million (ppm) with respect to residual DMSO (2.50 ppm).
Example 1. Synthesis of Compounds 109 and 110.
Step 1: Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4- methyl-6-( 5-methyl-lH-pyrazol-3-ylamino )pyridin-2-yl)cyclohexanecarboxamide ( Compound 109) and (lS,4R)-N-((S)-l-(6-(4-fluoro-lH yrazol-l-yl)pyridin-3-yl)e^
methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide ( Compound 110).
N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5-methyl-lH- pyrazol-3-yl)amino)pyridin-2-yl)cyclohex-3-enecarboxamide (50 mg, 0.10 mmol) and 10% Pd/C (20 mg) in MeOH (5 mL) was stirred at ambient temperature under a H2 atmosphere (1 atm) for 1 h. The mixture was then filtered through a pad of celite, and the filtered solution was concentrated and purified by preparative HPLC to give both of title compounds (1R,4S)-N-((S)- l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-lH-pyrazol-3- ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 109; 10.0 mg, 19.9%) and (1S,4R)- N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-lH-pyrazol- 3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 110; 24.8 mg, 49.5%) as a white solid. MS (ES+) C27H3iFN80 requires: 502, found: 503 [M+H]+.
(lR S)-N-((S)-l-(6-(4-fluoro-lH^yrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-m^
pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 109): 1H-NMR (400 MHz, DMSO-<ft5) <5 ppm 11.66 (s, 1H), 8.82 (s, 1H), 8.68 (d, 1H, 7 = 4.4 Hz), 8.39 (s, 1H), 8.35 (d, 1H, 7 = 6.8 Hz), 7.92-7.86 (m, 3H), 6.89 (s, 1H), 6.37 (s, 1H), 6.12 (s, 1H), 5.00-4.97 (m, 1H), 2.50- 2.44 (m, 1H), 2.40-2.15 (m, 7H), 1.90-1.85 (m, 4H), 1.55-1.45 (m, 4H), 1.40 (d, 3H, 7 = 6.4 Hz). (lS R)-N-((S)-l-(6-(4-fluoro-lH^yrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(^
pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 110): 1H-NMR (400 MHz, DMSO-<ft5) <5 ppm 11.62 (s, 1H), 8.78 (s, 1H), 8.66 (d, 1H, 7 = 4.4 Hz), 8.38 (d, 1H, 7 = 1.6 Hz), 8.23 (d, 1H, 7 = 7.6 Hz), 7.93-7.84 (m, 3H), 6.83 (s, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 5.03-5.00 (m, 1H), 2.59-2.50 (m, 1H), 2.50-2.46 (m, 1H), 2.14-2.02 (m, 6H), 2.02-1.84 (m, 4H), 1.63-1.55 (m, 4H), 1.40 (d, 3H, = 7.6 Hz).
Example 2. Synthesis of Compound 112.
Step 1: Synthesis of2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine.
Figure imgf000044_0001
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, at which point TLC (PE/EA, 5: 1, 1: 1) analysis showed the reaction was complete. The reaction mixture was cooled to 30 °C, poured into ice-water (800 mL), and 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 ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohex-3
Figure imgf000044_0002
A mixture of 2-chloro-6-methyl-N-(5-methyl-lH-pyrazol-3-yl)pyrimidin-4-amine (0.530 g, 2.37 mmol), ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.664 g, 2.37 mmol), and potassium carbonate (0.819 g, 5.92 mmol) in dioxane (8.89 ml) and water (2.96 ml) was sparged with nitrogen gas for 10 min, then Pd(PPh3)4 (0.137 g, 0.118 mmol) was added and the reaction vessel was sealed. The reaction mixture was heated in a microwave reactor at 125 °C for 80 min, then cooled to ambient temperature and partitioned between 5: 1 DCM/IPA and water. The aqueous layer was further extracted with 5: 1 DCM/IPA. The organic layers were combined and dried over sodium sulfate. The dried solution was filtered,
concentrated, and purified by silica gel chromatography (gradient elution, 0 to 10% methanol- DCM) to give ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohex- 3-ene-l-carboxylate (646 mg, 80%) as a yellow solid. MS (ES+) Ci8H23N502 requires: 341, found: 342 [M+H]+.
Step 3: Synthesis of ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexane-l-carboxylate.
Figure imgf000045_0001
Palladium on carbon (10 wt%, 0.125 g, 0.117 mmol) and ammonium formate (0.296 g, 4.69 mmol) were added to a solution of ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyrimidin-2-yl)cyclohex-3-enecarboxylate (0.40 g, 1.2 mmol) in ethanol (11.7 ml) and the resulting mixture was heated to 70 °C for 30 min. The reaction mixture was cooled to ambient temperature, and filtered through celite, rinsing the celite with methanol. The filtered solution was then concentrated onto silica gel and purified by silica gel chromatography
(gradient elution, 0 to 10% methanol-DCM) to give ethyl 4-(4-methyl-6-((5-methyl-lH-pyrazol- 3-yl)amino)pyrimidin-2-yl)cyclohexane-l-carboxylate as a 3: 1 mixture of cis:trans. MS (ES+) CisHisNsOi requires: 343, found: 344 [M+H]+.
Step 4: Synthesis of 4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexane-l -carboxylic acid.
Figure imgf000046_0001
Lithium hydroxide monohydrate (0.029 g, 0.70 mmol) was added to a solution of ethyl 4- (4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (0.12 g, 0.35 mmol) in THF (2.8 mL), EtOH (2.8 mL), and water at ambient temperature. The reaction mixture was stirred for 6 h, then concentrated aqueous HC1 (37%, 0.072 ml, 0.87 mmol) was added. The reaction mixture was concentrated and carried forward in the next step.
Step 5: Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4- methyl-6-((5-methyl-lH^yrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-l-carboxamide
(Compound 112).
Figure imgf000046_0002
HATU (162 mg, 0.427 mmol) was added to a solution of crude 4-(4-methyl-6-((5- methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylic acid (72 mg, 0.23 mmol),
(S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethanamine hydrochloride salt (97 mg, 0.40 mmol), and DIEA (0.34 mL, 1.9 mmol) in DMF (3.8 mL) at ambient temperature. The reaction mixture was stirred for 10 min, then was partitioned between EtOAc and H20. The organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution 0 to 10% methanol-dichloromethane with 2% triethylamine added) to give (lR,4S)-N-((S)-l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyrimidin-2-yl)cyclohexane-l-carboxamide (Compound 112; 26 mg, 13% yield) as a white solid. MS (ES+) C26H30FN9O requires: 503, found: 504 [M+H]"1".1!! NMR (500 MHz, DMSO-<¾) 6 11.88 (s, 1H), 9.48 (s, 1H), 8.66 (d, 7 = 4.5 Hz, 1H), 8.38 (d, 7 = 2.2 Hz, 1H), 8.30 (d, 7 = 7.7 Hz, 1H), 7.94 - 7.81 (m, 3H), 6.83 (s, 1H), 6.16 (s, 1H) 5.02 - 4.93 (m, 1H), 2-57- 2.49 (m, 1H), 2.26-2.16 (m, 7H), 1.99-1.92 (m, 2H), 1.88-1.80 (m, 2H), 1.58-1.36 (m, 7H).
Example 3. Synthesis of Compound 120.
Step 1: Synthesis of (lS,4S)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane- carboxylate and (lR,4R)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane- carboxylate.
Figure imgf000047_0001
(less polar by TLC) (more polar by TLC)
A solution of 2,6-dibromo-4-methylpyridine (1.00 g, 3.98 mmol) in DCM (30 mL) was cooled to -78 °C, and n-BuLi (2.5 M, 1.74 mL, 4.37 mmol) was added dropwise to the above solution at -78 °C. The solution was stirred at -78 °C for 15 minutes, followed by addition of ethyl 4-oxocyclohexanecarboxylate (811 mg, 4.77 mmol), and the resultant mixture was stirred at -78 °C for 30 min. The mixture was then quenched by addition of saturated aqueous NH4C1 solution and extracted with DCM. Organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (PE:EA = 2: 1) to give (lR,4R)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexanecarboxylate (less polar by TLC, 500 mg, 36.7%) as a white solid, MS (ES+) Ci5H2oBrN03 requires: 341, found: 342 [M+H]+, and (lS,4S)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexanecarboxylate (more polar by TLC, 500 mg, 36.7%) as a white solid. MS (ES+) Ci5H20BrNO3 requires: 341, found: 342 [M+H]+.
