Macrocyclic compounds and uses thereof

Abstract

Described herein are macrocyclic compounds of formula (I) that can inhibit kinases such as EGFR, including mutant forms such as the T790M EGFR mutant. Also described herein are pharmaceutical compositions comprising the compounds of formula (I) or any pharma- ceutically acceptable form thereof, processes for their preparation, and uses in therapy for the prevention or treatment of cancer. In particular, the compounds described herein may be effective in the treatment of EGFR-driven cancers, including non-small cell lung cancer (NSCLC). TIFF2024517023000250.tif5863

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 187,041, filed May 11, 2021, which is incorporated by reference in its entirety.

[0002] Described herein are macrocyclic compounds that can be used as kinase inhibitors.Specifically, the compounds described herein can inhibit epidermal growth factor receptor (EGFR), including mutant forms of EGFR.The compounds described herein can be effective in treating various disorders, including cancers, such as EGFR-driven cancers (e.g., non-small cell lung cancer (NSCLC) characterized by mutant EGFR). [Background technology]

[0003] Signal transduction refers to the transmission of stimulatory or inhibitory signals into and within a cell, often through a cascade of signal transduction events, leading to a biological response within the cell. Defects in various components of signal transduction pathways have been found to be the cause of many diseases, including many forms of cancer, inflammatory disorders, metabolic disorders, vascular diseases, and neurological diseases.

[0004] Signal transduction is often mediated by certain proteins called kinases. Kinases can be generally classified into protein kinases and lipid kinases, with certain kinases exhibiting dual specificity. For example, epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs) including EGFR / ERBB1, HER2 / ERBB2 / NEU, HER3 / ERBB3, and HER4 / ERBB4. Binding of a ligand such as epidermal growth factor (EGF) induces a conformational change in EGFR that promotes receptor homodimer or heterodimer formation, leading to activation of EGFR tyrosine kinase activity. Activated EGFR then phosphorylates its substrates, leading to activation of multiple downstream pathways in cells, including the PI3K-AKT-mTOR pathway involved in cell survival, and the RAS-RAF-MEK-ERK pathway involved in cell proliferation. (Chong et al. Nature Med. 2013;19(11):1389-1400).

[0005] Certain cancers are characterized by mutations in EGFR that lead to increased cell proliferation. Tyrosine kinase inhibitor (TKI) therapy that inhibits EGFR can result in clinical responses, but EGFR mutations can also confer resistance to such therapy. Therefore, there remains a need for new therapies to treat cancers associated with defective signaling pathways, including EGFR-driven cancers. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Chong et al.Nature Med.2013;19(11):1389-1400 Summary of the Invention

[0007] Described herein are new compounds that may be effective EGFR inhibitors. Such compounds may be useful in the treatment of a variety of diseases and disorders, including EGFR-driven cancers, such as non-small cell lung cancer (NSCLC), which are characterized by mutant EGFR.

[0008] A first aspect of the present invention relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 2 are independently N or CR 5 and X 3 and X 4 each independently represents a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR 6 C(O)NR 6 , or (C(R 7 ) 2 ) q and L 1 are independently a covalent bond, C 1 - 6 Heteroalkylene, C 1 - 6 Alkylene, C 2 - 6 Alkenylene, C 2 - 6 Alkynylene, C 3-6 cycloalkylene, 3- to 10-membered heterocyclylene, phenylene, naphthylene, or 5- to 10-membered heteroarylene; Each R 1 and R 2 is independent, [ka] OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10, CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 or two R 1 Or two R's 2 form a 5- to 10-membered ring together with the atoms to which they are attached. L 2 are independently a covalent bond, O, or NR L , C(O), C(O)NR L , N.R. L C(O), CR L 2 and R L are independently H or C 1-6 is alkyl, A is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C 3 -C 10 alicyclic or 3- to 10-membered heterocyclyl; B is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C 3 -C 10 alicyclic or 3- to 10-membered heterocyclyl; C is independently a 5- or 6-membered heteroaryl; Each R 3 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R.11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 and Each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , (CH 2 ) t OH, (CH 2 ) t OCH 3 , O(CH 2 ) t OH, O(CH 2 ) t OCH 3 , O(CH 2 ) r R 12 , or (CH 2 ) r R 12 or R 4 and R 6 , or R 4 and R 7 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 5 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 and Each R 6 are independently H, an N-protecting group, or C 1-6 alkyl or R 6 and R 4 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 7 are independently H or C 1-6 Alkyl or two R on the same carbon 7 may be combined to form an oxo (=O) group, or R 7 and R 4 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 8 , R 9 , and R 11 are independently H or C 1-6 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, or R 8 and R 11 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R 10 is independent, C 1-6 aliphatic, C 3-C 10 alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl, or R 10 and R 11 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R 12 is independent, C 3 -C 10 alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl; each m, n, and o is independently 0, 1, or 2; each p is independently 0, 1, 2, 3, or 4; each q is independently 1 or 2; each r is independently an integer from 0 to 4; each s is independently an integer from 2 to 6; Provided herein are compounds, or pharma- ceutically acceptable salts thereof, wherein each t is independently an integer from 1 to 6.

[0009] In some embodiments, each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , or (CH2 ) r R 12 or R 4 and R 6 , or R 4 and R 7 form a 5- or 6-membered ring together with the atoms to which they are attached, In several embodiments, m, n, o, and p are each independently 0, 1, or 2.

[0010] In some embodiments, at least one m or n is not 0.

[0011] In some embodiments, R 1 and R 2 is present and is a substructure A or a halogen.

[0012] In some embodiments, R 1 and R 2 is present, which is substructure A.

[0013] In some embodiments, no more than one moiety A is present.

[0014] In some embodiments, C is a 5- or 6-membered N-containing heteroaryl.

[0015] In embodiments, C is pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0016] In embodiments, the compound has the structure according to formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein X 1 is N or CR 5 It is.

[0017] In embodiments, the compound has the structure according to formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein: m is 0 or 1.

[0018] In embodiments, the compound has the structure according to formula (IC): [ka] or a pharma- ceutically acceptable salt thereof, wherein: m is 0 or 1.

[0019] In embodiments, the compound has the structure according to formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 1 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0020] In embodiments, the compound has the structure according to formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, m is 0.

[0022] In embodiments, the compound has a structure according to formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 2 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0023] In embodiments, the compound has the structure according to formula (III-A): [ka] or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, n is 0.

[0025] In some embodiments, X 1 and X 2 are each independently N or CH.

[0026] In some embodiments, X 1 is N.

[0027] In some embodiments, X 2 is CH.

[0028] In some embodiments, X 3 is O.

[0029] In some embodiments, X 4 is O.

[0030] In some embodiments, each X 3 and X 4 are independently a covalent bond, O, S, or NR 6 , C(O), CH 2 , C.H.H. 3 , or C(CH 3 ) 2 It is.

[0031] In some embodiments, X 2 is CH and X 3 is O and X 4 is O. In some embodiments, X 1 is N.

[0032] In some embodiments, L 1 is unsubstituted C 1 - 6 Alkylene or C containing 1 or 2 oxo (=O) substituents 1 - 6 It is alkylene.

[0033] In some embodiments, L 1 is unsubstituted C 1 - 6 Heteroalkylene or C containing 1 or 2 oxo (=O) substituents 1 - 6 It is a heteroalkylene.

[0034] In some embodiments, L 1 is an unsubstituted linear C 4-6 Alkylene or unsubstituted branched C 4-6 It is alkylene.

[0035] In some embodiments, L 1 teeth, [ka] where * is X 4 indicates the point of covalent attachment to X 3 The points of covalent attachment to

[0036] In some embodiments, C 1 - 6 The heteroalkylene contains 1, 2, or 3 heteroatoms which are independently oxygen or nitrogen.

[0037] In some embodiments, C 1 - 6 Heteroalkylene is O(CH 2 ) u , (CH 2 ) u O, O(CH 2 ) u O, OCH 2 OCH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 O-, OCH 2 CH 2. OCH 2 -, NH(CH 2 ) u , (CH 2 ) u NH or -NH(CH 2 ) u NH--, where u is an integer of 1 to 4.

[0038] In some embodiments, B is phenyl or 5-6 membered heteroaryl.

[0039] In embodiments, B is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0040] In some embodiments, B is [ka] where * indicates the point of covalent attachment to C and ** indicates X3 The points of covalent attachment to

[0041] In some embodiments, R 3 is methyl, halogen, or CN; and o is 0 or 1.

[0042] In some embodiments, A is phenyl or 5- to 6-membered heteroaryl.

[0043] In embodiments, A is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0044] In embodiments, the compound has the structure according to formula (IV): [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 1 is an unsubstituted linear or branched C 2 - 6 is alkylene, B is phenyl or 5-6 membered heteroaryl; R 3 is methyl, halogen, or CN; o is 0 or 1; R 1 and R 2 One of these is present as substructure A.

[0045] In embodiments, the compound has a structure according to formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 1 is -(CH 2 ) 3 - or -CH(CH 3 )CH 2 CH 2 -It is.

[0046] In some embodiments, the compound has a structure according to formula (VI-1) or (VI-2): [ka] or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the compound has a structure according to formula (VI-3) or (VI-4): [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the compound has a structure according to formula (VII-1) or (VII-2): [ka] or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, the compound has a structure according to formula (VII-3) or (VII-4): [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, A is phenyl or 5- to 6-membered heteroaryl.

[0051] In some embodiments, L 2 is a covalent bond.

[0052] In some embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0053] In embodiments, the compound has a structure according to formula (VIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0054] In embodiments, the compound has the structure according to formula (IX): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0055] In embodiments, the compound has a structure according to formula (X): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1; R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0056] In embodiments, the compound has a structure according to formula (XI): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0057] In embodiments, the compound has the structure according to formula (XII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on

[0058] In embodiments, the compound has a structure according to formula (XIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0059] In embodiments, the compound has the structure according to formula (XIV): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0060] In embodiments, the compound has a structure according to formula (XV): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on R 4C The third R 4 It is based on

[0061] In embodiments, the compound has the structure according to formula (XVI): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4C The first R 4 It is based on

[0062] In embodiments, the compound has the structure according to formula (XVII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0063] In embodiments, the compound has the structure according to formula (XVIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4C The first R 4 It is based on

[0064] In embodiments, the compound has a structure according to formula (XIX): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0065] In embodiments, the compound has a structure according to formula (XX): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0066] In embodiments, the compound has the structure according to formula (XXI): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1.

[0067] In embodiments, the compound has the structure according to formula (XXII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on R 4B The second R 4 It is based on p is 0 or 1; R4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0068] In embodiments, the compound has a structure according to formula (XXIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 4A The first R 4 It is based on

[0069] In some embodiments, the compounds described herein include one or more R 4 Group: -C≡N, -C≡CH, saturated linear or branched C containing 0-4 fluoro substituents 1-6 Aliphatic or C 1 - 6 Alkoxy, NR 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , O(CH 2 ) t OCH 3 , O(CH 2 ) r R 12 , and (CH 2 ) r R 12 In some embodiments, R 12 is C 3-6 cycloalkyl, 3-9 membered heterocyclyl containing 1-3 heteroatoms selected from O, N, and S, and 5-6 membered heteroaryl. 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino. 12 is 0 to 4 R14 wherein each R 14 are independently -CN, oxo (=O), halogen, -OH, -NH 2 , monoalkylamino, dialkylamino, unsubstituted C 3-6 In some embodiments, each R 14 are independently -CN, -F, OH, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , N(CH 2 CH 3 ) 2 , C.H. 3 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 3 , C.H. 2 CH 2 F, CH 2 CHF 2 , C.H. 2 CF 3 , -CH 2 CH 2 CH 3 , C.H. 2 CH 2 CH 2 F, C.H. 2 CH 2 CHF 2 , C.H. 2 CH 2 CF 3 , CH 2 CH 2 OCH 3 , COCH 3 , COCH 2 CH 3 , C.H. 2 COCH 3 , C.H. 2 COCH 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

[0070] In some embodiments, the compounds described herein are R selected from the following 4 Group: -CN, CH 3 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 3 , CH 2 CFH 2 , C.H. 2 CHF 2 , C.H. 2 CF 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , -C≡CH, [ka] [ka] and / or R selected from the following 4 Group, CH 2 OCH 3 , O.C.H. 3 , O.C.H. 2 F, O.C.H.F. 2 , OCF 3 , O.C.H. 2 CH 3 , O.C.H. 2 CH 2 F, O.C.H. 2 CHF 2 , O.C.H. 2 CF 3 , O.C.H. 2 CH 2 CH 3 , O.C.H. 2 CH(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , [ka] -CO 2 CH3 , and C.H. 3 Includes.

[0071] In some embodiments, R 4 is unsubstituted C 1-6 Alkyl, CO 2 (Unsubstituted C 1-6 alkyl), O-(unsubstituted C 1-6 alkyl), O-(C 1-6 haloalkyl), NH(CH 2 ) s NMe 2 , (CH 2 ) t NMe 2 or [ka] is selected from the group consisting of X 5 are independently CH or N; X 6 are independent, O, CHR 13 , or NR 13 and R 13 are independent of each other, H, C 1-6 Alkyl or C 3-6 is cycloalkyl, r is 0 or 1; s is an integer from 2 to 4; t is an integer from 1 to 6.

[0072] In some embodiments, one R 4 teeth [ka] and if present, the second R 4 is unsubstituted C 1-6 Alkyl, CO 2 (Unsubstituted C 1-6 alkyl), O-(unsubstituted C 1-6 alkyl), O-(C 1-6 haloalkyl), NH(CH 2 ) s NMe 2 , and (CH 2) t NMe 2 is selected from.

[0073] In some embodiments, [ka] teeth, [ka] where: A is phenyl or 5-6 membered heteroaryl. X 5 are independently CH or N; X 6 are independent, O, CHR 13 , or NR 13 and R 13 are independently H, unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 is cycloalkyl, r is 0 or 1; R 4 is unsubstituted C 1-6 Alkyl, CO 2 (Unsubstituted C 1-6 alkyl), O-(unsubstituted C 1-6 alkyl), O-(C 1-6 haloalkyl), or NH(CH 2 ) s NMe 2 is selected from p is 0 or 1; s is an integer from 2 to 6.

[0074] In some embodiments, [ka] teeth, [ka] Wherein, X 6 ,O,NCH 3 or N(cyclopropyl).

[0075] In some embodiments, r is 0.

[0076] In some embodiments, r is 1.

[0077] In some embodiments, the compound is CO 2 CH 3 , O.C.H. 2 CF 3 , C.H. 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , N.H.C.H. 2 CH 2 N(CH 3 ) 2 , or -CH 2 N(CH 3 ) 2 R 4 Contains a group.

[0078] In embodiments, A is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0079] In some embodiments, each R 4A , R 4B , and R 4C When present, each independently represents -C≡N, -C≡CH, a saturated linear or branched C 1-6 Aliphatic or C 1 - 6 Alkoxy, NR 11 (CH 2 ) s NR 8 R 9 ;(CH 2 ) t NR 8 R 9 ;O(CH 2 ) t OCH 3 ;O(CH 2 ) r R 12 , and (CH 2 )r R 12 is selected from.

[0080] In some embodiments, R 4A and / or R 4C The groups, when present, are CN, CH 3 , C.H. 2 F, CHF 2 , CF 3 , C.H. 2 CH 3 , C.H. 2 CFH 2 , C.H. 2 CHF 2 , C.H. 2 CF 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , -C≡CH, [ka] [ka] is selected from and / or R 4B The group, if present, is CH 2 OCH 3 , O.C.H. 3 , O.C.H. 2 F, O.C.H.F. 2 , OCF 3 , O.C.H. 2 CH 3 , O.C.H. 2 CH 2 F, O.C.H. 2 CHF 2 , O.C.H. 2 CF 3 , O.C.H. 2 CH 2 CH 3 , O.C.H. 2 CH(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , [ka] -CO 2 CH 3 , and C.H. 3 is selected from.

[0081] In embodiments, the compound is any of the exemplary compounds described herein, including any of the compounds described in Table A (e.g., any one of compounds (1)-(169)), or a pharma- ceutically acceptable salt thereof.

[0082] In another aspect, the invention features a pharmaceutical composition including any compound described herein, or a pharma- ceutically acceptable salt thereof.

[0083] In another aspect, the invention features a method of treating cancer, comprising administering to a human in need thereof an effective amount of any compound described herein, or a pharma- ceutically acceptable salt thereof, in a pharmaceutical composition.

[0084] In embodiments, the cancer is lung cancer.

[0085] In embodiments, the cancer is non-small cell lung cancer.

[0086] In embodiments, the cancer (e.g., lung cancer, such as non-small cell lung cancer) is an EGFR-driven cancer.

[0087] In embodiments, the cancer (eg, lung cancer, such as non-small cell lung cancer) is characterized by an EGFR mutation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] definition In order that the present invention may be more readily understood, certain terms are first defined below. Additional definitions for these terms and other terms are set forth throughout the specification. Publications and other reference materials referred to herein to describe the background of the art and to provide additional details regarding its practice are incorporated herein by reference.

[0089] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, animals may be transgenic animals, genetically engineered animals, and / or clones.

[0090] Approximately or about: As used herein, the term "approximately" or "about" when applied to one or more subject values, refers to a value similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that is within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the stated reference value (unless such number exceeds 100% of the possible values), unless otherwise stated or clear from the context.

[0091] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition includes a mixture of two or more such compositions.

[0092] Throughout the description and claims of this specification, the word "comprise" and other forms of that word, such as "comprising" and "comprises," are intended to mean, for example, the inclusion of other additives, components, integers, or steps, but are not intended to be exclusive thereof.

[0093] "Optional" or "optionally" means that the described event or circumstance may or may not occur, and is meant to include instances in which the event or circumstance occurs and instances in which the description does not occur.

[0094] Improved, increased, or decreased: As used herein, the terms "improved," "increased," or "decreased," or grammatical equivalents, refer to a value compared to a baseline measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control subject (or control subjects) in the absence of a treatment described herein. A "control subject" is a subject suffering from the same type of disease as the subject being treated, and who is about the same age as the subject being treated.

[0095] In vitro: As used herein, the term "in vitro" refers to events that take place not within a multicellular organism but in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc.

[0096] In vivo: As used herein, the term "in vivo" refers to events that occur within multicellular organisms, such as humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events that occur within living cells (as opposed to, for example, in vitro systems).

[0097] Patient: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal forms.

[0098] Pharmaceutically acceptable: As used herein, the term "pharmacologically acceptable" refers to a substance that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. Thus, "pharmacologically acceptable" refers to a substance that is biologically or otherwise undesirable, i.e., the substance can be administered to an individual together with the associated active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is included.

[0099] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-terminated salts. + (C 1-4 -alkyl) 4Examples of pharmaceutically acceptable salts include salts of the amines and the amine salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations, where appropriate, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include salts formed from the quaternization of amines using suitable electrophiles, for example, alkyl halides to form quaternary alkylated amino salts.

[0100] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is a human. A subject can be a patient, which refers to a human who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be afflicted with or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0101] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting all or nearly all extent or degree of a feature or characteristic of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, tend to complete and / or perfect, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of perfection inherent in many biological and chemical phenomena.

[0102] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the symptoms of the disease, disorder, and / or condition. One of skill in the art will understand that a therapeutically effective amount is typically administered in a dosing regimen comprising at least one unit dose.

[0103] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not exhibit signs of the disease and / or who exhibit only early signs of the disease for the purpose of reducing the risk of developing pathology associated with the disease.

[0104] Whenever a term (e.g., alkyl or aryl) or any of their prefix roots (e.g., alk- or ar-) appears in a substituent name, the name should be interpreted as including the limitations provided herein. For example, the addition of the suffix "-ene" to a group indicates that the group is a divalent moiety, e.g., arylene is a divalent moiety of aryl, heteroarylene is a divalent moiety of heteroaryl, cycloalkylene is a divalent moiety of cycloalkyl, heterocycloalkylene is a divalent moiety of heterocycloalkyl, or heterocyclene is a divalent moiety of heterocyclyl. Similarly, the addition of the suffix "-oxy" to a group indicates that the group is attached to the parent molecular structure through an oxygen atom (-O-).

[0105] Aliphatic: As used herein, the term aliphatic refers to hydrocarbons, including both saturated and unsaturated hydrocarbons. Aliphatic groups can be linear, branched, or cyclic. For example, C 1 -C 20 Aliphatic is C 1 -C 20 Alkyl (e.g., linear or branched C 1 -C 20 Saturated alkyl), C 2 -C 20 Alkenyl (e.g., linear or branched C 4 -C 20 Dienyl, linear or branched C 6 -C 20 trienyl, etc.), and C 2 -C 20 Alkynyl (e.g., linear or branched C 2 -C 20 alkynyl). 1 -C 20 Aliphatic is C 3 -C 20 Cycloaliphatic (e.g., C 3 -C 20 Cycloalkyl, C 4 -C 20 Cycloalkenyl, or C 8 -C 20 In certain embodiments, an aliphatic group may include one or more cycloaliphatic groups and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents, such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. An aliphatic group is unsubstituted or substituted with one or more substituents as described herein. For example, an aliphatic group may include halogen, -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2 , -SR' or -SO 2and R′ is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) R′, where each instance of R′ is independently selected from the group consisting of C 1 -C 20 Aliphatic (e.g., C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted C 1 -C 3 In some embodiments, the aliphatic group is an alkyl group. In some embodiments, the aliphatic group is unsubstituted. In some embodiments, the aliphatic group does not contain any heteroatoms.

[0106] Alkyl: As used herein, the term "alkyl" refers to acyclic straight-chain and branched hydrocarbon groups, such as, for example, "C 1 -C 20 "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms. 1 -C 4 "Alkyl" refers to an alkyl group having 1 to 4 carbons. Alkyl groups include those having C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl, C 1 -C 4 Alkyl, and C 1 -C 3 In some embodiments, the alkyl group is C 1 -C 4The alkyl group is an alkyl. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentylhexyl, isohexyl, and the like. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms, linear or branched alkyl. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of this disclosure. The alkyl group may be unsubstituted or substituted with one or more of the substituents described herein. For example, the alkyl group may be substituted with halogen, -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2 , -SR' or -SO 2 and R′ is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) R′, where each instance of R′ is independently selected from the group consisting of C 1 -C 20 Aliphatic (e.g., C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl, C 1 -C 4 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted C 1 -C 3In some embodiments, the alkyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkyl group is substituted with an -OH group, and may also be referred to herein as a "hydroxyalkyl" group, where the prefix refers to the -OH group and "alkyl" is as described herein. In some embodiments, the alkyl group is substituted with an -OR' group.

[0107] Alkylene: The term "alkylene" as used herein refers to a saturated divalent straight or branched chain hydrocarbon group, exemplified by methylene, ethylene, propylene, and the like. Similarly, the term "alkenylene" as used herein refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, and the term "alkynylene" as used herein refers to an unsaturated divalent straight or branched chain hydrocarbon group having one or more unsaturated carbon-carbon triple bonds that may occur at any stable point along the chain. In certain embodiments, an alkylene, alkenylene, or alkynylene group may contain one or more cyclic aliphatic and / or one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be optionally substituted with one or more substituents, such as alkyl, halo, alkoxyl, hydroxy, amino, aryl, ether, ester, or amide. For example, an alkylene, alkenylene, or alkynylene may be substituted with halogen, -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2 , -SR' or -SO 2 and R′ is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) R′, where each instance of R′ is independently selected from the group consisting of C 1 -C 20 Aliphatic (e.g., C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted C 1 -C 3 In certain embodiments, the alkylene, alkenylene, or alkynylene is unsubstituted. In certain embodiments, the alkylene, alkenylene, or alkynylene does not contain any heteroatoms.

[0108] Alkenyl: As used herein, "alkenyl" refers to any straight or branched hydrocarbon chain with one or more unsaturated carbon-carbon double bonds that may occur at any stable point along the chain, e.g., "C 2 -C 20 "Alkenyl" refers to an alkenyl group having 2 to 20 carbons. For example, alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In some embodiments, an alkenyl contains one, two, or three carbon-carbon double bonds. In some embodiments, an alkenyl contains a single carbon-carbon double bond. In some embodiments, multiple (e.g., two or three) double bonds are conjugated. An alkenyl group can be unsubstituted or substituted with one or more substituents described herein. For example, an alkenyl group can be substituted with halogen, -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2, -SR' or -SO 2 and R′ is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) R′, where each instance of R′ is independently selected from the group consisting of C 1 -C 20 Aliphatic (e.g., C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted C 1 -C 3 In some embodiments, the alkenyl is unsubstituted. In some embodiments, the alkenyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). In some embodiments, the alkenyl group is substituted with an -OH group, and may also be referred to herein as a "hydroxyalkenyl" group, where the prefix refers to the -OH group and "alkenyl" is as described herein.

[0109] Alkynyl: As used herein, "alkynyl" refers to any hydrocarbon chain in either a linear or branched configuration with one or more carbon-carbon triple bonds occurring at any stable point along the chain, e.g., "C 2 -C 20Alkynyl" refers to an alkynyl group having 2 to 20 carbons. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In some embodiments, an alkynyl group contains one carbon-carbon triple bond. An alkynyl group can be unsubstituted or substituted with one or more substituents described herein. For example, an alkynyl group can be a halogen, or -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2 , -SR' or -SO 2 and R′ is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) R′, where each instance of R′ is independently selected from the group consisting of C 1 -C 20 Aliphatic (e.g., C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In some embodiments, R' is independently an unsubstituted C 1 -C 3 In some embodiments, the alkynyl is unsubstituted. In some embodiments, the alkynyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents described herein).

[0110] Alkoxy: The term "alkoxy" refers to the group -O-alkyl containing from 1 to 10 carbon atoms in a linear, branched, saturated cyclic configuration, and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing from 1 to 6 carbons. In some embodiments, C 1-4 Alkoxy is an alkoxy group that includes both straight and branched chain alkyls having 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxy group may be optionally substituted with one or more substituents (e.g., those described herein for alkyl). The terms "alkenoxy" and "alkynoxy" mirror the description of "alkoxy" above, where the prefix "alk or alk" is replaced with "alken" or "alkyn", respectively, and the parent "alkenyl" or parent "alkynyl" terms are as described herein.

[0111] Amide: The term "amide" or "amido" refers to a group having the formula C(O)N(R') 2 "R" refers to a chemical moiety having the formula -C(O)N(R')-, -NR'C(O)R', or -NR'C(O)-, where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless otherwise stated herein, each of which moieties may itself be optionally substituted as described herein, or two R' may be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0112] Ureido: The term "ureido" refers to a chemical moiety having the formula -NR'C(O)NR'-, where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), unless otherwise stated herein, each of which moieties can itself be optionally substituted as described herein, or two R' can be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.

[0113] Amino: The term "amino" or "amine" refers to a radical -N(R') 2 "R" refers to the group, where each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), and unless otherwise stated herein, each of which moieties can itself be optionally substituted as described herein, or two R' can be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. In embodiments, the amino group is -NHR', where R' is aryl ("arylamino"), heteroaryl ("heteroarylamino"), or alkyl ("alkylamino").

[0114] Aryl: The term "aryl," used alone or as part of a larger moiety as in "aralkyl," refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, which has one point of attachment to the remainder of the molecule, at least one ring in the system is aromatic, and each ring in the system contains 4 to 7 ring members. In some embodiments, an aryl group has 6 ring carbon atoms ("C 6aryl" (e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl", e.g., anthracen. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Exemplary aryls include phenyl, naphthyl, and anthracene.

[0115] Arylalkyl: The term "arylalkyl" refers to an -(alkylene)-aryl radical, where aryl and alkylene are as disclosed herein and are optionally substituted with one or more of the exemplary substituents described herein. An "arylalkyl" group is attached to the parent molecular structure via an alkylene moiety. The term "arylalkoxy" refers to an -O-[arylalkyl] radical (-O-[(alkylene)-aryl]) attached to the parent molecular structure via an oxygen.

[0116] Arylene: As used herein, the term "arylene" refers to an aryl group that is divalent (i.e., has two points of attachment to the molecule). Exemplary arylenes include phenylene (e.g., unsubstituted or substituted phenylene).

[0117] Cyclic: As used herein, the term "cyclic" refers to any covalently closed structure. Cyclic moieties include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and heterocycloalkyl), aromatics (e.g., aryl and heteroaryl), and non-aromatic (e.g., cycloalkyl and heterocycloalkyl). In some embodiments, the cyclic moiety is optionally substituted. In some embodiments, the cyclic moiety forms part of a ring system.

[0118] Alicyclic: The term "alicyclic" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated or partially unsaturated. Fully saturated alicyclic groups can be referred to as "cycloalkyl". Partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond, and "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Alicyclic groups include groups having 3 to 13 ring atoms, such as C 3-13 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range, for example, "3 to 10 carbon atoms" means that the alicyclic group (e.g., cycloalkyl) can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10 carbon atoms. The term "alicyclic" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic alicyclic groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3-8 In some embodiments, "cycloalkyl" can be a C 3-5 Illustrative examples of alicyclic groups include, but are not limited to, the following moieties: C 3-6 The alicyclic group is cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like, but are not limited to these. C 3-7 Examples of alicyclic groups include norbornyl (C 7 ) are listed. C 3-8 Examples of alicyclic groups include the above-mentioned C 3-7 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, etc. 3-13 Examples of alicyclic groups include the above-mentioned C 3-8 Examples include carbocyclyl groups, as well as octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like.

[0119] Cyano: The term "cyano" refers to the group -CN.

[0120] Deuterium: The term "deuterium" is also referred to as heavy hydrogen. Deuterium is an isotope of hydrogen with a nucleus of one proton and one neutron, which is twice the mass of a nucleus of regular hydrogen (one proton). In some embodiments, deuterium is 2 It can also be identified as H.

[0121] Ester: The term "ester" refers to a group of formula -C(O)OR' or -R'OC(O)-, where R' is selected from alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl as described herein.

[0122] Halogen or Halo: As used herein, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0123] Heteroalkyl: The term heteroalkyl refers to a branched or unbranched alkyl, alkenyl, or alkynyl group having 1-14 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyl includes tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. Heteroalkyl groups can optionally contain monocyclic, bicyclic, or tricyclic rings, each of which desirably has 3-6 members. Examples of heteroalkyl include polyethers such as methoxymethyl and ethoxyethyl. Thus, the term "heteroalkoxy" refers to an -O-heteroalkyl group attached to the parent molecular structure through an oxygen.

[0124] Heteroalkylene: As used herein, the term "heteroalkylene" refers to a divalent form of the heteroalkyl groups described herein.