Step 2: Synthesis of (lS,4S)-ethyl 4-hydroxy-4-(4-methyl-6-(5-methyl-lH-pyrazol-3- ylamino)pyridin-2-yl)cyclohexanecarboxylate.
Figure imgf000048_0001
A mixture of (Is, 4s)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4- hydroxycyclohexanecarboxylate (500 mg, 1.46 mmol), 5-methyl-lH-pyrazol-3-amine (283 mg, 2.92 mmol), t-BuXPhos (185 mg, 0.438 mmol), Pd2(dba)3 (200 mg, 0.219 mmol) and KOAc (429 mg, 4.38 mmol) in DMF (2 mL) and toluene (10 mL) was heated to 140 °C for 2 h under microwave irradiation. After cooling to ambient temperature, the mixture was concentrated and purified by silica gel column (PE:EA = 1:2) to give (ls,4s)-ethyl 4-hydroxy-4-(4-methyl-6-(5- methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxylate (80 mg, 15%) as a white solid. MS (ES+) Ci9H26N403 requires: 358, found: 359 [M+H]+.
Step 3: Synthesis of (lS,4S)-4-hydroxy-4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin- 2 -yl )cyclohexanecarboxylic acid.
Figure imgf000048_0002
To a solution of (lS,4S)-ethyl 4-hydroxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyridin-2-yl)cyclohexanecarboxylate (80 mg, 0.2231 mmol) in MeOH (3 mL) was added 2 M aqueous NaOH (0.5 mL, 1 mmol) at 25 °C. The solution was stirred at 25 °C for 15 h and then concentrated to remove MeOH. The aqueous solution was acidified with 2 M HC1 to bring the pH to 6, which resulted in formation of a precipitate. The precipitated solid was collected and dried to give (lS,4S)-4-hydroxy-4-(4-methyl-6-(5-methyl-lH-pyrazol-3- ylamino)pyridin-2-yl)cyclohexanecarboxylic acid (60 mg, 81%) as a yellow solid. MS (ES+) Ci7H22N403 requires: 330, found: 331 [M+H]+. Step 4: Synthesis of (ls,4R )-N-( (S)-l-( 6-(4-fluoro-lH-pyrazol-l -yl)pyridin-3-yl)ethyl)-4-hydroxy- 4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
(Compound 120).
Figure imgf000049_0001
A mixture of (lS,4S)-4-hydroxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyridin-2-yl)cyclohexanecarboxylic acid (60 mg, 0.18 mmol), (S)-l-(6-(4-fluoro-lH- pyrazol-l-yl)pyridin-3-yl)ethanamine hydrochloride (44.0 mg, 0.1816 mmol), HATU (69.0 mg, 0.1816 mmol) and DIEA (70.4 mg, 0.545 mmol) in DMA (2 mL) was stirred at 25 °C for 2 h. The solution was concentrated and purified by preparative HPLC to give the title product (40 mg, 43%) as a white solid. MS (ES+) C27H31FN8O2 requires: 518, found: 519 [M + H]+. 1H- NMR (400 MHz, DMSO-i¾) δ ppm 11.71 (br. s., 1H), 8.92 (br. s., 1H), 8.69 (d, 1H, 7 = 4.4 Hz), 8.39 (d, 1H, 7 = 2.0 Hz), 8.31 (d, 1H, 7 = 7.6 Hz), 7.95-7.87 (m, 3H), 6.83 (br. s., 1H), 6.79 (s, 1H), 6.09 (br. s., 1H), 5.01-4.98 (m, 1H), 4.89 (s, 1H), 2.50-2.48 (m, 1H), 2.21 (s, 3H), 2.20 (s, 3H), 2.00-1.75(m, 4H), 1.65-1.50 (m, 4H), 1.41 (d, 3H, 7 = 7.2 Hz).
Example 4. Synthesis of Compounds 121 and 122.
Step 1 : Synthesis of (ls,4R )-4-fluoro-N-( (S)-l-(6-( 4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl )ethyl)- 4-(4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
(Compound 121), (lR,4S)-4-fluoro-N-((S)-l-(6-(4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl)ethyl)-4- (4-methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 122), and N-((S)-1 -(6-(4-fluoro-l H-pyrazol-1 -yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-lH- pyrazol-3-ylamino)pyridin-2-yl)cyclohex-3-enecarboxamide.
Figure imgf000050_0001
A mixture of (lR,4S)-N-((S)- l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4- hydroxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyridin-2- yl)cyclohexanecarboxamide (120 mg, 0.23 mmol) in DCM (6 mL) was cooled to 0 °C. DAST (111 mg, 0.69 mmol) was added to the mixture at 0 °C, and the resultant mixture was stirred at 25 °C for 2 h. The mixture was concentrated and purified by preparative HPLC to give the title compounds ( 1 S ,4R)-4-fluoro-N-((S)- 1 -(6-(4-fluoro- lH-pyrazol- 1 -yl)pyridin-3-yl)ethyl)-4-(4- methyl-6-(5-methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 121 ; 6.1 mg, 5.08%) and (lR,4S)-4-fluoro-N-((S)- l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)-4-(4-methyl-6-(5-methyl- lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 122; 13.2mg, 11.0%) as white solids. MS (ES+) C27H30F2N8O requires: 520, found: 521 [M+H]+. Also gave N-((S)-l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-4-(4-methyl- 6-(5-methyl- lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohex-3-enecarboxamide (50 mg, 43.4%) as a white solid. MS (ES+) C27H29FN8O requires: 500, found: 501 [M+H]+.
(lSAR)-4-fluoro-N-((S)-l-(6-(4-fluoro-lH^yrazol-l-yl)pyridin-3-yl)ethyl)-4-(^
methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 121): 1H-NMR (400 MHz, DMSO-ίΜ) δ ppm 11.73 (s, 1H), 9.01 (d, 1H, = 2.8 Hz), 8.69 (d, 1H, = 4.4 Hz), 8.41-8.38 (m, 2H), 7.95-7.87 (m, 3H), 6.92 (s, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 5.00 (q, 1H, = 7.2 Hz), 2.50-2.31 (m, 1H), 2.21-2.21 (m, 6H), 2.21-1.74 (m, 8H), 1.41 (d, 3H, / = 7.2 Hz). (lR S)A-fluoro-N-((S)-l-(6-(4-fluoro-lH^yrazol-l-yl)pyridin-3-yl)ethyl)-4-(4^
methyl-lH-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide (Compound 122): 1H-NMR (400 MHz, DMSO-ίΜ) ppm 11.65 (s, 1H), 9.01 (s, 1H), 8.65 (d, 1Η, = 4.4 Hz), 8.38-8.33 (m, 2H), 7.92-7.84 (m, 3H), 6.83 (s, 1H), 6.67 (s, 1H), 6.30 (s, 1H), 5.04 (q, 1H, J = 7.2 Hz), 2.70- 2.50 (m, 3H), 2.20 (s, 3H), 2.15 (s, 3H), 2.21-1.70 (m, 6H), 1.40 (d, 3H, = 7.2 Hz).
Example 5: Synthesis of Compounds 129 and 130.
Step 1: Synthesis of2-chloro-4-methyl-6-(methylthio)pyrimidine.
Figure imgf000051_0001
2,4-Dichloro-6-methylpyrimidine (20.0 g, 0.123 mol) was dissolved in THF (200 niL). MeSNa (20% aq, 43g, 0.129 mol) was added dropwise at -5 °C, and the resulting mixture was stirred overnight at room temperature. H20 (lOOmL) and EtOAc (lOOmL) were added, and the layers were separated. The organic layer was washed with brine (2x), dried over sodium sulfate, and concentrated to afford a yellow solid. The solid was washed by PE (lOOmL) to afford target compound (9.1g). MS (ES+) C6H7C1N2S requires: 174, found: 175 [M+H]+.
Step 2: Synthesis of Methyl l-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl)cyclohexane-l- carboxylate.
Figure imgf000051_0002
PdCI2dppf
Methyl 4-iodo-l-methoxycyclohexanecarboxylate (1.35 g, 4.53 mmol) was dissolved in dimethylacetamide (10 mL) in a pressure vessel under a stream of N2. Rieke Zinc (5.7 mL of a 50mg/mL suspension in THF, 4.34 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of N2 and 2-chloro-4-methyl-6-(methylthio)pyrimidine (659 mg, 3.8 mmol) was added followed by PdCl2dppf (138 mg, 0.19 mmol). The vessel was capped and heated to 80 °C for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H20 (3x), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% EtOAc-hexanes) to give methyl l-methoxy-4-(4-methyl-6- (methylthio)pyrimidin-2-yl)cyclohexanecarboxylate (828 mg, 70%) as a colorless oil. The product was determined to be -3:2 mixture of isomers by integration of the UV peaks in the LC/MS and integration of NMR. MS (ES+) C15H22N2O3S requires: 310, found: 311 [M+H]+. Step 3: Synthesis of Methyl l-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2- yl)cyclohexane-l -carboxylate.
Figure imgf000052_0001
Methyl l-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl)cyclohexanecarboxylate (825 mg, 2.66 mmol) was dissolved in DCM (12 mL) followed by the addition of mCPBA (1.10 g, 6.38 mmol) at ambient temperature. The reaction mixture was stirred for 16 h, then an additional portion of mCPBA was added (200 mg). After stirring for an additional 4 h, the reaction mixture was diluted with DCM and then washed with saturated sodium bicarbonate solution. The washed solution was dried over sodium sulfate, filtered, concentrated, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 60% ethyl acetate-hexane) to afford methyl l-methoxy-4-(4-methyl-6- (methylsulfonyl)pyrimidin-2-yl)cyclohexanecarboxylate (808 mg, 89%) as a colorless oil. MS (ES+) C15H22N2O5S requires: 342, found: 343 [M+H]+.
Step 4: Synthesis of Methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)-l -methoxycyclohexane-1 - carboxylate.
Figure imgf000052_0002
Methyl l-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2-yl)cyclohexane- carboxylate (600 mg, 1.75 mmol) was dissolved in acetic acid (5 mL) and heated to 80 °C for 1 h. The reaction mixture was then cooled to ambient temperature, concentrated under reduced pressure, triturated with H20, and filtered. The solids were washed with additional H20 and then dried under reduced pressure to afford the title compound, methyl 4-(4-hydroxy-6- methylpyrimidin-2-yl)-l-methoxycyclohexanecarboxylate (390 mg, 79%), as a pale yellow solid. MS (ES+) Ci4H20N2O4 requires: 280, found: 281 [M+H]+.
Step 5: Synthesis of Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-l -methoxycyclohexane-1 - carboxylate.
Figure imgf000053_0001
Methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)- 1-methoxycyclohexanecarboxylate (380 mg, 1.36 mmol) was suspended in POCl3 (3.2 mL, 33.9 mmol) and heated to 100 °C for 2 h. The reaction mixture was then cooled to ambient temperature, concentrated, and the residue was treated with crushed ice. The resulting suspension was partitioned with DCM, and the organic layer was extracted with saturated sodium bicarbonate solution and dried over sodium sulfate. The dried solution was filtered, concentrated, and the resulting residue was purified by flash- column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate -hexanes) to give methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-l-methoxycyclohexanecarboxylate (344 mg, 85%) as a pale orange oil that solidified on standing. MS (ES+) CMH19CIN2O3 requires: 298, found: 299 [M+H]+.
Step 6: Synthesis of Methyl 1 -methoxy-4-(4-methyl-6-((5-methyl-l H-pyrazol-3- yl)amino )pyrimidin-2-yl)cyclohexane-l -carboxylate.
Figure imgf000053_0002
Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)- 1-methoxycyclohexanecarboxylate (300 mg, 1.00 mmol), 3-methyl-l-pyrazol-5-amine (146 mg, 1.51 mmol), di-tert-butyl(2',4',6'- triisopropyl-[l,l'-biphenyl]-2-yl)phosphine (85 mg, 0.2 equiv.), Pd2(dba)3 (92 mg, 0.1 equiv.), and potassium acetate (394 mg, 4.02 mmol) were combined in a vial under nitrogen and 4 mL dioxane was added. The reaction mixture was heated to 100 °C for 1 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 10% methanol-dichloromethane) to give methyl l-methoxy-4-(4-methyl-6-((5- methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 53%) as a tan- colored foam. MS (ES+) Ci8H25N503 requires: 359, found: 360 [M+H]+.
Step 7: Synthesis of (lR,4S)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane- carboxamide (Compound 129) and (lS,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethyl)-l-methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2- yl)cyclohexanecarboxamide (Compound 130).
Figure imgf000054_0001
The title compounds were prepared from methyl l-methoxy-4-(4-methyl-6-((5-methyl- lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21 x 250 mm, 40% MeOH containing 0.25% DEA in C02, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (lR,4S)-N-((S)-l-(6-(4-fluoro- lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l-methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3- yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-(4-methyl-6-((5-methyl-lH-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane- carboxamide (130 mg, 46%) as a white solid.
Example 6. Synthesis of Compound 149
Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-l -methoxycyclohexane-1 - carboxylate.
Figure imgf000055_0001
PdCI2dppf
Methyl 4-iodo-l-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of N2 and 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80 °C for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H20 (3x), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4- yl)-l -methoxycyclohexane-1 -carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+)
Ci4Hi9ClN203 requires: 298, found: 299 [M+H]+.
Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6- methylpyrimidin-2-yl)amino)-5-methyl-lH-pyrazole-l -carboxylate.
Figure imgf000056_0001
Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)- 1-methoxycyclohexane- 1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-lH-pyrazole-l-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2',4',6'-triisopropyl-[l, -biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)3 (21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115 °C for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2- yl)amino)-5-methyl-lH-pyrazole-l-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N505 requires: 459, found: 460 [M+H]+.
Step 3: Synthesis of l-Methoxy-4-( 6-methyl-2-( ( 5 -methyl- lH-pyrazol-3-yl)amino )pyrimidin-4- yl)cyclohexane-l -carboxylic acid.
Figure imgf000056_0002
Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert- butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5- methyl-lH-pyrazole- 1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H20 (17: 1: 1, 1.8 mL) The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude l-methoxy-4-(6-methyl-2-((5- methyl-lH-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-l-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) Ci7H23N503 requires: 345, found: 346 [M+H]+. Step 4: Synthesis of (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l- methoxy-4-( 6-methyl-2-( ( 5 -methyl- lH-pyrazol-3-yl)amino )pyrimidin-4-yl)cyclohexane-l - carboxamide ( mpound 149).
Figure imgf000057_0001
The title compound was prepared from l-methoxy-4-(6-methyl-2-((5-methyl-lH-pyrazol- 3-yl)amino)pyrimidin-4-yl)cyclohexane-l-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1: 1) and purified by SFC (ChiralPak IC-H 21 x 250 mm, 40% MeOH containing 0.25% DEA in C02, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (ls,4R)-N-((S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethyl)-l-methoxy-4-(6-methyl-2-((5- methyl-lH-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-l-carboxamide (13.4 mg, 24%) as a white solid.
Synthesis of Intermediates
Example 7. Synthesis of Ketone and Boronate Intermediates.
A. Meth l l-methoxy-4-oxocyclohexane-l-carboxylate.
Figure imgf000057_0002
The title compound was prepared as described in WO 2014/130810 Al
Ethyl l-ethoxy-4-oxocyclohexane-l-carboxylate.
Figure imgf000058_0001
Step 1: Synthesis of ethyl 8-ethoxy-l ,4-dioxaspiro[4.5] decane-8-carboxylate.
A solution of l,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr3 (3234 g, 1280 mmol) was cooled to 0 °C and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE : EA =15 : 1 to 10 : 1) to obtain the title compound (18.0 g).
Step 2: Synthesis of ethyl 1 -ethoxy-4-oxocyclohexane-l -carboxylate.
To a solution of ethyl 8-ethoxy-l, 4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H20 and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE : EA =15 : 1 ) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20 - 4.13 (m, 2H), 3.43 (q, 7 = 6.9 Hz, 1H), 2.48 - 2.39 (m, 1H), 2.24 - 2.12 (m, 2H), 2.10 - 2.01 (m, 1H), 1.22 (t, 7 = 7.1 Hz, 2H), 1.17 (t, 7 = 7.0 Hz, 2H).
C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate.
Figure imgf000058_0002
Step 1: Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-l-carboxylate.
A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C and then cooled to -78 °C. The solution of ethyl 2-methyl- 4-oxocyclohex-2-ene-l-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between -40 °C to -20 °C for 2h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10: 1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-l-carboxylate (1.16 g). Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-l- carboxylate.
Ethyl 2,2-dimethyl-4-oxocyclohexane-l-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45 °C for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45 °C for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2 x 40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate- petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trif uoromethyl)sulfonyl)oxy)cyclohex-3-ene- 1-carboxylate (1 g).
Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex- 3-ene-l-carboxylate.
Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate (1 g, 3.03 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl2 (73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100 °C for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate (618 mg).