[0125] Heteroaryl: As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, which has one point of attachment to the remainder of the molecule, at least one ring in the system is aromatic, each ring in the system contains 4 to 7 ring members, and at least one ring atom is a heteroatom such as, but not limited to, nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The term N-containing heteroaryl refers to a heteroaryl group that contains at least one nitrogen in the ring system (e.g., a heteroaryl containing 1, 2, or 3 nitrogen atoms). Thus, the term "heteroaryloxy" refers to an --O-heteroaryl group that is attached to the parent molecular structure through an oxygen.

[0126] Heteroarylene: As used herein, the term "heteroalkylene" refers to a divalent form of the heteroaryl groups described herein.

[0127] Heteroarylalkyl: The term "heteroarylalkyl" refers to a -(alkylene)-heteroaryl radical, where heteroaryl and alkylene are as disclosed herein and are optionally substituted with one or more of the exemplary substituents described herein. A "heteroarylalkyl" group is attached to the parent molecular structure via an alkylene moiety. The term "heteroarylalkoxy" refers to an -O-[heteroarylalkyl] radical (-O-[(alkylene)-heteroaryl]) attached to the parent molecular structure via an oxygen.

[0128] Heterocycloalkyl: As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyran ... Heterocycloalkyl groups include pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolizinyl. Heterocycloalkyl groups can be substituted or unsubstituted.

[0129] Heterocycle: The terms "heterocycle" or "heterocyclyl" as used herein refer to heteroaryl and heterocycloalkyl, respectively, groups containing 1 to 4 heteroatoms selected from O, S, and N, with each heterocycle group having 4 to 10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. As used herein, the number of carbon atoms in a heterocycle (e.g., C 1 -C 6 Whenever a heterocyclic ring is indicated, at least one other atom (heteroatom) must be present in the ring. 1 -C 6Designations such as "heterocycle" refer only to the number of carbon atoms in the ring, and not to the total number of atoms in the ring. In some embodiments, it is understood that the heterocycle has additional heteroatoms in the ring. Designations such as "4- to 6-membered heterocycle" refer to the total number of atoms contained in the ring (i.e., a 4-, 5-, or 6-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are either carbon atoms or heteroatoms). In some embodiments, in a heterocycle having two or more heteroatoms, these two or more heteroatoms are the same as or different from one another. In some embodiments, the heterocycle is optionally substituted. In some embodiments, the bond to the heterocycle is at a heteroatom or through a carbon atom. Heterocycloalkyl groups include groups having only four atoms in their ring system, while heteroaryl groups must have at least five atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. In some embodiments, the aforementioned groups derived from the groups listed above are C- or N-linked, where possible. For example, in some embodiments, the group derived from pyrrole is pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, in some embodiments, the group derived from imidazole is imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, depending on the structure, the heterocycle group is a monoradical or a diradical (ie, a heterocyclene group).The heterocycles described herein are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, aryl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, amino, and amido moieties.

[0130] Isotope: The term "isotopes" refers to variants of a particular chemical element that differ in the number of neutrons, and therefore the number of nucleons. All isotopes of a given element have the same number of protons but different numbers of neutrons in each atom.

[0131] Nitro: The term "nitro" means -NO 2 Refers to the base.

[0132] Sulfonamide: The term "sulfonamide" or "sulfonamido" refers to the following group: -S(=O) 2 -(R') 2 , -N(R')-S(=O) 2 -R', -S(=O) 2 -N(R')- or -N(R')-S(=O) 2 In the formula, each R ’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (bonded through a chain carbon), cycloalkyl, aryl, arylalkyl, heteroaryl (bonded through a ring carbon), heteroarylalkyl, or heterocycloalkyl (bonded through a ring carbon), each of which moieties can itself be optionally substituted as described herein, or two R' can be joined to the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring, unless otherwise stated herein.

[0133] Nitrogen protecting group: In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group or N-protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0134] For example, an amide group (e.g., -C(=O)R aa Nitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0135] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylphenylcarbamate (Tm ... Tylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-phenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t -Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, albamate, Kyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrilebenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro bromomethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2 ,2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0136] Sulfonamide groups (e.g., -S(=O) 2 R aa Nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0137] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyl. 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine , quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine amine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-Dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0138] Moiety: The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often a recognized chemical entity that is embedded in or appended to a molecule.

[0139] Molecular groups herein may be substituted or unsubstituted (e.g., as described herein). The term "substituted" means that the specified group or moiety has one or more substituents, where at least one hydrogen present on the group atom (e.g., carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon replacement of the hydrogen results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it is meant that substitution occurs at any valence-allowed position on that system. In embodiments, the groups described herein are substituted. In embodiments, the groups described herein are unsubstituted. When a particular moiety or group is not expressly described as being optionally substituted or substituted with any particular substituent, it is understood that such moiety or group is intended to be unsubstituted.

[0140] A wide variety of substituents are well known, as are methods for forming them and introducing them into various parent groups. Representative substituents include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di-, and trihaloalkyl, mono-, di-, and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo (e.g., -Cl and -Br), nitro, oximino, -COOR ... 50 , -COR 50 , -SO 0-2 R 50 , -SO 2 NR 50 R 51 , -NR 52 SO2 R 50 , =C(R 50 R 51 ), =N-OR 50 , =N-CN, =C(halo) 2 , =S, =O, -CON(R 50 R 51 ), -OCOR 50 , -OCON(R 50 R 51 ), -N(R 52 )CO(R 50 ), -N(R 52 )COOR 50 , -N(R 52 )CON(R 50 (R 51 ), -P(OR 50 ) 2 , -P(O)R 50 R 51 , and -P(O)OR 50 OR 51 In particular, but not limited to, R 50 , R 51 , and R 52 are independently selected from the following: hydrogen atoms and branched or linear chains, C 1-6 -Alkyl, C 3-6 -Cycloalkyl, C 4-6 - may be selected from heterocycloalkyl, heteroaryl, and aryl groups (with or without substitution). Where permitted, R 50 and R 51 can be joined together to form a carbocyclic or heterocyclic ring system.

[0141] In a preferred embodiment, the substituents are halogen, -COR', -CO 2 H, -CO 2 R', -CN, -OH, -OR', -OCOR', -OCO 2 R', -NH 2 , -NHR', -N(R') 2 , -SR', and -SO 2 R′, wherein each instance of R′ is independently selected from 1 -C 20 Aliphatic (e.g., C 1 -C 20Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 In certain embodiments thereof, R' is independently an unsubstituted alkyl (e.g., an unsubstituted C 1 -C 20 Alkyl, C 1 -C 15 Alkyl, C 1 -C 10 Alkyl or C 1 -C 3 Preferably, R' is independently an unsubstituted C 1 -C 3 It is an alkyl.

[0142] Any formula provided herein is intended to represent a compound having a structure shown by the structural formula, as well as certain variations or forms. In particular, any compound of the formula provided herein may have an asymmetric center and therefore may exist in different enantiomeric forms. All optical isomers and stereoisomers of a compound of the general formula, as well as mixtures thereof, are considered to be within the scope of the formula. Thus, any formula provided herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, a particular structure may exist as a geometric isomer (i.e., cis and trans isomers), as a tautomer, or as an atropisomer. In addition, any formula provided herein is intended to encompass hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof.

[0143] Compounds of the Invention Described herein are new compounds that may be effective EGFR inhibitors. Such compounds may be useful in the treatment of a variety of diseases and disorders, including EGFR-driven cancers, such as non-small cell lung cancer (NSCLC), which are characterized by mutant EGFR.

[0144] Exemplary compounds and exemplary structural features are described herein.

[0145] Compounds of formulae (I) to (XXIII) In one embodiment, a compound having a structure according to formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 2 are independently N or CR 5 and X 3 and X 4 each independently represents a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR 6 C(O)NR 6 , or (C(R 7 ) 2 ) q and L 1 are independently a covalent bond, C 1 - 6 Heteroalkylene, C 1 - 6 Alkylene, C 2 - 6 Alkenylene, C 2 - 6 Alkynylene, C 3-6 cycloalkylene, 3- to 10-membered heterocyclylene, phenylene, naphthylene, or 5- to 10-membered heteroarylene; Each R 1 and R 2 is independent, [ka] OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 or two R 1 Or two R's 2 form a 5- to 10-membered ring together with the atoms to which they are attached, L 2 are independently a covalent bond, O, or NR L , C(O), C(O)NR L , N.R. L C(O), CR L 2 ; and R L are independently H or C 1-6 is alkyl, A is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C 3 -C 10 alicyclic or 3- to 10-membered heterocyclyl; B is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C 3 -C 10 alicyclic or 3- to 10-membered heterocyclyl; C is independently a 5- or 6-membered heteroaryl; Each R 3 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R.11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 and Each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , (CH 2 ) t OH, (CH 2 ) t OCH 3 , O(CH 2 ) t OH, O(CH 2 ) t OCH 3 , O(CH 2 ) r R 12 , or (CH 2 ) r R 12 or R 4 and R 6 , or R 4 and R 7 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 5 are independently H, OH, CN, halogen, C 1- 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or (CH 2 ) r R 12 and Each R 6 are independently H, an N-protecting group, or C 1-6 alkyl or R 6 and R 4 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 7 are independently H or C 1-6 Alkyl or two R on the same carbon 7 may be combined to form an oxo (=O) group, or R 7 and R 4 form a 5- or 6-membered ring together with the atoms to which they are attached, Each R 8 , R 9 , and R 11 are independently H or C 1-6 alkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, or R 8 and R 11 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R 10 is independent, C 1-6 aliphatic, C 3 -C 10alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl, or R 10 and R 11 together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R 12 is independent, C 3 -C 10 alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl; each m, n, and o is independently 0, 1, or 2; each p is independently 0, 1, 2, 3, or 4; each q is independently 1 or 2; each r is independently an integer from 0 to 4; each s is independently an integer from 2 to 6; Provided herein is a compound, or a pharma- ceutically acceptable salt thereof, wherein each t is independently an integer from 1 to 6.

[0146] In some embodiments, each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , or (CH 2 )r R 12 or R 4 and R 6 , or R 4 and R 7 form a 5- or 6-membered ring together with the atoms to which they are attached.

[0147] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 1 or 2.

[0148] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 or 2.

[0149] In some embodiments, m is not 0. In some embodiments, n is not 0. In some embodiments, at least one of m or n is not 0. In some embodiments, m is 1 and n is 0. In some embodiments, n is 1 and m is 0.

[0150] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0151] In some embodiments, R 1 In some embodiments, R 2 In some embodiments, R 1 and R 2 In some embodiments, at least one of R 1 and R 2 In some embodiments, R 1 and R 2 In some embodiments, no more than one of R 1 and R 2 There is one of [ka] or halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1 and R 2 There is one of [ka] It is.

[0152] In some embodiments, [ka] is not present. In some embodiments, one substructure A group is present. In some embodiments, no more than one substructure A is present. In some embodiments, two substructure A groups are present (e.g., two substructure A groups having the same or different structures). In some embodiments, three or more substructure A groups are present (e.g., three or more substructure A groups having the same or different structures). In some embodiments, no more than one substructure A group is present.

[0153] In embodiments, C is a 5- or 6-membered N-containing heteroaryl. In embodiments, C is pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0154] In embodiments, A is pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0155] In embodiments, B is pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0156] In some embodiments, each of A and B is pyrazolyl.In some embodiments, A is pyridyl or pyrimidyl.

[0157] In embodiments, the compound of formula (I) has the structure according to formula (IA): [ka] or a pharma- ceutically acceptable salt thereof, wherein X 1 is N or CR 5 It is.

[0158] In some embodiments, B, R 1 , R 2 , R 3 , L 1 , X 2 , X 3 , X 4 , m, o, and p are according to any embodiment described herein.

[0159] In some embodiments, C is pyrazolyl.

[0160] In embodiments, the compound of formula (I) has the structure according to formula (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

[0161] In some embodiments, B, R 1 , R 2 , R 3 , L 1 , X 2 , X 3 , X 4 , o, and p are according to any embodiment described herein.

[0162] In some embodiments, C is thiazolyl.

[0163] In embodiments, the compound of formula (I) has the structure according to formula (IC): [ka] or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

[0164] In some embodiments, B, R 1 , R 2 , R 3 , L 1 , X 2 , X 3 , X 4 , o, and p are according to any embodiment described herein.

[0165] In embodiments, the compound of formula (I) has the structure according to formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 1 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0166] In some embodiments, A, B, R 1 , R 3 , R 4 , L 1 , X 1 , X 2 , X 3 , X 4 , m, o, and p are according to any embodiment described herein.

[0167] In some embodiments, R 1 are independently OH, CN, halogen, C 1 - 6 aliphatic, C1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0168] In some embodiments, the compound of Formula (I) or Formula (II) has the structure according to formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, A, B, R 1 , R 3 , R 4 , L 1 , X 1 , X 2 , X 3 , X 4 , m, o, and p are according to any embodiment described herein.

[0170] In some embodiments, X 3 is a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR 6 C(O)NR 6 , or (C(R 7 ) 2 ) q In some embodiments, X 3 is O. In some embodiments, X 4 is a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR6 C(O)NR 6 , or (C(R 7 ) 2 ) q In some embodiments, X 4 is O. In some embodiments, X 3 and X 4 are the same. In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 are both O.

[0171] In embodiments, the compound of formula (I) has the structure according to formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Each R 2 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0172] In some embodiments, A, B, R 2 , R 3 , R 4 , L 1 , X 1 , X 2 , X 3 , X 4 , n, o, and p are according to any embodiment described herein.

[0173] In some embodiments, each R 2 are independently OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , or R 12 It is.

[0174] In some embodiments, the compound of Formula (I) or Formula (III) has a structure according to formula (III-A): [ka] or a pharma- ceutically acceptable salt thereof.

[0175] In some embodiments, A, B, R 2 , R 3 , R 4 , L 1 , X 1 , X 2 , X 3 , X 4 , n, o, and p are according to any embodiment described herein.

[0176] In some embodiments, X 3 is a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR 6 C(O)NR 6 , or (C(R 7 ) 2 ) qIn some embodiments, X 3 is O. In some embodiments, X 4 is a covalent bond, O, S, NR 6 , C(O)NR 6 , N.R. 6 C(O), NR 6 C(O)NR 6 , or (C(R 7 ) 2 ) q In some embodiments, X 4 is O. In some embodiments, X 3 and X 4 are the same. In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 are both O.

[0177] In embodiments, the compound of formula (I) has the structure according to formula (IV): [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 1 is an unsubstituted linear or branched C 2 - 6 is alkylene, B is phenyl or 5-6 membered heteroaryl; R 3 is methyl, halogen, or CN; o is 0 or 1; R 1 and R 2 One of these is present as substructure A.

[0178] In some embodiments, B, R 1 , R 2 , R 3 , L 1 , m, n, and o are according to any embodiment described herein.

[0179] In some embodiments, L 1is an unsubstituted linear or branched C 2 - 6 Alkylene (e.g., -(CH 2 ) 3 - or -CH(CH 3 )CH 2 CH 2 -).

[0180] In some embodiments, B is phenyl. In some embodiments, B is a substituted 5-6 membered heteroaryl (eg, pyrazolyl).

[0181] In some embodiments, R 3 is methyl, halogen, or CN. In some embodiments, R 3 is methyl.

[0182] In some embodiments, o is 0. In some embodiments, o is 1.