D. Ethyl 6-methyl-4-( 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l- carboxylate.
Figure imgf000060_0001
Ethyl 6-methyl-4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 - carboxylate was prepared using the same synthetic protocol as described above using ethyl 2- methyl-4-oxocyclohexane-l-carboxylate as the starting material.
E. Methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate
Figure imgf000060_0002
Figure imgf000060_0003
Step 1: Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate
A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180 °C for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ethenethyl acetate = 100: 1 to
80: 1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDC13): δ 6.38 (d, J = 6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s,
3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).
Step 2: Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in
tetrahydrofuran) dropwise at -5 °C. The reaction mixture was stirred at 0 °C for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0 °C and stirred at 30 °C for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2X). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether: ethyl acetate =10: 1 to 1: 1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.
Step 3: Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate
To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDC13): δ 4.25 (d, = 17.6 Hz, 1H), 4.07 (d, = 17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).
Example 8. Synthesis of Iodide Intermediates
A. Methyl l-m thoxy-4-iodocyclohexane-l-carboxylate.
Figure imgf000061_0001
Step 1: Synthesis of methyl 1 -methoxy-4-hydroxycyclohexane-l -carboxylate.
Methyl l-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved methanol (100 mL) and the solution was cooled to 0 °C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4C1 solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3 x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl l-methoxy-4-hydroxycyclohexane-l-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9Hi604 requires: 188, found: 211 [M+Na]+.
Step 2: Synthesis of methyl 1 -methoxy-4-iodocyclohexane-l -carboxylate.
Methyl l-methoxy-4-hydroxycyclohexane-l -carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0 °C, and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IO3 requires: 298, found: 299 [M+H]+.
B. Ethyl l-ethox -4-iodocyclohexane-l-carboxylate.
Figure imgf000062_0001
The title compound was prepared as described above using ethyl l-ethoxy-4- oxocyclohexane- 1 -carboxylate as a starting material. C11H19IO3 requires: 326, found: 327
[M+H]+.
Example 9. Synthesis of Amine Intermediates.
A. (S)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l-amine.
Figure imgf000063_0001
Step 1: Synthesis of 1 -(6-(4-fluoro-l H-pyrazol-1 -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 for 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, after which 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.
Step 2: Synthesis of (R)-N-((S)-1 -(6-(4-fluoro-l H-pyrazol-1 -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.
Step 3: Synthesis of (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 for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and 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). LC-MS confirmed desired product in high purity. MS: M+l = 207.1.
B. (S)-l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethan-l-amine.
Figure imgf000064_0001
Step 1: Synthesis of 1 -(5-(4-fluoro-l H-pyrazol-1 -yl)pyrazin-2-yl)ethan-l -one.
Sodium hydride (60 wt%, 276 mg, 6.90 mmol) was added to a mixture of l-(5- chloropyrazin-2-yl)ethanone (800 mg, 5.11 mmol) and 4-fluoro-lH-pyrazole (484 mg, 5.62 mmol) in N,N-dimethylformamide (6.0 mL) at ambient temperature for 10 minutes. The reaction mixture was then poured into water (70 mL) and sonicated and stirred for 20 minutes. A dark red solid was isolated by filtration, washed with small amounts of water, and dried to l-(5-(4-fluoro- lH-pyrazol-l-yl)pyrazin-2-yl)ethan-l-one (919 mg, 95% yield). MS: M+l = 207.
Step 2: Synthesis of (R)-N-((S)-1 -(5-(4-fluoro-l H-pyrazol-1 -yl)pyrazin-2-yl)ethyl)-2- methylpropane-2-sulfinamide. To a stirred room temperature solution of l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2- yl)ethan-l-one (4.67 g, 22.7 mmol) in THF (45 mL) was added (R)-(+)-t-butylsulfinamide (2.75 g, 22.7 mmol) followed by titanium (IV) ethoxide (10.3 g, 45.3 mmol). The solution was stirred at 75°C on an oil bath for 20 hours. The reaction solution was cooled to room temperature and then to -78°C before the next step. To the -78°C solution was added dropwise over 50 minutes L- Selectride (50.1 mL of 1 N in THF, 50.1 mmol). During addition, some bubbling was observed. After the addition was completed, the reaction was then stirred for 15 minutes before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to -60 °C and quenched slowly with methanol (1 mL), then poured into water (100 mL) and stirred. The mixture was filtered and the solids were washed further with ethyl acetate. The filtrate was diluted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, concentrated, and the resulting residue was purified by flash- column chromatography (gradient elution, 0 to 100% ethyl acetate-dichloromethane) to give (R)- N-((S)-l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.04 g, 14% ) as a brown solid. MS: M+l = 312. 1H NMR (400 MHz, DMSO-i¾) δ 9.12 (d, 7 = 1.4 Hz, 1H), 8.73 (d, 7 = 4.5 Hz, 1H), 8.59 (d, 7 = 1.4 Hz, 1H), 8.03 (d, 7 = 4.1 Hz, 1H),
5.69 (d, 7 = 5.7 Hz, 1H), 4.62 (p, 7 = 6.8 Hz, 3H), 1.57 (d, 7 = 6.9 Hz, 3H), 1.12 (s, 9H).
Step 3: Synthesis of (S)-l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethan-l -amine.
A solution of (R)-N-((S)-l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethyl)-2- methylpropane-2-sulfinamide (1.04 g, 3.34 mmol) in methanol (7.8 mL) and 4N HCl/dioxane (8.34 mL, 33.4 mmol) was stirred for 1.5 h at ambient temperature. The reaction mixture was poured into diethyl ether (100 mL), and a light beige solid was isolated by filtration to afford (S)- l-(5-(4-fluoro-lH-pyrazol-l-yl)pyrazin-2-yl)ethan-l-amine (689 mg, 85% yield). MS: M+l = 208.
C. (5-(4-fluoro-lH- razol-l-yl)pyrazin-2-yl)methanamine.
Figure imgf000065_0001
Step 1: Synthesis of 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 100 °C for 4 hours, then 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, 82%). The structure was confirmed by LC-MS. Step 2: Synthesis of (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.
D. (6-(3,5- imethyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine.
Figure imgf000066_0001
Step 1: Synthesis of '6-( 3, 5 -dimethyl- IH-pyrazol-l -yl)nicotinonitrile.
To a solution of 6-chloronicotinonitrile (300 mg, 2.2 mmol) in DMF (10 mL) was added 3,5-dimethyl-lH-pyrazole (210 mg, 2.2 mmol ) and Cs2C03 (1.4 g, 4.4 mmol), and the mixture was stirred at 90 °C for 16 h. The mixture was then diluted with H20 (25 mL) and filtered. The solids were washed with water and dried under vacuum to give 6-(3,5-Dimethyl-lH-pyrazol-l- yl)nicotinonitrile (320 mg, 74.6%).
Step 2: Synthesis of tert-Butyl ((6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate. To 6-(3,5-dimethyl-lH-pyrazol-l-yl)nicotinonitrile (300 mg, 1.5 mmol) in MeOH (10 mL) was added NiCl2 (19 mg, 0.15 mmol), (Boc)20 (654 mg, 3.0 mmol), and NaBH4 (142 mg, 3.8 mmol), and the mixture was stirred at ambient temperature for 3 h. Saturated aqueous ammonium chloride solution was added, and MeOH was removed under vacuum. The aqueous suspension was partitioned with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution (2 x 50mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 450 mg target compound which was used in the next step without further purification.
Step 3: Synthesis of ' (6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-3-yl)methanamine.
A solution of HC1 in dioxane (4.0 M, 10 mL) was added to compound tert-buty\ ((6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (450 mg), and the mixture was stirred for 2h. The mixture was then concentrated under reduced pressure to give the title compound (350 mg) as a light brown solid that was carried forward without further purification. 1H NMR (400 MHz, DMSO-iM) δ 8.51 (d, 7 =2.1 Hz, 1H), 8.34 (s, 3H), 8.03 (dd, 7 = 8.5, 2.4 Hz, 1H), 7.87 (d, 7 = 8.5 Hz, 1H), 6.14 (s, 1H), 4.12 (q, 7 = 5.7 Hz, 2H), 2.59 (s, 3H), 2.21 (s, 3H).