[0183] In some embodiments, R 1 and R 2 One of these is present as substructure A.

[0184] In embodiments, the compound of Formula (I) or Formula (IV) has a structure according to Formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein: L 1 is -(CH 2 ) 3 - or -CH(CH 3 )CH 2 CH 2 -It is.

[0185] In some embodiments, R 1 , R 2 , L 1 , m, and n are according to any embodiment described herein.

[0186] In some embodiments, L 1is -(CH 2 ) 3 In some embodiments, L 1 is -CH(CH 3 )CH 2 CH 2 -It is.

[0187] In some embodiments, R 1 and R 2 One of these is present as substructure A.

[0188] In some embodiments, the compound of formula (I) or formula (V) has a structure according to formula (VI-1) or (VI-2): [ka] or a pharma- ceutically acceptable salt thereof.

[0189] In some embodiments, R 4 and p is according to any embodiment described herein.

[0190] In some embodiments, CH 3 Substituted with sp 3 The carbon has the (R)-configuration.

[0191] In some embodiments, CH 3 Substituted with sp 3 The carbon has the (S)-configuration.

[0192] In some embodiments, the compound of Formula (I), Formula (V), or Formula (VI-2) has a structure according to Formula (VI-3) or (VI-4): [ka] or a pharma- ceutically acceptable salt thereof.

[0193] In some embodiments, R 4 and p is according to any embodiment described herein.

[0194] In embodiments, the compound of Formula (I) or Formula (V) has a structure according to formula (VII-1) or (VII-2): [ka] or a pharma- ceutically acceptable salt thereof.

[0195] In some embodiments, R 4 and p is according to any embodiment described herein.

[0196] In some embodiments, CH 3 Substituted with sp 3 The carbon has the (R)-configuration.

[0197] In some embodiments, CH 3 Substituted with sp 3 The carbon has the (S)-configuration.

[0198] In some embodiments, the compound of Formula (I), Formula (V), or Formula (VII-2) has a structure according to Formula (VII-3) or Formula (VII-4): [ka] or a pharma- ceutically acceptable salt thereof.

[0199] In some embodiments, R 4 and p is according to any embodiment described herein.

[0200] In embodiments, the compound of formula (I) has the structure according to formula (VIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, and p is 0 or 1.

[0201] In some embodiments, R4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0202] In embodiments, the compound of formula (VIII) has the structure according to formula (VIII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0203] In some embodiments, the compound of formula (VIII) has the structure according to formula (VIII-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0204] In embodiments, the compound of formula (VIII) has the structure according to formula (VIII-3): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0205] In some embodiments, the compound of formula (VIII) has the structure according to formula (VIII-4): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R4B are independently according to any embodiment described herein.

[0206] In some embodiments, the compound of formula (VIII) has the structure according to formula (VIII-5): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A according to any of the embodiments described herein.

[0207] In some embodiments, the compound of formula (VIII) has the structure according to formula (VIII-6): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A according to any of the embodiments described herein.

[0208] In embodiments, the compound of formula (I) has the structure according to formula (IX): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, and p is 0 or 1.

[0209] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0210] In an embodiment, the compound of formula (IX) has the structure according to formula (IX-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0211] In embodiments, the compound of formula (IX) has the structure according to formula (IX-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0212] In embodiments, the compound of formula (I) has a structure according to formula (X): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, p is 0 or 1, R 4D The third R 4 It is based on

[0213] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4B is independently according to any embodiment described herein. In some embodiments, R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0214] In embodiments, the compound of formula (X) has a structure according to formula (X-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R4A and R 4D are independently according to any embodiment described herein.

[0215] In embodiments, the compound of formula (X) has a structure according to formula (X-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4D are independently according to any embodiment described herein.

[0216] In embodiments, the compound of formula (X) has a structure according to formula (X-3): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4D are independently according to any embodiment described herein.

[0217] In embodiments, the compound of formula (X) has a structure according to formula (X-4): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4D are independently according to any embodiment described herein.

[0218] In embodiments, the compound of formula (I) has a structure according to formula (XI): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4D The second R 4 It is based on

[0219] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4D is independently according to any embodiment described herein. In some embodiments, R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0220] In embodiments, the compound of formula (XI) has the structure according to formula (XI-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4D are independently according to any embodiment described herein.

[0221] In embodiments, the compound of formula (I) has the structure according to formula (XII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A is the first R 4 It is based on

[0222] In some embodiments, R 4A are independently according to any embodiment described herein.

[0223] In embodiments, the compound of formula (XII) has the structure according to formula (XII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0224] In embodiments, the compound of formula (I) has a structure according to formula (XIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, and p is 0 or 1.

[0225] In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0226] In embodiments, the compound of formula (XIII) has the structure according to formula (XIII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0227] In some embodiments, the compound of formula (XIII) has the structure according to formula (XIII-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0228] In some embodiments, the compound of formula (XIII) has the structure according to formula (XIII-3): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0229] In some embodiments, the compound of formula (XIII) has the structure according to formula (XIII-4): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0230] In some embodiments, the compound of formula (XIII) has the structure according to formula (XIII-5): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0231] In embodiments, the compound of formula (I) has the structure according to formula (XIV): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, and p is 0 or 1.

[0232] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0233] In embodiments, the compound of formula (XIV) has the structure according to formula (XIV-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0234] In embodiments, the compound of formula (XIV) has the structure according to formula (XIV-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0235] In embodiments, the compound of formula (XIV) has the structure according to formula (XIV-3): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B are independently according to any embodiment described herein.

[0236] In embodiments, the compound of formula (XIV) has the structure according to formula (XIV-4): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0237] In embodiments, the compound of formula (I) has the structure according to formula (XV): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 R 4C The third R4 It is based on

[0238] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, each R 4A , R 4B , and R 4C are independently according to any embodiment described herein.

[0239] In embodiments, the compound of formula (I) has the structure according to formula (XVI): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4C is the first R 4 It is based on

[0240] In some embodiments, R 4C are independently according to any embodiment described herein.

[0241] In embodiments, the compound of formula (I) has the structure according to formula (XVII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4D is R 4 In some embodiments, R 4D is unsubstituted C 1-6 It is an alkyl.

[0242] In some embodiments, R 4D Any occurrence of is independently according to any embodiment described herein.

[0243] In embodiments, the compound of formula (XVII) has the structure according to formula (XVII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R4D Any occurrence of is independently according to any embodiment described herein.

[0244] In embodiments, the compound of formula (I) has the structure according to formula (XVIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4C is the first R 4 It is based on

[0245] In some embodiments, R 4C Any occurrence of is independently according to any embodiment described herein.

[0246] In embodiments, the compound of formula (I) has the structure according to formula (XIX): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4D is R 4 In some embodiments, R 4D is unsubstituted C 1-6 It is an alkyl.

[0247] In some embodiments, R 4D Any occurrence of is independently according to any embodiment described herein.

[0248] In embodiments, the compound of formula (XIX) has the structure according to formula (XIX-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4D Any occurrence of is independently according to any embodiment described herein.

[0249] In some embodiments, the compound of formula (XIX) has the structure according to formula (XIX-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4D Any occurrence of is independently according to any embodiment described herein.

[0250] In embodiments, the compound of formula (I) has a structure according to formula (XX): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 is a group, R 4B The second R 4 group, and p is 0 or 1.

[0251] In some embodiments, R 4A and R 4B Any occurrence of is independently according to any embodiment described herein.

[0252] In some embodiments, the compound of formula (XX) has a structure according to formula (XX-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A Any occurrence of is independently according to any embodiment described herein.

[0253] In some embodiments, the compound of formula (XX) has a structure according to formula (XX-2): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B Each of is independently according to any embodiment described herein.

[0254] In some embodiments, the compound of formula (XX) has a structure according to formula (XX-3): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0255] In some embodiments, the compound of formula (XX) has a structure according to formula (XX-4): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4B Any occurrence of is independently according to any embodiment described herein.

[0256] In embodiments, the compound of formula (I) has the structure according to formula (XXI): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 is a group, R 4B The second R 4 group, and p is 0 or 1.

[0257] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A and R 4B Any occurrence of is independently according to any embodiment described herein.

[0258] In some embodiments, the compound of formula (XXI) has the structure according to formula (XXI-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0259] In embodiments, the compound of formula (I) has the structure according to formula (XXII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A The first R 4 R 4B The second R 4 group, p is 0 or 1, R 4D is unsubstituted C 1-6 R is alkyl 4 It is based on

[0260] In some embodiments, R 4 Any occurrence of is independently according to any embodiment described herein. In some embodiments, R 4A , R 4B , and R 4D Any occurrence of is independently according to any embodiment described herein.

[0261] In some embodiments, the compound of formula (XXII) has the structure according to formula (XXII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A and R 4D Any occurrence of is independently according to any embodiment described herein.

[0262] In embodiments, the compound of formula (I) has a structure according to formula (XXIII): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 4A is the first R 4 It is based on

[0263] In some embodiments, R 4AAny occurrence of is independently according to any embodiment described herein.

[0264] In some embodiments, the compound of formula (XXIII) has the structure according to formula (XXIII-1): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 4A are independently according to any embodiment described herein.

[0265] Exemplary embodiments of structural features Provided herein are still further exemplary embodiments of structural features that may be present in any formula described herein (e.g., any of formulas (I)-(XXIII) or any other formula described herein). The exemplary embodiments of structural features may occur in combination with any other exemplary structural features described herein.

[0266] In some embodiments, X 1 is N. In some embodiments, X 2 CR 5 (e.g., CH).

[0267] In some embodiments, X 2 is N. In some embodiments, X 2 CR 5 (e.g., CH).

[0268] In some embodiments, X 3 is a covalent bond.

[0269] In some embodiments, X 3 is O.

[0270] In some embodiments, X 3 is S.

[0271] In some embodiments, X 3 is NR 6, C(O)NR 6 , N.R. 6 C(O) or NR 6 C(O)NR 6 In some embodiments, R 6 is H. In some embodiments, R 6 is an N-protecting group (e.g., an amide, carbamate, or sulfonamide group). In some embodiments, R 6 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (eg, containing 1, 2, or 3 substituents).

[0272] In some embodiments, X 3 is (C(R 7 ) 2 ) q In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, R 7 is H. In some embodiments, R 7 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (e.g., contains 1, 2, or 3 substituents). In some embodiments, two R 7 are linked to form an oxo (=O) group. In some embodiments, X 3 is C(O), CH 2 , C.H.H. 3 , or C(CH 3 ) 2 It is.

[0273] In some embodiments, X 4 is a covalent bond.

[0274] In some embodiments, X 4 is O.

[0275] In some embodiments, X4 is S.

[0276] In some embodiments, X 4 is NR 6 , C(O)NR 6 , N.R. 6 C(O) or NR 6 C(O)NR 6 In some embodiments, R 6 is H. In some embodiments, R 6 is an N-protecting group (e.g., an amide, carbamate, or sulfonamide group). In some embodiments, R 6 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (eg, containing 1, 2, or 3 substituents).

[0277] In some embodiments, X 4 is (C(R 7 ) 2 ) q In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, R 7 is H. In some embodiments, R 7 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (e.g., contains 1, 2, or 3 substituents). In some embodiments, two R 7 are linked to form an oxo (=O) group. In some embodiments, X 4 is C(O), CH 2 , C.H.H. 3 , or C(CH 3 ) 2 It is.

[0278] In some embodiments, X 3 is O and X 4 is O.

[0279] In some embodiments, X 2 is CH and X 3 is O and X 4 is O. In some embodiments, X 1 is N.

[0280] In some embodiments, R 6 and R 4 together with the atoms to which they are attached form a 5- or 6-membered ring. In some embodiments, the 5- or 6-membered ring is [ka] wherein the M ring is the newly formed ring. A is a covalent bond. In some embodiments, L A is alkylene (e.g., -CH 2 -). In embodiments, alkylene is unsubstituted. In embodiments, alkylene is substituted (e.g., containing 1 or 2 substituents).

[0281] In some embodiments, R 7 and R 4 together with the atoms to which they are attached form a 5-6 membered ring. In some embodiments, the 5-6 membered ring is [ka] wherein the M ring is the newly formed ring. A is a covalent bond. In some embodiments, L A is an alkylene (e.g., -CH 2 -). In embodiments, alkylene is unsubstituted. In embodiments, alkylene is substituted (e.g., containing 1 or 2 substituents).

[0282] In some embodiments, X 3 and X 4are the same. In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 are both O.

[0283] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1-6 Heteroalkylene (e.g., containing 1, 2, or 3 heteroatoms that are independently oxygen or nitrogen). L1 is a branched C 1-6 In some embodiments, L1 is a linear C 1-6 In some embodiments, L1 is unsubstituted C 1 - 6 In some embodiments, L1 is an unsubstituted branched C 1 - 6 In some embodiments, L1 is an unsubstituted linear C 1 - 6 In some embodiments, L is heteroalkylene. 1 is a substitution C 1 - 6 Heteroalkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, L is an alkyl group, and L includes 1, 2, or 3 substituents such as alkyl. 1 is a substituted branched C 1 - 6 Heteroalkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, L is an alkyl group, and L includes 1, 2, or 3 substituents such as alkyl. 1 is a substituted linear C 1 - 6 Heteroalkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, C1 - 6 Heteroalkylene is -O(CH 2 ) u , (CH 2 ) u O, O(CH 2 ) u O. OCH 2 OCH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 O-, OCH 2 CH 2 OCH 2 -, NH(CH 2 ) u , (CH 2 ) u NH or -NH(CH 2 ) u NH-, where u is an integer from 1 to 4. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4.

[0284] In some embodiments, L 1 is C 1-6 Alkylene (e.g., CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 , (CH 2 ) 5 , or (CH 2 ) 6 In some embodiments, L1 is a branched C 1-6 In some embodiments, L1 is a linear C 1-6 In some embodiments, L1 is unsubstituted C 1 - 6 In some embodiments, L1 is an unsubstituted branched C 1 - 6In some embodiments, L1 is an unsubstituted linear C 1 - 6 In some embodiments, L is alkylene. 1 is a substitution C 1 - 6 Alkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, L is an alkyl group, and L includes 1, 2, or 3 substituents such as alkyl. 1 is a substituted branched C 1 - 6 Alkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, L is an alkyl group, and L includes 1, 2, or 3 substituents such as alkyl. 1 is a substituted linear C 1 - 6 Alkylene (e.g., OH, oxo (=O), or unsubstituted C 1-3 In some embodiments, the alkyl group may include one, two, or three substituents such as alkyl. L1 is unsubstituted C 1 - 6 In some embodiments, L1 is an unsubstituted branched C 2 - 6 In some embodiments, L1 is an unsubstituted linear C 2 - 6 It is alkylene.

[0285] In some embodiments, L 1 is C 2-6 Alkenylene (e.g., C 2 H 4 , C 3 H 6 , C 4 H 8 , C 5 H 10 , or C 6 H 12 In some embodiments, L 1 is unsubstituted C 2-6 In some embodiments, L is alkenylene. 1 is a substitution C 2-6alkenylene (eg, containing 1, 2, or 3 substituents).

[0286] In some embodiments, L 1 is C 2-6 Alkynylene (e.g., C 2 H 2 , C 3 H 4 , C 4 H 6 , C 5 H 8 , or C 6 H 10 In some embodiments, L 1 is unsubstituted C 2-6 In some embodiments, L is alkynylene. 1 is a substitution C 2-6 Alkynylene (eg, containing 1, 2 or 3 substituents).