E. ( 6-(4-chlor -lH-pyrazol-l-yl)pyridin-3-yl)methanamine.
Figure imgf000067_0001
Step 1: Synthesis of 6-(4-Chloro-l H-pyrazol-1 -yl)nicotinonitrile
To a solution of 6-chloronicotinonitrile (300 mg, 2.2 mmol) in DMF (10 mL) was added 4-chloro-lH-pyrazole (227 mg, 2.2 mmol) and Cs2C03 (1.4 g, 4.4 mmol) and the mixture was stirred at 90 °C for 16 h. The mixture was then diluted with H20 (25 mL) and filtered. The solids were washed with H20 and dried under vacuum to give 6-(4-chloro-lH-pyrazol-l- yl)nicotinonitrile (380 mg, 84%), which was used in the next step without further purification. Step 2: Synthesis of tert-Butyl ((6-(4-chloro-lH-pyrazol-l-yl)pyridin-3-yl)methyl)carbamate
To 6-(4-chloro-lH-pyrazol-l-yl)nicotinonitrile (350 mg, 1.7 mmol) in MeOH (10 niL), was added NiCl2 (19 mg, 0.17 mmol), (Boc)20 (741 mg, 3.4 mmol) and NaBH4 (163 mg, 4.3 mmol), and the mixture was stirred at ambient temperature for 3h. Saturated aqueous NH4C1 solution was added, and the MeOH was removed under vacuum. The aqueous suspension was then partitioned with EtOAc, and the organic layer was washed with saturated sodium
bicarbonate solution (2 x 50mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 480 mg of the title compound, which was used in the next step without further purification.
Step 3: Synthesis of (6-(4-chloro-lH-pyrazol-l -yl)pyridin-3-yl)methanamine
A solution of HCI in dioxane (4.0 M, 10 mL) was added to tert-b tyl ((6-(4-chloro-lH- pyrazol-l-yl)pyridin-3-yl)methyl)carbamate (450 mg, 1.5 mmol) at ambient temperature. The mixture was stirred for 2 h, then concentrated under reduced pressure to give the title compound (290 mg) as a light brown solid that was used without further purification. MS: M+l = 209. F. R)-l-( 6-(4-fluoro-lH-pyrazol-l -yl )pyridin-3-yl)ethan-l -amine
Figure imgf000068_0001
Steps 1-3: (R)-l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3-yl)ethan-l -amine
The title compound was prepared from l-(6-(4-fluoro-lH-pyrazol-l-yl)pyridin-3- yl)ethan-l-one using the same sequence that was described to prepare the S enantiomer of this compound, except that (R)-(-)-t-Butylsulfinamide was replaced with (S)-(-)-t-Butylsulfinamide as the chiral auxiliary. MS (ES+) Ci0HnFN4 requires: 206, found: 207 [M+H]+.
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. Compound Synthetic MS
IH NMR
Number Protocol (M+l)
1H NMR (400 MHz, DMSO-c/6) δ 8.56 (s, IH), 8.44 (s,
IH), 8.35 (s, IH), 7.85 (s, 2H), 7.81 (s, IH), 6.66 (d, 7 =
100 2 15.8 Hz, IH), 6.57 (s, IH), 4.36 (s, 2H), 3.17 (s, 3H), 472
2.21 (d, 7 = 29.3 Hz, 3H), 2.06 (d, 7 = 13.0 Hz, 4H),
1.80 (s, 2H), 1.63 (s, 2H).
1H NMR (400 MHz, DMSO) δ 8.61 (d, 7 = 2.5 Hz, IH),
8.46 (d, 7 = 6.0 Hz, IH), 8.36 (s, IH), 7.91 (d, 7 = 8.4
Hz, IH), 7.87 - 7.84 (m, IH), 7.82 (s, IH), 6.72 - 6.66
101 2 472
(m, IH), 6.59 - 6.57 (m, IH), 4.34 (d, 7 = 5.8 Hz, 2H),
3.17 (s, 3H), 2.27 (s, 3H), 2.04 (s, 2H), 1.96 (d, 7 = 11.6
Hz, 2H), 1.59 (dd, 7 = 27.2, 14.4 Hz, 4H).
IH NMR (400 MHz, DMSO) δ 8.56 (s, IH), 8.44 (s,
IH), 8.35 (s, IH), 7.83 (d, 7 = 15.0 Hz, 3H), 6.66 (d, 7 =
102 2 15.8 Hz, IH), 6.57 (s, IH), 4.36 (s, IH), 3.17 (s, 3H), 486
2.42 (s, 2H), 2.21 (d, 7 = 29.3 Hz, 3H), 2.06 (d, 7 = 13.0
Hz, 4H), 1.78 (d, 7 = 16.2 Hz, 2H), 1.63 (s, 2H).
1H NMR (400 MHz, DMSO-c/6) δ 8.61 (d, 7 = 2.5 Hz,
IH), 8.46 (d, 7 = 6.0 Hz, IH), 8.36 (s, IH), 7.92 - 7.82
103 2 (m, 3H), 6.72 - 6.66 (m, IH), 6.58 - 6.57 (m, IH), 4.33 486
(s, IH), 3.17 (s, 3H), 2.42 (s, 2H), 2.27 (s, 3H), 2.06 - 1.94 (m, 4H), 1.56 (dd, 7 = 28.0, 12.9 Hz, 4H).
1H NMR (400 MHz, DMSO-c/6) δ 14.03 (s, IH), 12.33
(s, IH), 8.70 - 8.31 (m, 4H), 7.86 (d, 7 = 30.5 Hz, 3H),
104 6.57 (s, IH), 4.34 (s, 2H), 2.82 (s, IH), 2.41 (s, 3H),
2 486
2.21 (s,5H), 1.94 (d, 7 = 12.4 Hz, IH), 1.67 (dd, 7 =
45.4, 19.9 Hz, 5H), 1.24 (s, IH), 0.94 (d, 7 = 6.4 Hz,
3H).
1H NMR (400 MHz, DMSO-c/6) δ 8.64 (s, IH), 8.46 (s,
IH), 8.35 (s, IH), 7.92 (d, 7 = 4.2 Hz, IH), 7.86 (d, 7 =
6.5 Hz, 2H), 6.66 (d, 7 = 21.2 Hz, IH), 4.36 (s, 2H),
105 2 490
2.91 (s, IH), 2.42 (s, 2H), 2.21 (d, 7 = 33.5 Hz, 3H),
2.07 (dd, 7 = 14.5, 7.1 Hz, 4H), 1.80 (s, 2H), 1.64 (d, 7 =
11.5 Hz, 2H).
1H NMR (400 MHz, DMSO-c/6) δ 11.55 (s, IH), 11.24
(s, IH), 8.90 (d, 7 = 5.0 Hz, IH), 8.44 (s, IH), 8.33 (s,
IH), 8.01 - 7.95 (m, OH), 7.81 - 7.78 (m, IH), 6.68 (s,
106 2 IH), 6.10 (s, IH), 5.93 (s, IH), 4.35 (s, 2H), 2.91 (s, 500
OH), 2.54 (s, IH), 2.44 (d, 7 = 20.0 Hz, 2H), 2.22 (d, 7 =
22.8 Hz, 5H), 2.13 - 1.96 (m, 4H), 1.79 (d, 7 = 8.4 Hz,
2H), 1.62 (s, 2H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
*H NMR (400 MHz, DMSO-J6) δ 14.57 (s, IH), 12.87
(s, IH), 11.57 (s, IH), 8.61 (d, J = 2.5 Hz, IH), 8.47 - 8.35 (m, 2H), 7.94 - 7.85 (m, 2H), 7.82 (d, J = 1.0 Hz,
IH), 7.11 (s, IH), 6.95 (s, IH), 6.58 (dd, J = 2.5, 1.7 Hz,
107 1 501
IH), 6.02 (s, IH), 5.92 (s, IH), 4.40 - 4.29 (m, 2H),
2.45 (s, 3H), 2.31 (s, IH), 2.27 (s, 3H), 2.05 - 1.96 (m,
2H), 1.93 - 1.81 (m, 3H), 1.54 (d, J = 9.9 Hz, IH), 0.98
(d, J = 7.2 Hz, 3H).
*H NMR (500 MHz, DMSO-J6) δ 11.85 (s, IH), 9.43
(s, IH), 8.64 (d, 7 = 4.5 Hz, IH), 8.35 (d, 7 = 2.2 Hz,
IH), 8.20 (d, 7 = 7.7 Hz, IH), 7.92 - 7.81 (m, 3H), 6.79
111 2 (s, IH), 6.17 (s, IH), 5.02 - 4.92 (m, IH), 2.72 (s, IH), 504
2.41-2.31 (m, IH), 2.27-2.12 (m, 8H), 1.83-1.48 (m,
6H), 1.38 (d, 7 = 7.1 Hz, 3H).
1H NMR (400 MHz, DMSO-c/6) δ 11.55 (s, OH), 11.23
(s, OH), 8.83 (d, 7 = 4.8 Hz, OH), 8.74 (s, OH), 8.46 (s,
OH), 8.36 (s, OH), 7.95 (s, OH), 7.90 - 7.81 (m, IH),
113 2 506
4.63 - 4.48 (m, OH), 4.36 (s, IH), 2.91 (s, OH), 2.55 (s,
OH), 2.44 (d, 7 = 17.9 Hz, IH), 2.20 (d, 7 = 32.7 Hz,
IH), 2.12 - 1.85 (m, IH), 1.62 (s, IH).
1H NMR (400 MHz, DMSO-c/6) δ 14.60 (s, IH), 12.88
(s, IH), 11.53 (s, IH), 8.61 (m, IH), 8.36 (dd, 7 = 12.9,
7.1 Hz, 2H), 7.90 (m, 2H), 7.82 (d, 7 = 1.0 Hz, IH), 7.12
114 (s, IH), 6.94 (s, IH), 6.58 (dd, 7 = 2.5, 1.7 Hz, IH), 6.02
1 515 (s, IH), 5.91 (s, IH), 4.40 (dd, 7 = 15.2, 5.9 Hz, 2H),
4.30 (m, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.17 (d, 7 = 9.7
Hz, 3H), 1.83 (d, 7 = 21.1 Hz, 2H), 1.66 (t, 7 = 16.3 Hz,
2H), 1.13 (s, 3H), 0.94 (s, 3H).
1H NMR (400 MHz, DMSO-c/6) δ 13.88 (s, IH), 12.46
(s, IH), 11.37 (d, 7 = 120.9 Hz, IH), 8.69 (d, 7 = 4.4 Hz,
IH), 8.50 - 8.36 (m, 2H), 7.98 - 7.86 (m, 2H), 7.59 (s,
0.5H), 6.86 (d, 7 = 27.8 Hz, IH), 6.66 (s, 0.5H), 5.91 (s,
116 2 0.5H), 5.00 (s, IH), 2.82 (s, IH), 2.43 (d, 7 = 20.6 Hz, 518
3H), 2.22 (s, 3H), 2.11 (s, IH), 2.04 - 1.84 (m, 2H),
1.82 - 1.57 (m, 3H), 1.54 (d, 7 = 12.6 Hz, IH), 1.42 (d,
7 = 5.1 Hz, 3H), 1.24 (s, IH), 1.01 (d, 7 = 6.8 Hz, IH),
0.80 (s, IH) Compound Synthetic MS
IH NMR
Number Protocol (M+l)
'H-NMR (400 MHz, DMSO-i¾) δ ppm 11.63 (s, IH),
8.85 (s, IH), 8.65 (d, IH, 7 = 4.4 Hz), 8.36 (d, IH, 7 =
2.0 Hz), 8.25 (d, IH, 7 = 7.2 Hz), 7.92-7.83 (m, 3H),
119 1 519
6.79 (s, IH), 6.66 (s, IH), 6.24 (s, IH), 5.00 (q, IH, 7 =
7.2 Hz), 4.81 (s, IH), 2.49-2.30 (m, 3H), 2.18 (s, 3H),
2.16 (s, 3H), 1.85-1.53 (m, 4H), 1.50-1.34 (m, 5H).
*H NMR (400 MHz, DMSO-J6) δ 13.84 (s, IH), 12.40
(d, 7 = 48.8 Hz, IH), 11.52 (s, IH), 8.68 (d, 7 = 3.2 Hz,
IH), 8.41 (t, 7 = 11.2 Hz, 2H), 7.93 (dd, 7 = 8.4, 2.1 Hz,
2H), 7.89 (dd, 7 = 8.3, 5.2 Hz, IH), 6.92 (d, 7 = 24.0 Hz,
124 2 532
IH), 6.65 (s, IH), 4.98 (s, IH), 3.00 (s, IH), 2.40 (s,
6H), 2.22 (s, IH), 2.12 (s, 2H), 1.85 (s, 2H), 1.67 (d, 7 =
15.1 Hz, 2H), 1.42 (d, 7 = 5.7 Hz, 3H), 1.31 (m, 2H),
1.04 (m, 6H).
1H NMR (400 MHz, DMSO-J6) δ 14.54 (s, IH), 12.87
(s, IH), 11.61 (s, IH), 8.68 (d, J = 4.5 Hz, IH), 8.41 (dd,
J = 6.4, 2.0 Hz, IH), 8.31 (dd, J = 28.8, 7.8 Hz, IH),
7.97 - 7.86 (m, 3H), 7.09 (s, IH), 6.96 (s, IH), 5.92 (d, J
128 1 534
= 3.7 Hz, IH), 5.04 (d, J = 7.3 Hz, IH), 2.46 (s, 3H),
2.32 (s, IH), 2.27 (d, J = 5.1 Hz, 3H), 2.12 - 1.77 (m,
6H), 1.49 (d, J = 10.0 Hz, IH), 1.42 (d, J = 7.0 Hz, 3H),
1.03 (s, IH), 0.84 (d, J = 7.2 Hz, 2H).
1H NMR (400 MHz, DMSO-J6) δ 11.85 (s, IH), 9.46
(s, IH), 8.65 (d, 7 = 4.5 Hz, IH), 8.48 - 8.35 (m, 2H),
7.96 (dd, 7 = 8.5, 2.3 Hz, IH), 7.89 (d, 7 = 4.2 Hz, IH),
129 3 7.84 (d, 7 = 8.5 Hz, IH), 6.77 (s, IH), 6.15 (s, IH), 5.12 534
- 5.02 (m, IH), 3.06 (s, 3H), 2.67 (t, 7 = 6.4 Hz, IH),
2.20 (s, 3H), 2.16 (s, 5H), 1.95 (dd, 7 = 28.8, 9.8 Hz,
2H), 1.87 - 1.76 (m, 2H), 1.58 - 1.38 (m, 5H).
*H NMR (500 MHz, DMSO-J6) δ 11.89 (s, IH), 9.51
(bs, IH), 8.68 (dd, 7 = 4.5, 0.7 Hz, IH), 8.46 (d, 7 = 8.5
Hz, IH), 8.44 (d, 7 = 2.3 Hz, IH), 7.99 (dd, 7 = 8.5, 2.3
Hz, IH), 7.91 (dd, 7 = 4.4, 0.8 Hz, IH), 7.88 (d, 7 = 8.6
130 3 Hz, IH), 6.86 (bs, IH), 6.20 (bs, IH), 5.06 (dq, 7 = 7.8, 534
7.6 Hz IH), 3.14 (s, 3H), 2.58 (bt, 7 = 12 Hz, IH), 2.24
(s, 3H), 2.21 (s, 3H), 1.99 (bd, 7 = 12.1 Hz, IH), 1.93
(dd, 7 = 13.8, 2.4 Hz, IH), 1.88-1.69 (m, 5H), 1.63 (td, 7
= 14, 4 Hz, IH), 1.47 (d, 7 = 7.1 Hz, 3H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
*H NMR (400 MHz, DMSO-J6) δ 11.88 (s, IH), 9.51
(s, IH), 9.12 (d, 7 = 1.4 Hz, IH), 8.73 (d, 7 = 4.4 Hz,
IH), 8.51 (d, 7 = 1.4 Hz, IH), 8.41 (d, 7 = 8.0 Hz, IH),
131 3 8.02 (d, 7 = 4.1 Hz, IH), 6.85 (s, IH), 6.18 (s, IH), 5.18 535
- 5.07(m, IH), 3.17 (s, 3H), 2.64 - 2.52 (m, IH), 2.23 (s,
3H), 2.19 (s, 3H), 2.02 - 1.91 (m, 2H), 1.89 - 1.61 (m,
6H), 1.49 (d, 7 = 7.1 Hz, 3H).
1H NMR (400 MHz, DMSO-c/6) δ 14.58 (m, IH), 12.89
(m, 2H), 11.52 (s, IH), 8.69 (t, 7 = 4.3 Hz, IH), 8.43 (d,
7 = 2.0 Hz, IH), 8.27 (m, IH), 7.97 (m, 4H), 7.59 (m,
IH), 7.06 (s, IH), 6.95 (s, IH), 5.98 (s, IH), 5.91 (s,
135 1 547
IH), 5.06 (dd, 7 = 13.5, 7.0 Hz, IH), 2.46 (s, 3H), 2.27
(s, 3H), 2.17 (s, 2H), 1.83 (d, 7 = 29.4 Hz, 2H), 1.62 (s,
2H), 1.52 (d, 7 = 7.0 Hz, IH), 1.44 (d, 7 = 7.1 Hz, 3H),
1.16 (s, IH), 1.04 (s, 2H), 1.02 (s, IH), 0.88 (s, 2H).