[0287] In some embodiments, L 1 is C 3-6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene). In some embodiments, L 1 is unsubstituted C 3-6 In some embodiments, L is cycloalkylene. 1 is a substitution C 3-6 and cycloalkylene (eg, containing 1, 2, or 3 substituents).

[0288] In some embodiments, L 1 Base sp 3 The carbon has the (R)-configuration.

[0289] In some embodiments, L 1 Base sp 3 The carbon has the (S)-configuration.

[0290] In some embodiments, L 1 is a 3- to 10-membered heterocyclylene (e.g., a monocyclic or bicyclic heterocyclylene). 1is an unsubstituted 3- to 10-membered heterocyclylene. In some embodiments, L 1 is a substituted 3-10 membered heterocyclylene (eg, containing 1, 2, or 3 substituents).

[0291] In some embodiments, L 1 is phenylene or naphthylene. In some embodiments, L 1 is unsubstituted phenylene or unsubstituted naphthylene. In some embodiments, L 1 is a substituted phenylene or substituted naphthylene (eg, containing 1, 2, or 3 substituents).

[0292] In some embodiments, L 1 is 5- to 10-membered heteroarylene. In some embodiments, L 1 is unsubstituted 5-10 membered heteroarylene. In some embodiments, L 1 is a substituted 5-10 membered heteroarylene (eg, containing 1, 2, or 3 substituents).

[0293] In some embodiments, L 1 is an unsubstituted linear C 4-6 Alkylene or unsubstituted branched C 4-6 It is alkylene.

[0294] In some embodiments, L 1 is -(CH 2 ) 3 In some embodiments, L 1 is -CH(CH 3 )CH 2 CH 2 -It is.

[0295] In some embodiments, L 1 teeth, [ka] It is.

[0296] In some embodiments, L 1 teeth, [ka] where * is X 4 indicates the point of covalent attachment to X 3 The points of covalent attachment to

[0297] In some embodiments, -X 4 -L 1 -X 3 - , -OL 1 -O-.

[0298] In some embodiments, -X 4 -L 1 -X 3 - is -O(CH 2 ) 3 It is O-.

[0299] In some embodiments, -X 4 -L 1 -X 3 - is -OCH(CH 3 )CH 2 CH 2 It is O-.

[0300] In some embodiments, -X 4 -L 1 -X 3 -teeth, [ka] It is.

[0301] In some embodiments, X 4 -L 1 -X 3 forms or contains a urea group (e.g., NHC(O)NH). In some embodiments, X 3 and / or X 4 is NR 6 C(O)NR 6 In some embodiments, X 3 and X 4 One of them is NR 6 C(O)NR 6 It is.

[0302] In some embodiments, X 4 -L 1 -X 3 forms or contains a carboxamide group (e.g., C(O)NH or NH(CO)). In some embodiments, X 3 and / or X 4 is C(O)NR 6 or NR 6 In some embodiments, X is C(O). 3 and X 4 One of them is C(O)NR 6 or NR 6 C(O).

[0303] In some embodiments, X 4 -L 1 -X 3 -CHR 7 -O(C 1-2 (alkylene)-OCHR 7 -or-CHR 7 -O(C 1-2 alkylene)-O-.

[0304] In embodiments, B is phenyl. In embodiments, B is naphthyl. In embodiments, B is 5-13 membered heteroaryl (e.g., monocyclic or bicyclic heteroaryl). In embodiments, B is bicyclic 8-12 membered heteroaryl (e.g., nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, B is monocyclic 5-6 membered heteroaryl. Exemplary monocyclic 5-6 membered heteroaryls include, but are not limited to, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl. In embodiments, B is phenyl or 5-6 membered heteroaryl. In embodiments, B is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl. In embodiments, B is pyrazolyl.

[0305] In embodiments, B is unsubstituted phenyl. In embodiments, B is unsubstituted naphthyl. In embodiments, B is unsubstituted 5-13 membered heteroaryl (e.g., unsubstituted monocyclic or bicyclic heteroaryl). In embodiments, B is unsubstituted bicyclic 8-12 membered heteroaryl (e.g., unsubstituted nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, B is unsubstituted monocyclic 5-6 membered heteroaryl. In embodiments, B is unsubstituted pyridyl, unsubstituted pyrimidyl, unsubstituted pyrazolyl, unsubstituted pyrrolyl, unsubstituted thiazolyl, unsubstituted oxazolyl, or unsubstituted imidazolyl.

[0306] In embodiments, B is a substituted phenyl (e.g., containing one or two substituents as described herein). In embodiments, B is a substituted naphthyl (e.g., containing one or two substituents as described herein). In embodiments, B is a substituted 5-13 membered heteroaryl (e.g., a substituted monocyclic or bicyclic heteroaryl containing one or two substituents as described herein). B is a substituted bicyclic 8-12 membered heteroaryl (e.g., a substituted nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, B is a substituted monocyclic 5-6 membered heteroaryl. In embodiments, B is a substituted pyridyl, substituted pyrimidyl, substituted pyrazolyl, substituted pyrrolyl, substituted thiazolyl, substituted oxazolyl, or substituted imidazolyl. In embodiments, B is a substituted pyrazolyl (e.g., an N-substituted pyrazolyl such as N-methylpyrazolyl). In embodiments, B is one or more R groups as described herein. 3 Substituted with a group (eg, methyl, halogen, or CN).

[0307] In some embodiments, B is [ka] where * indicates the point of covalent attachment to C and ** indicates X 3 The points of covalent attachment to

[0308] In some embodiments, C is a 5- or 6-membered heteroaryl. In some embodiments, C is a 5- or 6-membered N-containing heteroaryl. Exemplary 5- to 6-membered heteroaryls include, but are not limited to, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl. In some embodiments, C is pyridyl or pyrimidyl. In some embodiments, C is pyrazolyl or thiazolyl.

[0309] In some embodiments, C is an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, C is an unsubstituted 5- or 6-membered N-containing heteroaryl. Exemplary unsubstituted 5- or 6-membered heteroaryls include, but are not limited to, unsubstituted pyridyl, unsubstituted pyrimidyl, unsubstituted pyrazolyl, unsubstituted pyrrolyl, unsubstituted thiazolyl, unsubstituted oxazolyl, and unsubstituted imidazolyl. In some embodiments, C is an unsubstituted pyridyl or pyrimidyl. In some embodiments, C is an unsubstituted pyrazolyl or thiazolyl.

[0310] In some embodiments, C is a substituted 5- or 6-membered heteroaryl (e.g., containing one or two substituents as described herein). In some embodiments, C is a substituted 5- or 6-membered N-containing heteroaryl (e.g., containing one or two substituents as described herein). In some embodiments, C is a substituted pyridyl, substituted pyrimidyl, substituted pyrazolyl, substituted pyrrolyl, substituted thiazolyl, substituted oxazolyl, or substituted imidazolyl. In some embodiments, C is a substituted pyridyl (e.g., substituted with moiety A). In some embodiments, C is a substituted pyrimidyl (e.g., substituted with moiety A). In some embodiments, C is a substituted pyrazolyl (e.g., N-substituted pyrazolyl, such as N-methylpyrazolyl). In some embodiments, C is a substituted thiazolyl (e.g., methyl-substituted thiazolyl). In some embodiments, C is one or more R as described herein. 1 It is substituted with a group (eg, moiety A or methyl).

[0311] In some embodiments, A is pyrazolyl, B is pyrazolyl, and C is pyridyl or pyrimidyl. In some embodiments, A and B are substituted.

[0312] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 1 or 2.

[0313] In some embodiments, m is not 0. In some embodiments, R 1 exists.

[0314] In some embodiments, R 1 teeth, [ka] In some embodiments, L 2 are independently a covalent bond, O, or NR L , C(O), C(O)NR L , N.R. L C(O), CR L 2 where R L are independently H or C 1-6 In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 In some embodiments, L is an alkyl group (e.g., containing 1, 2, or 3 substituents). 2 is a covalent bond.

[0315] In some embodiments, each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , or (CH 2 ) r R 12 In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0316] In some embodiments, R 1 is OH. In some embodiments, R 1 is CN. In some embodiments, R 1 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1 is C 1 - 6 In some embodiments, R 1 is unsubstituted C 1 - 6 In some embodiments, R 1 is a substitution C 1 - 6 In some embodiments, R is aliphatic (e.g., containing 1, 2, or 3 substituents). 1 is C 1 - 6 In some embodiments, R 1 is unsubstituted C 1 - 6 In some embodiments, R 1 is a substitution C 1 - 6In some embodiments, R is an alkoxy group (e.g., containing 1, 2, or 3 substituents). 1 is NR 8 R 9 In some embodiments, R 1 is C(O)R 10 In some embodiments, R 1 CO 2 R 10 In some embodiments, R 1 is C(O)NR 8 R 9 In some embodiments, R 1 is NR 11 C(O)R 10 In some embodiments, R 1 is NR 11 CO 2 R 10 In some embodiments, R 1 is NR 11 C(O)NR 8 R 9 In some embodiments, R 1 is (CH 2 ) r R 12 In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, R 1 is a halogen (e.g., F, Cl, Br, or I).

[0317] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 or 2.

[0318] In some embodiments, n is not 0. In some embodiments, R 2 exists.

[0319] In some embodiments, R 2 teeth, [ka] In some embodiments, L 2 are independently a covalent bond, O, or NR L , C(O), C(O)NR L , N.R. L C(O), CR L 2 where R L are independently H or C 1-6 In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 In some embodiments, L is an alkyl group (e.g., containing 1, 2, or 3 substituents). 2 is a covalent bond.

[0320] In some embodiments, each R 4 are independently H, OH, CN, halogen, C 1 - 6 aliphatic, C 1 - 6 Alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , N.R. 11 C(O)R 10 , N.R. 11 CO 2 R 10 , N.R. 11 C(O)NR 8 R 9 , N.R. 11 (CH 2 ) s NR 8 R 9 , (CH 2 ) t NR 8 R 9 , or (CH 2 ) r R 12In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0321] In some embodiments, R 2 is OH. In some embodiments, R 2 is CN. In some embodiments, R 2 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 2 is C 1 - 6 In some embodiments, R 2 is unsubstituted C 1 - 6 In some embodiments, R 2 is a substitution C 1 - 6 In some embodiments, R is aliphatic (e.g., containing 1, 2, or 3 substituents). 2 is C 1 - 6 In some embodiments, R 2 is unsubstituted C 1 - 6 In some embodiments, R 2 is a substitution C 1 - 6 In some embodiments, R is an alkoxy group (e.g., containing 1, 2, or 3 substituents). 2 is NR 8 R 9 In some embodiments, R 2 is C(O)R 10 In some embodiments, R 2 CO 2 R 10 In some embodiments, R 2 is C(O)NR 8 R 9 In some embodiments, R 2 is NR 11 C(O)R 10 In some embodiments, R 2 is NR 11 CO 2 R 10In some embodiments, R 2 is NR 11 C(O)NR 8 R 9 In some embodiments, R 2 is (CH 2 ) r R 12 In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, R 2 is a halogen (e.g., F, Cl, Br, or I).

[0322] In some embodiments, R 1 In some embodiments, R 2 In some embodiments, R 1 and R 2 In some embodiments, R 1 and R 2 There is one of [ka] or halogen (e.g., F, Cl, Br, or I). In some embodiments, R 1 and R 2 There is one of [ka] It is.

[0323] In some embodiments, two R 1 Or two R's 2 together with the atoms to which they are attached form a 5- to 10-membered ring (eg, a 5- to 10-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring).

[0324] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 1 or 2. In some embodiments, o is 0 or 1.

[0325] In some embodiments, o is not 0. In some embodiments, R 3 exists.

[0326] In some embodiments, R 3 is OH. In some embodiments, R 3 is CN. In some embodiments, R 3 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 3 is C 1 - 6 In some embodiments, R 3 is unsubstituted C 1 - 6 In some embodiments, R 3 is a substitution C 1 - 6 In some embodiments, R is aliphatic (e.g., containing 1, 2, or 3 substituents). 3 is C 1 - 6 In some embodiments, R 3 is unsubstituted C 1 - 6 In some embodiments, R 3 is a substitution C 1 - 6 In some embodiments, R is an alkoxy group (e.g., containing 1, 2, or 3 substituents). 3 is NR 8 R 9 In some embodiments, R 3 is C(O)R 10 In some embodiments, R 3 CO 2 R 10 In some embodiments, R 3 is C(O)NR 8 R 9In some embodiments, R 3 is NR 11 C(O)R 10 In some embodiments, R 3 is NR 11 CO 2 R 10 In some embodiments, R 3 is NR 11 C(O)NR 8 R 9 In some embodiments, R 3 is (CH 2 ) r R 12 In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, R 3 is methyl, halogen, or CN. In some embodiments, R 3 is methyl.

[0327] In some embodiments, R 5 is H.

[0328] In some embodiments, R 5 is OH. In some embodiments, R 5 is CN. In some embodiments, R 5 is halogen (e.g., F, Cl, Br, or I). In some embodiments, R 5 is C 1 - 6 In some embodiments, R 5 is unsubstituted C 1 - 6 In some embodiments, R 5 is a substitution C 1 - 6 In some embodiments, R is aliphatic (e.g., containing 1, 2, or 3 substituents). 5 is C 1 - 6 In some embodiments, R 5is unsubstituted C 1 - 6 In some embodiments, R 5 is a substitution C 1 - 6 In some embodiments, R is an alkoxy group (e.g., containing 1, 2, or 3 substituents). 5 is NR 8 R 9 In some embodiments, R 5 is C(O)R 10 In some embodiments, R 5 CO 2 R 10 In some embodiments, R 5 is C(O)NR 8 R 9 In some embodiments, R 5 is NR 11 C(O)R 10 In some embodiments, R 5 is NR 11 CO 2 R 10 In some embodiments, R 5 is NR 11 C(O)NR 8 R 9 In some embodiments, R 5 is (CH 2 ) r R 12 In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1.

[0329] In some embodiments, R 8 is H. In some embodiments, R 8 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (eg, containing 1, 2, or 3 substituents).

[0330] In some embodiments, R 9 is H. In some embodiments, R 9 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (eg, containing 1, 2, or 3 substituents).

[0331] In some embodiments, R 11 is H. In some embodiments, R 11 is C 1-6 In some embodiments, C 1-6 Alkyl is unsubstituted. In some embodiments, C 1-6 The alkyl is substituted (eg, containing 1, 2, or 3 substituents).

[0332] In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl. In several embodiments, the 3- to 10-membered heterocyclyl is unsubstituted. In several embodiments, the 3- to 10-membered heterocyclyl is unsubstituted (e.g., containing 1, 2, or 3 substituents).

[0333] In some embodiments, R 8 and R 11 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl. In several embodiments, the 3- to 10-membered heterocyclyl is unsubstituted. In several embodiments, the 3- to 10-membered heterocyclyl is unsubstituted (e.g., containing 1, 2, or 3 substituents).

[0334] In some embodiments, R 10 is C 1-6 In some embodiments, R 10 is C 3 -C 10 In some embodiments, R is alicyclic (e.g., monocyclic or bicyclic alicyclic). 10is 3-10 membered heterocyclyl (e.g., monocyclic or bicyclic heterocyclyl). In some embodiments, R 10 is phenyl. In some embodiments, R 10 is naphthyl. In some embodiments, R 10 is a 5-12 membered heteroaryl (eg, monocyclic or bicyclic heteroaryl).

[0335] In some embodiments, R 10 is unsubstituted C 1-6 In some embodiments, R 10 is unsubstituted C 3 -C 10 In some embodiments, R 10 is unsubstituted 3-10 membered heterocyclyl. In some embodiments, R 10 is unsubstituted phenyl. In some embodiments, R 10 is unsubstituted naphthyl. In some embodiments, R 10 is an unsubstituted 5-12 membered heteroaryl.

[0336] In some embodiments, R 10 is a substitution C 1-6 In some embodiments, R 10 is a substitution C 3 -C 10 In some embodiments, R 10 is a substituted 3- to 10-membered heterocyclyl. In some embodiments, R 10 is substituted phenyl. In some embodiments, R 10 is substituted naphthyl. In some embodiments, R 10 is a substituted 5-12 membered heteroaryl. In embodiments, the substituents include 1, 2, or 3 substituents described herein.

[0337] In some embodiments, R 10 and R 11together with the atom to which they are attached form a 3- to 10-membered heterocyclyl. In several embodiments, the 3- to 10-membered heterocyclyl is unsubstituted. In several embodiments, the 3- to 10-membered heterocyclyl is substituted (e.g., containing 1, 2, or 3 substituents).

[0338] In some embodiments, R 12 is C 3 -C 10 In some embodiments, R is alicyclic (e.g., monocyclic or bicyclic alicyclic). 12 is 3-10 membered heterocyclyl (e.g., monocyclic or bicyclic heterocyclyl). In some embodiments, R 12 is phenyl. In some embodiments, R 12 is naphthyl. In some embodiments, R 12 is a 5-12 membered heteroaryl (eg, monocyclic or bicyclic heteroaryl).

[0339] In some embodiments, R 12 is unsubstituted C 3 -C 10 In some embodiments, R 12 is unsubstituted 3-10 membered heterocyclyl. In some embodiments, R 12 is unsubstituted phenyl. In some embodiments, R 12 is unsubstituted naphthyl. In some embodiments, R 12 is an unsubstituted 5-12 membered heteroaryl.

[0340] In some embodiments, R 12 is a substitution C 3 -C 10 In some embodiments, R 12 is a substituted 3- to 10-membered heterocyclyl. In some embodiments, R 12 is substituted phenyl. In some embodiments, R 12 is substituted naphthyl. In some embodiments, R 12is a substituted 5-12 membered heteroaryl. In embodiments, the substituents include 1, 2, or 3 substituents described herein. Partial structure A

[0341] Still further exemplary substructure A groups are described herein, i.e., embodiments of compounds of formula (I) (e.g., any compound according to formulas (I)-(XXIII) and subformulas thereof) can feature any substructure A group described herein.

[0342] In some embodiments, [ka] is not present. In some embodiments, one substructure A group is present. In some embodiments, two substructure A groups are present (e.g., two substructure A groups having the same or different structures). In some embodiments, three or more substructure A groups are present (e.g., three or more substructure A groups having the same or different structures). In some embodiments, no more than one substructure A group is present.

[0343] In some embodiments, L 2 is a covalent bond. In some embodiments, moiety A is [ka] It has the structure:

[0344] In some embodiments, L 2 is O. In some embodiments, moiety A is [ka] It has the structure:

[0345] In some embodiments, L 2 is NR L In some embodiments, R L is H. In some embodiments, R L is C 1-6In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 alkyl (e.g., containing 1, 2, or 3 substituents). In some embodiments, moiety A is [ka] It has the structure:

[0346] In some embodiments, L 2 is C(O). In some embodiments, moiety A is [ka] It has the structure:

[0347] In some embodiments, L 2 is C(O)NR L In some embodiments, R L is H. In some embodiments, R L is C 1-6 In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 alkyl (e.g., containing 1, 2, or 3 substituents). In some embodiments, moiety A is [ka] It has the structure:

[0348] In some embodiments, L 2 is NR L C(O). In some embodiments, R L is H. In some embodiments, R L is C 1-6In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 alkyl (e.g., containing 1, 2, or 3 substituents). In some embodiments, moiety A is [ka] It has the structure:

[0349] In some embodiments, L 2 CR L 2 In some embodiments, R L is H. In some embodiments, R L is C 1-6 In some embodiments, R L is unsubstituted C 1 - 6 In some embodiments, R L is a substitution C 1 - 6 alkyl (e.g., containing 1, 2, or 3 substituents). In some embodiments, moiety A is [ka] It has the structure:

[0350] In embodiments, A is phenyl. In embodiments, A is naphthyl. In embodiments, A is 5-13 membered heteroaryl (e.g., monocyclic or bicyclic heteroaryl). In embodiments, A is bicyclic 8-12 membered heteroaryl (e.g., nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, A is monocyclic 5-6 membered heteroaryl. Exemplary monocyclic 5-6 membered heteroaryls include, but are not limited to, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, and imidazolyl. In embodiments, A is phenyl or 5-6 membered heteroaryl. In embodiments, A is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

[0351] In embodiments, A is unsubstituted phenyl. In embodiments, A is unsubstituted naphthyl. In embodiments, A is unsubstituted 5-13 membered heteroaryl (e.g., unsubstituted monocyclic or bicyclic heteroaryl). In embodiments, A is unsubstituted bicyclic 8-12 membered heteroaryl (e.g., unsubstituted nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, A is unsubstituted monocyclic 5-6 membered heteroaryl. In embodiments, A is unsubstituted pyridyl, unsubstituted pyrimidyl, unsubstituted pyrazolyl, unsubstituted pyrrolyl, unsubstituted thiazolyl, unsubstituted oxazolyl, or unsubstituted imidazolyl.

[0352] In embodiments, A is a substituted phenyl (e.g., containing one or two substituents as described herein). In embodiments, A is a substituted naphthyl (e.g., containing one or two substituents as described herein). In embodiments, A is a substituted 5-13 membered heteroaryl (e.g., a substituted monocyclic or bicyclic heteroaryl containing one or two substituents as described herein). A is a substituted bicyclic 8-12 membered heteroaryl (e.g., a substituted nitrogen-containing bicyclic 8-12 membered heteroaryl). In embodiments, A is a substituted monocyclic 5-6 membered heteroaryl. In embodiments, A is a substituted pyridyl, substituted pyrimidyl, substituted pyrazolyl, substituted pyrrolyl, substituted thiazolyl, substituted oxazolyl, or substituted imidazolyl.

[0353] In several embodiments, A is substituted pyrazolyl.

[0354] In several embodiments, A is substituted pyridyl.

[0355] In several embodiments, A is substituted pyrimidylyl.

[0356] In several embodiments, A is substituted pyrrolyl.

[0357] In several embodiments, A is substituted thiazolyl.

[0358] In several embodiments, A is substituted oxazolyl.

[0359] In embodiments, A is substituted imidazolyl.

[0360] In some embodiments, A is one or more of R 4 In some embodiments, A is substituted with one to three R groups as described herein. 4 is substituted with a group.

[0361] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 1 or 2.

[0362] In some embodiments, p is not 0. In some embodiments, R 4 exists.

[0363] In some embodiments, R 4 is H. In some embodiments, R 4 is present and is a non-hydrogen moiety, R 4 represents a substituent. Thus, for any value of p described herein, it is also understood that hydrogen is present as necessary to satisfy the valence requirements at the constituent atoms of A such that the molecule is a stable compound (e.g., the molecule is a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). A, R 4 Exemplary embodiments of p are described herein.

[0364] In some embodiments, R 4 is OH. In some embodiments, R 4 is CN. In some embodiments, R 4 is a halogen (e.g., F, Cl, Br, or I).

[0365] In some embodiments, R 4 is C 1 - 6 Aliphatic (e.g., C 1 - 6 In some embodiments, R 4 is unsubstituted C 1 - 6 Aliphatic (e.g., unsubstituted C 1 - 6 In some embodiments, R 4 is replaced C 1 - 6 It is aliphatic (eg, containing 1, 2, or 3 substituents).

[0366] In some embodiments, R 4 is C 1 - 6 In some embodiments, R 4 is unsubstituted C 1 - 6 Alkoxy (e.g., O-(unsubstituted C 1-6 In some embodiments, R 4 is a substitution C 1 - 6 Alkoxy (eg, containing 1, 2, or 3 substituents, or O-(C1-6 haloalkyl)).

[0367] In some embodiments, R 4 is NR 8 R 9 It is.

[0368] In some embodiments, R 4 is C(O)R 10 It is.

[0369] In some embodiments, R 4 CO 2 R 10 (e.g., CO 2 (Unsubstituted C 1-6 alkyl).

[0370] In some embodiments, R 4 is C(O)NR 8 R 9 It is.

[0371] In some embodiments, R 4 is NR 11 C(O)R 10 It is.

[0372] In some embodiments, R 4 is NR 11 CO 2 R 10 It is.

[0373] In some embodiments, R 4 is NR 11C(O)NR 8 R 9 It is.

[0374] In some embodiments, R 4 is NR 11 (CH 2 ) s NR 8 R 9 (For example, NH(CH 2 ) s NMe 2 ). In some embodiments, s is an integer from 2 to 6. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, s is an integer from 2 to 4.

[0375] In some embodiments, R 4 is (CH 2 ) t NR 8 R 9 (For example, (CH 2 ) t NMe 2 ). In some embodiments, t is an integer from 1 to 6. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. In some embodiments, t is 6.

[0376] In some embodiments, R 4 is (CH 2 ) r R 12 In some embodiments, r is an integer from 0 to 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1.

[0377] In some embodiments, R 4 and R6 , or R 4 and R 7 together with the atoms to which they are attached form a 5- or 6-membered ring.

[0378] In some embodiments, R 4 teeth, [ka] where: X 5 are independently CH or N; X 6 are independent, O, CHR 13 , or NR 13 and R 13 are independent of each other, H, C 1-6 Alkyl or C 3-6 is cycloalkyl, r is 0 or 1;

[0379] In some embodiments, X 5 is CH. In some embodiments, X 5 is N,

[0380] In some embodiments, X 6 is O. In some embodiments, X 6 is CHR 13 In some embodiments, X 6 is NR 13 (e.g., NMe or N(cyclopropyl)).

[0381] In some embodiments, R 13 is H. In some embodiments, R 13 is C 1-6 Alkyl (e.g., Me). In some embodiments, R 13 is C 3-6 It is cycloalkyl (eg, cyclopropyl).

[0382] In some embodiments, r is 0. In some embodiments, r is 1.

[0383] In some embodiments, the compounds described herein include one R 4 In some embodiments, the compounds described herein include a plurality of R 4 In some embodiments, the compounds described herein include two R 4 In some embodiments, the compounds described herein include three R 4 In some embodiments, the compounds described herein include four R 4 R 4 The groups are independently selected and include any combination of any of the exemplary embodiments described herein.

[0384] In some embodiments, R 4 is selected from the group consisting of: 2 CH 3 , OCH 2 CF 3 , C.H. 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , N.H.C.H. 2 CH 2 N(CH 3 ) 2 , C.H. 2 N(CH 3 ) 2 , [ka]

[0385] In some embodiments, R 4 is selected from: -C≡N, -C≡CH, saturated linear or branched C 1-6 Aliphatic or C 1 - 6 Alkoxy, NR 11 (CH 2 ) s NR 8 R 9 ;(CH 2 )t NR 8 R 9 ;O(CH 2 ) t OCH 3 ;O(CH 2 ) r R 12 , and (CH 2 ) r R 12 In some embodiments, R 12 is C 3-6 cycloalkyl, 3-9 membered heterocyclyl containing 1-3 heteroatoms selected from O, N, and S, and 5-6 membered heteroaryl. 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino. 12 is 0 to 4 R 14 wherein each R 14 are independently -CN, oxo (=O), halogen, -OH, -NH 2 , monoalkylamino, dialkylamino, unsubstituted C 3-6 In some embodiments, each R 14 are independently -CN, -F, OH, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , N.H.C.H. 2 CH 3 , N(CH 2 CH 3 ) 2 , C.H. 3 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 3 , C.H. 2 CH 2 F, C.H. 2 CHF 2 , C.H. 2 CF 3 , -CH 2 CH2 CH 3 , C.H. 2 CH 2 CH 2 F, C.H. 2 CH 2 CHF 2 , C.H. 2 CH 2 CF 3 , C.H. 2 CH 2 OCH 3 , COCH 3 , COCH 2 CH 3 , C.H. 2 COCH 3 , C.H. 2 COCH 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl.

[0386] In some embodiments, one or more R 4 The groups are independently selected from the permissible R 4 is selected from a first group of the moiety, the group being: CN, CH 3 , C.H. 2 F, CHF 2 , CF 3 , C.H. 2 CH 3 , C.H. 2 CFH 2 , C.H. 2 CHF 2 , C.H. 2 CF 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , -C≡CH, [ka] [ka] It is.

[0387] In some embodiments, one or more R 4 The groups are independently selected from the permissible R 4a second group of the moiety, said group being selected from 2 OCH 3 , O.C.H. 3 , O.C.H. 2 F, O.C.H.F. 2 , OCF 3 , O.C.H. 2 CH 3 , O.C.H. 2 CH 2 F, O.C.H. 2 CHF 2 , O.C.H. 2 CF 3 , O.C.H. 2 CH 2 CH 3 , O.C.H. 2 CH(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , [ka] -CO 2 CH 3 , and C.H. 3 It is.

[0388] In some embodiments, the compound comprises: (1) an acceptable R 4 one or more R independently selected from the first group of the moiety 4 groups, and (2) any of the permitted R 4 one or more R independently selected from the second group of the moiety 4 Contains a group.

[0389] In some embodiments, R 4 is R as described herein. 4A In some embodiments, R 4A is R as described herein. 4 In some embodiments, R 4A is an acceptable R 4 is selected from the first group of the moiety.

[0390] In some embodiments, R 4 is R as described herein. 4B In some embodiments, R 4B is R as described herein. 4 In some embodiments, R 4B is an acceptable R 4 is selected from the first group of the moiety.

[0391] In some embodiments, R 4 is R as described herein. 4C In some embodiments, R 4C is R as described herein. 4 In some embodiments, R 4C is an acceptable R 4 is selected from the first group of the moiety.

[0392] In some embodiments, R 4 is R as described herein. 4D In some embodiments, R 4D is R as described herein. 4 In some embodiments, R 4D is C 1-6 In some embodiments, R 4D is unsubstituted C 1-6 It is an alkyl.

[0393] In some embodiments, each R 4A , R 4B , and R 4C When present, each independently represents -C≡N, -C≡CH, a saturated linear or branched C 1-6 Aliphatic or C 1 - 6 Alkoxy, NR 11 (CH 2 ) s NR 8 R 9 ;(CH 2 ) t NR 8 R9 ;O(CH 2 ) t OCH 3 ;O(CH 2 ) r R 12 , and (CH 2 ) r R 12 is selected from.

[0394] In some embodiments, R 4A and / or R 4C The groups, when present, are CN, CH 3 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 3 , C.H. 2 CFH 2 , C.H. 2 CHF 2 , C.H. 2 CF 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , -C≡CH, [ka] [ka] is selected from.