1H NMR (400 MHz, DMSO-J6) δ 11.89 (s, IH), 9.53
(s, IH), 8.67 (d, 7 = 4.4 Hz, IH), 8.41 (d, 7 = 2.2 Hz,
IH), 8.28 (d, 7 = 8.2 Hz, IH), 7.98 (dd, 7 = 8.5, 2.3 Hz,
IH), 7.93 - 7.80 (m, 2H), 6.74 (s, IH), 6.28 (s, IH), 5.09
136 3 548
- 4.95 (m, IH), 3.28 - 3.20 (m, 2H), 2.61 - 2.51 (m, IH),
2.22 (s, 3H), 2.19 (s, 3H), 2.02 - 1.91 (m, 2H), 1.90 - 1.78 (m, 2H), 1.71 (d, 7 = 10.4 Hz, 3H), 1.63 - 1.51 (m,
IH), 1.45 (d, 7 = 7.1 Hz, 3H), 1.21 (t, 7 = 6.9 Hz, 3H).
1H NMR (400 MHz, DMSO-J6) δ 11.71 (s, IH), 8.91
(s, IH), 8.64 (d, 7 = 4.5 Hz, IH), 8.48 - 8.36 (m, 2H),
7.97 (dd, 7 = 8.5, 2.3 Hz, IH), 7.89 (d, 7 = 4.2 Hz, IH),
137 1 7.83 (d, 7 = 8.5 Hz, IH), 6.70 (s, IH), 6.68 (s, IH), 6.17 549
(s, IH), 5.17 - 5.08 (m, , IH), 4.88 (s, IH), 3.08 (s, 3H),
2.25 - 2.15 (m, 7H), 2.02 - 1.73 (m, 6H), 1.59 - 1.48 (m,
2H), 1.45 (d, 7 = 7.0 Hz, 3H).
*H NMR (400 MHz, DMSO-J6) δ 11.67 (s, IH), 8.96
(s, IH), 8.68 (d, 7 = 4.5 Hz, IH), 8.48 (d, 7 = 8.3 Hz,
IH), 8.43 (d, 7 = 2.2 Hz, IH), 7.99 (dd, 7 = 8.6, 2.3 Hz,
IH), 7.94 - 7.81 (m, 2H), 6.77 (s, IH), 6.67 (s, IH), 6.39
138 1 549
(s, IH), 5.09 - 5.01 (m, IH), 4.84 (s, IH), 3.18 (s, 3H),
2.29 - 2.03 (m, 9H), 1.97 (td, 7 = 13.7, 3.5 Hz, IH), 1.72
(dd, 7 = 20.5, 14.9 Hz, 2H), 1.46 (d, 7 = 7.0 Hz, 3H),
1.40 - 1.26 (m, 2H). Compound Synthetic MS
IH NMR
Number Protocol (M+l)
*H NMR (400 MHz, DMSO-J6) δ 11.64 (s, IH), 9.01
(s, IH), 8.64 (d, 7 = 4.5 Hz, IH), 8.55 (d, 7 = 8.3 Hz,
IH), 8.40 (d, 7 = 2.3 Hz, IH), 7.97 (dd, 7 = 8.5, 2.4 Hz,
IH), 7.89 (d, 7 = 4.2 Hz, IH), 7.84 (d, 7 = 8.5 Hz, IH),
141 1 551
6.78 (s, IH), 6.66 (s, IH), 6.27 (s, IH), 5.14 (t, 7 = 7.5
Hz, IH), 3.10 (s, 3H), 2.45 - 2.29 (m, 2H), 2.20 (s, 3H),
2.16 (s, 3H), 2.14 - 2.01 (m, 2H), 1.91 - 1.68 (m, 4H),
1.46 (d, 7 = 7.1 Hz, 3H).
'H NMR (400 MHz, DMSO-J6) δ 11.71 (s, IH), 9.11
(s, IH), 8.67 (d, 7 = 4.5 Hz, IH), 8.56 (d, 7 = 8.3 Hz,
IH), 8.43 (d, 7 = 2.2 Hz, IH), 7.99 (dd, 7 = 8.5, 2.3 Hz,
142 1 IH), 7.93 - 7.84 (m, 2H), 6.77 (s, IH), 6.63 (s, IH), 6.32 551
(s, IH), 5.10 - 05.13 (m, IH), 3.20 (s, 3H), 2.43 - 2.15
(m, 8H), 2.06 - 1.81 (m, 4H), 1.78 - 1.61 (m, 2H), 1.47
(d, 7 = 7.1 Hz, 3H).
1H NMR (500 MHz, DMSO-J6) δ 11.89 (s, IH), 9.48
(s, IH), 8.67 (d, 7 = 4.5 Hz, IH), 8.49 - 8.30 (m, 2H),
7.96 - 7.77 (m, 3H), 7.09 (d, 7 = 7.4, IH), 6.81 (s, IH),
144 2 6.19 (s, IH), 5.01 (q, 7 = 7.0 Hz, IH), 3.16 (d, 7 = 4.9 502
Hz, IH), 2.75 (t, 7 = 18.9 Hz, IH), 2.41 - 2.28 (m, 2H),
2.25 (d, 7 = 1.9 Hz, 3H), 2.20 (s, 3H), 2.10 - 1.87 (m,
IH), 1.65 -1.49 (m, 2H),1.41 (dd, 7 = 7.0, 2.0 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, IH), 8.91
(s, IH), 8.69 (d, J = 4.4 Hz, IH), 8.44 (d, J = 2.3 Hz,
IH), 8.18 (d, J = 8.2 Hz, IH), 7.99 (dd, J = 8.6, 2.4 Hz,
IH), 7.93 - 7.87 (m, 2H), 6.90 (s, IH), 6.84 (s, IH), 6.12
146 1 (s, IH), 5.22 (s, IH), 5.08 (dt, J = 14.5, 7.2 Hz, IH), 521
3.93 - 3.81 (m, 2H), 3.72 - 3.63 (m, IH), 2.30 - 2.23 (m,
IH), 2.21 (s, 3H), 2.19 (s, 3H), 1.84 - 1.74 (m, 2H), 1.74
- 1.65 (m, IH), 1.47 (d, J = 7.0 Hz, 3H).
'H-NMR (400 MHz, CD3OD): δ ppm 8.53-8.51 (m,
2H), 8.43 (d, J = 7.6 Hz, IH), 8.04-8.02 (m, IH), 7.95
(d, J = 8.8 Hz, IH), 7.71 (d, J = 4.0 Hz, IH), 7.01 (s,
IH), 6.72 (s, IH), 5.91 (s, IH), 5.18-5.15 (m, IH), 4.19
147 1 (d, J = 11.6 Hz, IH), 3.60 (d, J = 12.0 Hz, IH), 2.38 (s, 535
3H), 2.38-2.29 (m, IH), 2.29 (s, 3H), 2.18-2.13 (m, IH),
1.81-1.78 (m, IH), 1.59 (d, J = 7.2 Hz, 3H), 1.59-1.51
(m, IH), 1.51 (s, 3H). Compound Synthetic MS
1H NMR
Number Protocol (M+l)
'H-NMR (400 MHz, CD3OD): δ ppm 8.52 (d, J = 4.4
Hz, 1H), 8.47 (d, J = 9.2 Hz, 1H), 7.99-7.93 (m, 2H),
7.71 (d, J = 4.0 Hz, 1H), 7.08 (s, 1H), 6.76 (s, 1H), 5.88
(s, 1H), 5.19-5.16 (m, 1H), 4.21 (d, J = 12.0 Hz, 1H),
148 1 535
3.70 (d, J = 12.0 Hz, 1H), 2.41 (s, 3H), 2.41-2.30 (m,
1H), 2.30 (s, 3H), 2.30-2.22 (m, 1H), 1.92-1.87 (m, 1H),
1.64 (d, J = 7.2 Hz, 3H), 1.63-1.46 (m, 1H), 1.46 (s,
3H).
*H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.13
(s, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.47 (d, J = 8.3 Hz,
1H), 8.42 (d, J = 2.3 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz,
1H), 7.90 (d, J = 4.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H),
149 4 534
6.51 (s, 1H), 6.50 (s, 1H), 5.04 (p, J = 7.6 Hz, 1H), 3.13
(s, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 1.95 (dd, J = 29.5,
11.6 Hz, 2H), 1.84 - 1.54 (m, 7H), 1.45 (d, J = 7.1 Hz,
3H).