[0395] In some embodiments, R 4B The group, if present, is CH 2 OCH 3 , O.C.H. 3 , O.C.H. 2 F, O.C.H.F. 2 , OCF 3 , O.C.H. 2 CH 3 , O.C.H. 2 CH 2 F, O.C.H. 2 CHF 2 , O.C.H. 2 CF 3 , O.C.H. 2 CH 2 CH3 , O.C.H. 2 CH(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , [ka] -CO 2 CH 3 , and C.H. 3 is selected from.

[0396] In some embodiments, [ka] teeth, [ka] R 4 In some embodiments, [ka] teeth, [ka] R 4 , and the second R 4 In some embodiments, the second R 4 The group is an unsubstituted C 1-6 Alkyl (e.g., -CH 3 or -CH 2 CH 3 ), CO 2 (Unsubstituted C 1-6 alkyl) (e.g., -CO 2 CH 3 ), O-(unsubstituted C 1-6 alkyl) (e.g., -OCH 3 or -OCH 2 CH 3 ), O-(C 1-6 haloalkyl) (e.g., -OCH 2 CF 3 ), NH(CH 2 ) s NMe2 (For example, -NHCH 2 CH 2 N(CH 3 ) 2 ), and (CH 2 ) t NMe 2 (For example, -CH 2 N(CH 3 ) 2 ).

[0397] In some embodiments, [ka] teeth, [ka] where: A is phenyl or 5-6 membered heteroaryl. X 5 are independently CH or N; X 6 are independent, O, CHR 13 , or NR 13 and R 13 are independently H, unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 is cycloalkyl, r is 0 or 1; R 4 is unsubstituted C 1-6 Alkyl, CO 2 (Unsubstituted C 1-6 alkyl), O-(unsubstituted C 1-6 alkyl), O-(C 1-6 haloalkyl), or NH(CH 2 ) s NMe 2 is selected from p is 0 or 1; s is an integer from 2 to 6.

[0398] In some embodiments, [ka] teeth, [ka] Wherein X 6 ,O,NCH 3 or N(cyclopropyl).

[0399] In some embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0400] In several embodiments, the partial structure A is selected from the group consisting of (a1) to (a20).

[0401] In several embodiments, the partial structure A is selected from the group consisting of (a20) to (a23).

[0402] In some embodiments, [ka] teeth, [ka] [ka] is selected from the group consisting of:

[0403] In some embodiments, [ka] teeth [ka] and p is 1. In some embodiments, moiety A is [ka] is selected from the group consisting of:

[0404] Exemplary Compounds Exemplary compounds (e.g., according to Formulas (I)-(XXIII) or any other formula described herein) include any one of the following compounds in Table A. Thus, exemplary compounds include any of compounds (1)-(169), or a pharma-ceutically acceptable salt thereof. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8] [Table A-9] [Table A-10] [Table A-11] [Table A-12] [Table A-13]

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

Table A-22

Table A-23

Table A-24

Table A-25

Table A-26

Table A-27

Table A-28

Table A-29

[0405] In embodiments, the compounds described herein can be potent and reversible inhibitors of kinases such as EGFR. Thus, in embodiments, the compounds described herein (e.g., any compound of formula (I)-(XXIII), including those exemplified by any of compounds (1)-(169)) do not contain a functional group selected from acrylamide, vinyl sulfonate, quinone, alkynylamide, propargylic acid derivative, α-haloketone, thiocyanate, nitrile, epoxide, sulfonyl fluoride, and cyclic 1,3-diketone as a group that tolerates any variation within its structure.

[0406] Deuterated Compounds The compounds described herein may contain atoms exhibiting their natural isotopic abundance, or may contain one or more of those atoms having the same atomic number, but which may be artificially enriched in a particular isotope having an atomic mass or mass number different from that found predominantly in nature. The term "isotopologue" refers to a species having the same chemical structure and formula as a particular compound provided herein, except for the position of isotopic substitution and / or level of isotopic enrichment at one or more positions, e.g., hydrogen versus deuterium. The present invention is intended to include all suitable isotopic variations of the compounds of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), as well as compositions enriched for isotopologues of any of the compounds described herein.

[0407] In some embodiments, one or more of the hydrogens of the compounds described herein are replaced by deuterium. When a position is designated as "H" or "hydrogen", the position is understood to have hydrogen in its natural abundance isotopic composition. 2When a position is designated "H" or "deuterium," it is understood that the position has deuterium in an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., 2 (The term "H" or "deuterium" refers to an incorporation of at least 50.1% deuterium.) Accordingly, the invention also features compositions enriched in deuterated compounds.

[0408] In embodiments, compositions of any of the compounds provided herein may have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium present at a site designated as a potential deuteration site on the compound.

[0409] Synthesis method The compounds described herein can be prepared according to methods known in the art. For example, the exemplary synthetic methods described in the Examples can be used to prepare further compounds of the invention.

[0410] Thus, the disclosed compounds can generally be synthesized by an appropriate combination of commonly known synthetic methods. Techniques useful for synthesizing these chemical entities are readily apparent to, and available to, those skilled in the art based on the present disclosure. Many of the starting compounds and other reactants that are optionally substituted are commercially available, for example, from Aldrich Chemical Company (Milwaukee, Wis.), or can be readily prepared by those skilled in the art using commonly used synthetic methodologies.

[0411] Exemplary synthetic schemes for preparing certain compounds according to the invention are provided in Schemes 1-3. [ka] [ka] [ka] [ka]

[0412] Table A herein summarizes the MS characterization of exemplary compounds of formula (I).

[0413] Pharmaceutical Compositions In another exemplary aspect, the invention features a pharmaceutical composition including any compound herein, or a pharma- ceutically acceptable form thereof (e.g., any compound of Formulas (I)-(XXIII), such as any of Compounds (1)-(169), or a pharma- ceutically acceptable salt thereof).

[0414] In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of any compound described herein, or any pharma- ceutically acceptable form thereof.

[0415] In embodiments, pharma- ceutically acceptable forms of a compound include any pharma- ceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof.

[0416] In embodiments, the pharmaceutical composition comprises any of the compounds described herein, or a pharma- ceutically acceptable salt thereof.

[0417] In embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable excipient.

[0418] For purposes of the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the description of the invention, and these terms are defined herein as "ingredients used in the practice of formulating safe and effective pharmaceutical compositions."

[0419] Formulators will understand that excipients are primarily used to aid in the delivery of safe, stable, and functional pharmaceuticals, serving not only as part of the overall vehicle for delivery, but also as a means to achieve effective absorption of the active ingredient by the recipient.Excipients may play a simple and straightforward role, similar to inert fillers, or the excipients used herein may be part of a pH stabilizing system or coating to ensure that the ingredient is delivered safely to the stomach.Formulators can also take advantage of the fact that the compounds of the present invention have improved cellular efficacy, pharmacokinetic properties, as well as improved oral bioavailability.

[0420] Thus, in some embodiments, provided herein are pharmaceutical compositions comprising one or more compounds disclosed herein, or pharma- ceutically acceptable forms thereof (e.g., pharma- ceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives), and one or more pharma- ceutical acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. In some embodiments, the pharmaceutical compositions described herein comprise a second active agent, such as an additional therapeutic agent (e.g., a chemotherapeutic agent).

[0421] Thus, the present teachings also provide pharmaceutical compositions comprising at least one compound described herein, or any pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared according to accepted pharmaceutical procedures, such as those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharma- ceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely interact with the active ingredient. Thus, a pharma- ceutical acceptable carrier is one that is compatible with other ingredients in the composition and is biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical composition.

[0422] The compounds of the present teachings can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Suitable solid carriers can include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents, or encapsulating materials. The compounds can be formulated in a conventional manner, for example, in a manner similar to that used for known 5-hydroxytryptamine receptor 7 activity modulators. Pharmaceutical compositions in the form of oral preparations containing the compounds disclosed herein can include any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges, and oral liquids, suspensions, or solutions. In powders, the carrier can be a finely divided solid, which is a mixture with the finely divided compound. In tablets, the compounds disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets can contain up to 99% of the compound.

[0423] Capsules can contain a mixture of one or more compounds disclosed herein with pharma- ceutically acceptable inert fillers and / or diluents, such as starch (e.g., corn, potato, or tapioca starch), sugar, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flour, gelatin, gums, and the like.

[0424] Useful tablet formulations can be made by conventional compression, wet granulation, or dry granulation techniques and utilize pharma- ceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents, or stabilizers, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, gum acacia, xanthan gum, sodium citrate, silicic acid complexes, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphate salts, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations described herein can utilize standard retard or sustained release formulations to alter the absorption of the compound. Oral formulations can also consist of administering the compound disclosed herein with water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[0425] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhalation delivery. The compounds of the present teachings can be dissolved or suspended in pharma- ceutically acceptable liquid carriers, such as water, organic solvents, or mixtures thereof, or pharma- ceutically acceptable oils or fats. Liquid carriers can include other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colors, viscosity regulators, stabilizers, and osmolality regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (including, among others, additives described herein, e.g., cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols), and derivatives thereof, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharma- ceutically acceptable propellant.

[0426] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0427] In some embodiments, the pharmaceutical composition is in unit dosage form, for example, as a tablet, capsule, powder, solution, suspension, emulsion, granule, or suppository. In such form, the pharmaceutical composition can be subdivided into unit doses containing an appropriate amount of the compound. The unit dosage form can be, for example, a packaged composition, such as a packeted powder, a vial, an ampoule, a pre-filled syringe, or a sachet containing a liquid. Alternatively, the unit dosage form can be a capsule or tablet itself, or an appropriate number of any such composition in packaged form. Such unit dosage forms can contain from about 1 mg / kg of the compound to about 500 mg / kg of the compound, and can be administered in a single dose or in two or more doses. Such doses can be administered in any manner useful for directing the compound into the bloodstream of the recipient, for example, orally, via an implant, parenterally (including intravenous, intraperitoneal, and subcutaneous injection), rectally, vaginally, and transdermally.

[0428] When administered to treat or suppress a particular disease state or disorder, it is understood that the effective dosage may vary depending on the particular compound utilized, the mode of administration, and the severity of the condition being treated, as well as various physical factors associated with the individual being treated. In therapeutic applications, the compounds of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage used to treat a particular individual must typically be subjectively determined by the attending physician. The variables involved include the particular condition and its condition, as well as the size, age, and response pattern of the patient.

[0429] In some cases, it may be desirable to administer the compound directly to the patient's airways using devices such as, but not limited to, metered dose inhalers, breath-actuated inhalers, multi-dose dry powder inhalers, pumps, squeeze-activated atomizing spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into liquid, solid, or aerosol compositions. Liquid compositions can, for example, contain one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharma- ceutically acceptable solvents, and can be administered, for example, by a pump or squeeze-activated atomizing spray dispenser. The solvent can be, for example, isotonic saline or bacteriostatic water. Solid compositions can, for example, be powder preparations containing one or more compounds of the present teachings mixed with lactose or other inert powders acceptable for intrabronchial use, and can be administered, for example, by an aerosol dispenser or device that breaks or punctures the capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of example, one or more compounds of the present teachings, a propellant, a surfactant, and a cosolvent, and can be administered, for example, by a metered dose device. The propellant can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellant that is physiologically and environmentally acceptable.

[0430] The compounds described herein can be administered parenterally or intraperitoneally.The solutions or suspensions of these compounds or their pharma-ceutically acceptable salts, hydrates, or esters can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.Under normal storage and use conditions, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[0431] Pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions, and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form may be sterile, and its viscosity allows the form to flow through a syringe. The form is preferably stable under the conditions of manufacture and storage, and can be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0432] The compounds described herein can be administered transdermally, i.e., across the surface of the body and the inner walls of bodily passages, including epithelial and mucosal tissues. Such administration can be carried out using a compound of the present teachings (including pharma- ceutically acceptable salts, hydrates, or esters thereof) in the form of lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal suppositories).

[0433] Transdermal administration can be achieved by using a transdermal patch containing a compound such as the compounds disclosed herein, and the carrier can be inert to the compound, can be non-toxic to the skin, and can allow the compound to be delivered for systemic absorption through the skin into the bloodstream. The carrier can take any number of forms, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the bloodstream, such as a semipermeable membrane covering a reservoir containing the compound, with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0434] The compound described herein can be administered rectally or vaginally in the form of conventional suppository.Suppository preparation can be made from traditional materials including cocoa butter (with or without the addition of wax to change the melting point of suppository) and glycerin.Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used.

[0435] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0436] In order to enhance the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with other drugs that are effective in treating the target disease. For example, other active compounds (i.e., other active ingredients or drugs) that are effective in treating the target disease can be administered together with the compounds of the present teachings. The other drugs can be administered at the same time or at different times as the compounds disclosed herein.

[0437] kit In some embodiments, kits are provided herein. The kits can include the compounds described herein or a pharma- ceutically acceptable form thereof, or pharmaceutical compositions, in suitable packaging, and written materials, which may include instructions for use, discussion of clinical studies, lists of side effects, and the like. The kits are well suited for delivery of solid oral dosage forms, such as tablets or capsules. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries thereof, showing or establishing the activity and / or benefits of the pharmaceutical compositions, and / or describing dosing, administration, side effects, drug interactions, or other information useful to health care providers. Such information can be based on the results of various studies, for example, studies using laboratory animals involving in vivo models, and studies based on human clinical trials.

[0438] Treatment method Compounds of the present teachings (e.g., any compound of Formulas (I)-(XXIII), such as any of Compounds (1)-(169), or a pharma- ceutically acceptable salt thereof) can be useful for treating or inhibiting a pathological condition or disorder in a mammal, e.g., a human subject. Thus, the present teachings provide a method of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings (including a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition comprising one or more compounds of the present teachings in combination or with a pharma- ceutically acceptable carrier. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for treating or inhibiting a pathological condition or disorder.

[0439] Thus, the compounds described herein may be particularly useful in the treatment of diseases or disorders associated with defects in various components of signal transduction pathways and which respond to the modulation (eg, inhibition) of protein kinases. In embodiments, the compounds described herein modulate (e.g., are inhibitors of) a protein kinase that is abl, Akt, bcr-abl, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, or Zap70. In some embodiments, the compounds described herein modulate (e.g., inhibit) a wild-type kinase (e.g., EGFR). In some embodiments, the compounds described herein modulate (e.g., inhibit) a mutant kinase (e.g., EGFR).

[0440] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, modulate (e.g., inhibit) a kinase that is a tyrosine kinase (e.g., KIT, erb2, PDGFR, EGFR, VEGFR, src, or abl).

[0441] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, modulate (e.g., inhibit) a kinase that is a serine / threonine kinase (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, or Akt).

[0442] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, can be used to inhibit or inhibit the activity of protein kinases (e.g., abl, Akt, bcr-abl, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK In one embodiment, a disease or disorder responsive to modulation (eg, inhibition) of the IL-1 or Zap70 signaling pathway can be treated or prevented.

[0443] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, can be used to treat or prevent a disease or disorder that responds to modulation (e.g., inhibition) of a tyrosine kinase (e.g., KIT, erb2, PDGFR, EGFR, VEGFR, src, or abl).

[0444] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, can be used to treat or prevent a disease or disorder that responds to modulation (e.g., inhibition) of a serine / threonine kinase (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, or Akt).

[0445] In some embodiments, the compounds described herein modulate (e.g., inhibit) a wild-type kinase (e.g., EGFR). In some embodiments, the compounds described herein modulate (e.g., inhibit) a mutant kinase (e.g., EGFR).