1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 9.50 (s,
1H), 9.11 (d, J = 1.4 Hz, 1H), 8.72 (d, J = 4.4 Hz, 1H),
8.64 (t, J = 6.0 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H), 8.02
150 3 (d, J = 4.2 Hz, 1H), 6.85 (s, 1H), 6.17 (s, 1H), 4.48 (d, J 521
= 5.9 Hz, 2H), 3.19 (s, 3H), 2.64 - 2.53 (m, 1H), 2.23 (s,
3H), 2.19 (s, 3H), 1.96 (d, J = 14.2 Hz, 2H), 1.86 - 1.67
(m, 6H).
1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 9.50 (s,
1H), 8.66 (d, J = 4.4 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H),
8.41 (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz, 1H),
151 3 7.92 - 7.82 (m, 2H), 6.84 (s, 1H), 6.18 (s, 1H), 5.08 - 534
5.01 (m, 1H), 3.12 (s, 3H), 2.61 - 2.51 (m, 1H), 2.22 (s,
3H), 2.19 (s, 3H), 2.00 - 1.87 (m, 2H), 1.83 - 1.56 (m,
6H), 1.45 (d, J = 7.1 Hz, 3H).
Example 10: 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 was used. Fluorescently labeled substrate peptide was incubated in the presence of kinase and ATP so that a reflective proportion of the peptide was phosphorylated. At the end of the reaction, the mix of phosphorylated (product) and non-phosphorylated (substrate) peptides were 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.
A. 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) was incubated in a total of 12.5 of buffer (100 mM HEPES pH 7.5, 0.015% Bri/ 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 was 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 was then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data was normalized to 0% and 100% inhibition controls and the IC50 calculated using a 4-parameter fit in the CORE LIMS.
B . 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) was incubated in a total of 12.5 μΐ, of buffer (100 mM HEPES pH 7.5, 0.015% Bri/ 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 was 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 was then read on a Caliper EZReader 2 (protocol settings: -1.7 psi, upstream voltage -500, downstream voltage -3000, post sample sip 35s). Data was 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; and > 100 nM = C.
Figure imgf000075_0001
Compound Wild-type V804L Compound Wild-type V804L Number RET Mutant Number RET Mutant
100 C C 124 C B
101 A A 128 A A
102 C C 129 C C
103 A A 130 A A
104 C C 131 A A
105 B B 135 B B
106 A B 136 A A
107 A A 137 C C
109 A A 138 A A
110 B B 141 B B
111 B A 142 A A
112 A A 144 A A
113 A A 146 A A
114 A A 147 B B
116 C B 148 A A
119 C C 149 B B
120 A A 150 A A
121 A A 151 A A
122 B B
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 com ound having the structural formula (A):
Figure imgf000077_0001
, or a pharmaceutically acceptable salt thereof, wherein:
ring A is an aryl or heteroaryl ring;
each of X1 and X2 is independently selected from N and C(R6);
each of Y 1 and Y 2 is independently selected from -CH2- and -0-, wherein no more than one of Y1 or Y2 is -0-;
1 7
each R and each R is independently selected from selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, -C(0)R, -OC(0)R, - C(0)OR, -(Ci-Ce alkylene)-C(0)R, -SR, -S(0)2R, -S(0)2-N(R)(R), -(Ci-C6 alkylene)- S(0)2R, -(Ci-C6 alkylene)-S(0)2-N(R)(R), -N(R)(R), -C(0)-N(R)(R), -N(R)-C(0)R, -N(R)- C(0)OR, -(Ci-C6 alkylene)-N(R)-C(0)R, -N(R)S(0)2R, and -P(0)(R)(R); wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra; or two R1 or two R are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb;
each of R2, if present, R3a, R3b, R4, R8a and R8b is independently selected from hydrogen, C C6 alkyl, Ci-C6 alkoxy, halo, hydroxyl, Ci-C6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra; each of R5 and R9 is independently selected from hydrogen, Ci-C6 alkyl, and Ci-C6 heteroalkyl; wherein each alkyl and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra; each R6 is independently selected from hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy, halo, Ci-C6 heteroalkyl, and -N(R)(R); wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of Ra;
each R is independently selected from hydrogen, hydroxyl, halo, thiol, Ci-C6 alkyl, Ci-C6 thioalkyl, Ci-C6 alkoxy, Ci-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra, 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 each Rb is independently selected from Ci-C6 alkyl, halo, hydroxyl, Ci-C6 heteroalkyl, Ci-C6 alkoxy, cycloalkyl, heterocyclyl, or cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R'; each R' is independently selected from Ci-C6 alkyl, Ci-C6 heteroalkyl, halo, hydroxyl, cycloalkyl or cyano; or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;
= represents a single or double bond;
m is 0, 1, or 2;
n is 0, 1, 2, or 3; and
each o is 0 when = is a double bond; and
each o is 1 when = is a single bond.
2. The compound of claim 1 having the structural formula (I):
Figure imgf000079_0001
(I), or a pharmaceutically acceptable salt thereof, wherein each of ring A, X1, X2, R1, R2, R3a, R3b, R4, R5, R6, R7, R8a, R8b, R9, R, Ra, Rb, R', m, and n is as defined in claim 1.
3. The compound of claim 1 or 2, wherein m is 1; R1 is located at the 5-position; and R1 is Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.
2
4. The compound of any one of claims 1-3, wherein R is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl.
5. The compound of any one of claims 1-4, wherein each of R a, R , R a and R , if R is present, is independently selected from hydrogen and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.
6. The compound of any one of claims claim 1-5, wherein at least one pair of R a and R or
R 8a and R 8b is simultaneously hydrogen.
7. The compound of any one of claims 1-6, wherein R4 is selected from hydrogen, Ci-C4 alkyl and 0-Ci-C4 alkyl, wherein each alkyl portion of R4 is optionally substituted with 0-3 occurrences of Ra.
8. The compound of any one of claims 1-7, wherein R5 is selected from hydrogen, Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.
9. The compound of any one of claims 1-8, wherein each R6 is independently selected from hydrogen, halo, and Ci-C4 alkyl optionally substituted with 0-3 occurrences of Ra.
10. The compound of any one of claims 1-9, wherein ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom.
11. The compound of claim 10, wherein ring A is selected from
Figure imgf000080_0001
and
12. The compound of any one of claims 1-11, wherein n is 1 ; and R is pyrazol- l-yl an optionally substituted with 0-3 occurrences of Rb.
13. The compound of any one of claims 1-12, wherein R9 is hydrogen.
14. A compound having the structural formula (II):
Figure imgf000080_0002
(Π),
or a pharmaceutically acceptable salt thereof, wherein:
X1 is selected from N, CH and C(halo);
X is selected from N and CH;
X is selected from N and CH;
R 12 is selected from hydrogen, hydroxyl, halo and 0-Ci-C4 alkyl;
each of R13a, R13b, R18a and R18b is independently selected from hydrogen and C C4 alkyl;
R14 is selected from hydrogen, -Ci-C4 alkyl and -0-Ci-C4 alkyl;
R15 is selected from hydrogen and -Ci-C4 alkyl;
R16 is selected from hydrogen and -Ci-C4 alkyl;
R17b is selected from hydrogen and halo; and
R17a and R17c are independently selected from hydrogen and -Ci-C4 alkyl.
15. The compound of claim 14, wherein:
XI is selected from N, CH and C(C1);
X is selected from N and CH;
X is selected from N and CH;
R 12 is selected from hydrogen, hydroxyl, fluoro and -0-CH3;
each of R13a, R13b, R18a and R18b is independently selected from hydrogen, methyl and ethyl; and wherein at least one pair of R13a and R13b or R18a and R18b is simultaneously hydrogen.;
R14 is selected from hydrogen, -CH3, -CH2CH3, -OCH3 and -OCH2CH3;
R15 is selected from hydrogen and -CH3;
R16 is selected from hydrogen and -CH3;
R17b is selected from hydrogen, chloro and fluoro;
R17a and R17c are simultaneously hydrogen or -CH3, wherein when R17a and R17c are simultaneously -CH3, R17b is hydrogen.
16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15; and a pharmaceutically acceptable carrier.
17. A method for inhibiting RET activity in a cell or in a patient, comprising the step of contacting the cell or administering to the patient a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16.
18. 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 to 15 or a pharmaceutical composition of claim 16.
19. 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 to 15 or a pharmaceutical composition of claim 16.
20. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for inhibiting RET activity in a cell or in a patient.
21. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for treating a subject suffering from a condition mediated by aberrant RET activity.
22. A use of a compound of any one of claims 1 to 15 or a pharmaceutical composition of claim 16 in the manufacture of a medicament for treating a subject who has developed resistance to a cancer treatment.
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