[0446] Selective inhibition of kinases In some embodiments, the compounds described herein, or any pharma- ceutically acceptable salts thereof, inhibit one kinase or form of a kinase more than another kinase or form of a kinase. Exemplary compounds include any compound of formula (I)-(XXIII), such as any of compounds (1)-(169), or a pharma- ceutically acceptable salt thereof.

[0447] The terms "selective inhibition" or "selectively inhibit" as applied to a bioactive agent refer to the ability of an agent to selectively reduce target signaling activity relative to off-target signaling activity, either through direct interaction with the target or through a reciprocal interaction.

[0448] In some embodiments, the compounds described herein, or any pharma- ceutically acceptable salts thereof, selectively inhibit one kinase or kinase form over another kinase or kinase form, hi several embodiments, the compounds selectively inhibit a mutant kinase form over a wild-type form of the same kinase.

[0449] In embodiments, the compounds described herein, or any pharma- ceutically acceptable salts thereof, selectively inhibit one kinase (eg, EGFR) over other kinases.

[0450] In embodiments, the compounds described herein, or any pharma- ceutically acceptable salts thereof, selectively inhibit one kinase form (e.g., mutant EGFR) over another kinase form (e.g., wild-type EGFR).

[0451] As non-limiting examples, the selectivity ratio can be greater than about 10, greater than about 20, greater than about 30, greater than about 40, greater than about 50, greater than about 60, greater than about 70, greater than about 80, greater than about 100, greater than about 120, or greater than about 150, and the selectivity can be measured by in vitro assays known in the art. Non-limiting examples of assays for measuring selectivity include enzyme assays, cell proliferation assays, and EGFR phosphorylation assays. In one embodiment, the selectivity can be determined by a cell proliferation assay. In another embodiment, the selectivity can be determined by an EGFR phosphorylation assay. In some embodiments, the mutant EGFR inhibitory activity of the compounds disclosed herein can be less than about 1000 nM, less than about 100 nM, less than about 50 nM, less than about 30 nM, or less than about 10 nM.

[0452] In some embodiments, the IC of the kinase inhibitor compound 50 can be less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, or less than about 1 pM.

[0453] I C 50 Determination of the value can be performed according to methods known in the art.

[0454] In embodiments, the compounds described herein, or any pharma- ceutically acceptable form thereof, such as a pharma- ceutically acceptable salt thereof, can be used to treat or prevent a disease or disorder that is cancer, an inflammatory disorder, a metabolic disorder, a vascular disease, or a neurological disease.

[0455] The compounds described herein, or any pharma- ceutically acceptable form thereof, or any pharmaceutical composition thereof, may be useful in the treatment of diseases and disorders associated with abnormal cell proliferation.

[0456] In embodiments, the compounds described herein, or a pharma- ceutically acceptable form thereof (e.g., a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof, can be used to treat cancer.

[0457] cancer The compounds provided herein (e.g., any compound of Formula (I)-(XXIII), such as any of Compounds (1)-(169), or a pharma- ceutically acceptable salt thereof), and compositions and methods thereof, can be potentially useful in the treatment of cancer, including tumors such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers, and sarcomas.

[0458] In embodiments, the cancer is a cardiac cancer, such as a sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, or teratoma.

[0459] In embodiments, the cancer is a lung cancer, such as bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, or mesothelioma.

[0460] In embodiments, the cancer is a gastrointestinal cancer, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), or colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma).

[0461] In some embodiments, the cancer is a genitourinary cancer, such as kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (dermoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0462] In embodiments, the cancer is a liver cancer, such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemangioma.

[0463] In embodiments, the cancer is a bone cancer, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondrofibroma, osteoid osteoma, and giant cell tumor.

[0464] In embodiments, the cancer is a cancer of the central nervous system (CNS), such as of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma).

[0465] In some embodiments, the cancer is a gynecological cancer such as of the uterus (endometrial cancer), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), or fallopian tube (carcinoma).

[0466] In embodiments, the cancer is a blood cancer, such as hematological (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma).

[0467] In embodiments, the cancer is a skin cancer, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplasia nevus, lipoma, hemangioma, dermatofibroma, keloid, or psoriasis.

[0468] In embodiments, the cancer is an adrenal cancer, such as neuroblastoma. Thus, the term "cancerous cell" as provided herein includes a cell afflicted by or associated with any one of the above-identified conditions.

[0469] In some embodiments, the cancer is an EGFR-driven cancer (e.g., those described herein). In some embodiments, the EGFR-driven cancer is non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), BAC with local invasion, adenocarcinoma with BAC characteristics, and large cell carcinoma; neuronal tumors, e.g., glioblastoma; pancreatic cancer, head and neck cancer (e.g., squamous cell carcinoma); breast cancer; colorectal cancer; epithelial cancer, e.g., squamous cell carcinoma; ovarian cancer; prostate cancer; or adenocarcinoma.

[0470] In some embodiments, the cancer is an EGFR mutant cancer (e.g., as described herein). In some embodiments, the EGFR mutant cancer is non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), BAC with local invasion, adenocarcinoma with BAC characteristics, and large cell carcinoma; neural tumors, e.g., glioblastoma; pancreatic cancer, head and neck cancer (e.g., squamous cell carcinoma); breast cancer; colorectal cancer; epithelial cancer, e.g., squamous cell carcinoma; ovarian cancer; prostate cancer; or adenocarcinoma.

[0471] In one embodiment, the compositions and methods provided herein are useful for the treatment of lung and pancreatic cancer, most particularly non-small cell lung cancer (NSCLC).

[0472] In some embodiments, the cancer is resistant to TKI therapy (e.g., erlotinib, gefitinib, dacomitinib, afatinib, osimertinib).

[0473] lung cancer In embodiments, the cancer is lung cancer.

[0474] Lung cancer is the most common cause of cancer mortality worldwide and the second most common cancer in both men and women. Approximately 14% of all new cancers are lung cancer. In the United States (US), there are expected to be 222,500 new cases of lung cancer (116,990 in men and 105,510 in women) and 155,870 deaths from lung cancer (84,590 in men and 71,280 in women) in 2017.

[0475] The two main forms of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC is a heterogeneous disease consisting of adenocarcinoma, large cell carcinoma, and squamous cell carcinoma (sqNSCLC), which constitutes approximately 80%-85% of all lung cancers. Squamous cell carcinoma of the lung accounts for 20%-30% of NSCLC cases. Despite advances in early detection and standard treatments, NSCLC is often diagnosed at an advanced stage, has a poor prognosis, and is the leading cause of cancer deaths worldwide.

[0476] Platinum-based doublet therapy, maintenance chemotherapy, and antiangiogenic agents in combination with chemotherapy have contributed to improved patient outcomes in advanced NSCLC.

[0477] In some embodiments, the advanced lung cancer is stage III or stage IV cancer. In some embodiments, the advanced lung cancer is stage III cancer. In some embodiments, the advanced lung cancer is stage IV cancer. In some embodiments, the advanced lung cancer is locally advanced. In some embodiments, the advanced lung cancer is metastatic.

[0478] In embodiments, the lung cancer is small cell lung cancer (SCLC).

[0479] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma (sqNSCLC). In some embodiments, the NSCLC is lung adenocarcinoma. In some embodiments, the NSCLC is lung large cell carcinoma. In some embodiments, the NSCLC is lung squamous cell carcinoma (sqNSCLC).

[0480] In some embodiments, the lung cancer (e.g., NSCLC) is an EGFR-mutated lung cancer (e.g., EGFR-mutated NSCLC). In some embodiments, the cancer is an NSCLC with an identified EGFR mutation (e.g., advanced NSCLC).

[0481] EGFR-driven and EGFR-mutated cancers The invention features compounds (e.g., any compound of Formulas (I)-(XXIII), such as any of Compounds (1)-(169), or a pharmaceutically acceptable salt thereof) that may be useful in treating a patient having an EGFR-driven cancer, including a cancer that is or has become resistant to erlotinib, gefitinib, dacomitinib, afatinib, osimertinib, or a cancer that has an EGFR mutation identified herein, by administering a compound of Formula (I) to a subject.

[0482] That is, the compounds described herein may be effective inhibitors of mutant forms of EGFR, such as single, double, or mutant EGFR with L858R ("L") mutation, T790M ("T") mutation, C797S ("C") mutation, and / or exon 19 (Del19 or "D") mutation, or any combination thereof. Such inhibitors may be particularly beneficial for the therapy of patients who have developed mutations after undergoing certain other cancer therapies. For example, patients may present with single mutations (D, L), but after certain treatments, patients may develop secondary mutations and even tertiary mutations (e.g., after osimertinib treatment). Thus, new inhibitors with activity against cancers characterized by single, double, and / or triple mutant EGFR may confer significant benefit to cancer patients, including those who have developed resistance to previous therapies.

[0483] EGFR-driven cancers that can be treated using the compositions and methods of the invention include, for example, EGFR mutants that contain one or more deletions, substitutions, or additions in the amino acid or nucleotide sequence of EGFR, or fragments thereof.

[0484] EGFR-driven cancers can result from EGFR fusions. For example, the N-terminus of EGFR can be linked to various fusion partners, such as RAD51. Cancers (e.g., lung cancers) characterized by EGFR fusions (e.g., EGFR-RAD51 fusions) can be particularly suitable for therapy with any of the compounds described herein, or any pharma- ceutically acceptable form thereof (e.g., pharma-ceutically acceptable salts).

[0485] EGFR mutations can occur anywhere in the EGFR sequence. Generally, EGFR mutants result from mutations in the kinase domain (i.e., exons 18-24 of the EGFR sequence) or the extracellular domain (i.e., exons 2-16 of the EGFR sequence).

[0486] The EGFR mutation can be an activating mutation, which results in ligand-independent activation of TK activity. The EGFR mutation can also be a resistance mutation, which can confer resistance to TKI therapy, such as resistance to one or more of erlotinib, gefitinib, dacomitinib, afatinib, or osimertinib.

[0487] For example, mutations typically occur in the kinase domain and include point mutations in exon 18 (e.g., L688P, V689M, P694L / S, N700D, L703V, E709K / Q / A / G / V, I715S, L718P, G719C / A / S / R, or S720P / F), deletions in exon 19 that may or may not include insertions (e.g., delG719, delE746_E749, delE746_A750, delE746_A750insRP, delE746_A750insQP, delE746_T751, delE746 _T751insA / I / V, delE746_T751insVA, delE746_S752, delE746_S752insA / V / D, delE746_P53insLS, delL747_E749, delL747_A750, delL747_A750ins P, delL747_T751, delL747_T751insP / S / Q, delL747_T751insPI, delL747_S752, delL747_S752insQ, delL747_P753, delL747_P753insS / Q, delL747_L 754insSR, delE749_A750, delE749_A750insRP, delE749_T751, delT751_I759, delT751_I759insS / N, or delS752_I759), duplication in exon 19 (e.g., K739_I44dupKIPVAI), point mutation in exon 19 (e.g., L730F, W731Stop, P733L, G735S, V742A, E746V / K, A750P, T751I, S752Y, P753S, A754P, or D761Y), inflation in exon 20 (e.g., K739_I44dupKIPVAI), insertions (e.g., D761_E762insEAFQ, A767_S768insTLA, V769_D770insY, V769_D770insCV, V769_D770insASV, D770_N771insD / G, D770_N771insNPG, D770_N771insSVQ, P772_H773insN / V, P772_H773insYNP, or V774_C775insHV), deletions in exon 20 with or without insertions (e.g., delM766_A767, delM766_A767insAI,delA767_V769, delD770, or delP772_H773insNP), duplications in exon 20 (e.g., S768_D770dupSVD, A767_V769dupASV, or H773dupH), point mutations in exon 20 (e.g., D761N, A763V, V765A / M, S768I, V769L / M, S768I, P772R, N771T, H773R / Y / L, V774M, R776G / H / C, G779S / F, T783A, T784F, L792P, L798H / F, T790M, R803W, K806E, or L814P), or a point mutation in exon 21 (e.g., G810S, N826S, L833V, H835L, L838V, A839T, K846R, T847I, H850N, V851I / A, I853T, L858M / R, A859T, L861Q / R, G863D, A864T, E866K, or G873E).

[0488] Activating mutations are typical in lung cancer.

[0489] In some embodiments, the mutation is a resistance mutation. Specifically, the drug resistance in 50% of lung cancers is caused by T790M point mutation. Other exemplary resistance mutations include point mutations such as C797X (e.g., C797S, C797G, or C797N), G796X (e.g., G796R, G796S, or G796D), L792X (e.g., L792H, L792F, L792R, or L792Y), G724S, L718X (e.g., L718P, L718Q, or L718V), S768I, or G719A.

[0490] In glioblastoma, mutations such as EGFR variant I (EGFRvI), which lacks the extracellular domain and resembles the v-erbB oncoprotein; EGFRvII, which lacks 83 amino acids from domain IV; and EGFRvIII, which lacks amino acids 30-297 from domains I and II, typically occur in, but are not limited to, the extracellular domain, which is the most common amplification and has been reported in 30-50% of glioblastomas and 5% of squamous cell carcinomas. Other glioblastoma mutations include one or more of the following: a point mutation in exon 2 (e.g., D46N or G63R), a point mutation in exon 3 (e.g., R108K in domain I), a point mutation in exon 7 (e.g., T263P or A289D / T / V in domain II), a point mutation in exon 8 (e.g., R324L or E330K), a point mutation in exon 15 (e.g., P596L or G598V in domain IV), or a point mutation in exon 21 (L861Q in the kinase domain).

[0491] EGFR mutants also include those having combinations of two or more mutations as described herein. Exemplary combinations include S768I and G719A, S768I and V769L, H773R and W731Stop, R776G and L858R, R776H and L861Q, T790M and L858R, T790M and delE746_A750, R803W and delE746_T751insVA, delL747_E749 and A750P, delL747_S752 and E746V, delL747_S752 and P753S, P772_H773insYNP and H773Y, P772_H773insNP and H773Y, and D770_N771insG and N771T. Other exemplary combinations include those that include T790M (e.g., T790M and L858R or T790M and delE746_A750.

[0492] EGFR mutants can be either activating or resistant mutants. Activating mutants include those with substitutions that increase drug sensitivity (e.g., G719C / S / A, delE746_A750, or L858R). Resistant mutants include those with substitutions that increase drug resistance (e.g., T790M or any combination including T790M).

[0493] In some embodiments, the EGFR mutation is a deletion of exon 19 (del19). In some embodiments, the EGFR mutation is a T790M mutation. In some embodiments, the EGFR mutation is a L858R mutation. In some embodiments, the EGFR mutation is a C797S mutation. In some embodiments, the EGFR-driven cancer (e.g., non-small cell lung cancer) is characterized by at least one of these mutations. In some embodiments, the EGFR-driven cancer (e.g., non-small cell lung cancer) is characterized by at least two of these mutations. In some embodiments, the EGFR-driven cancer (e.g., non-small cell lung cancer) is characterized by at least three of these mutations.

[0494] EGFR-driven cancers include those with any of the mutations described herein.For example, EGFRvIII is commonly found in glioblastoma, and has also been reported in breast cancer, ovarian cancer, prostate cancer, and lung cancer.Exemplary EGFR-driven cancers: glioblastoma, lung cancer (e.g., squamous cell carcinoma, non-small cell lung cancer, adenocarcinoma, bronchioloalveolar carcinoma (BAC), BAC with local invasion, adenocarcinoma with BAC characteristics, and large cell carcinoma), pancreatic cancer, head and neck cancer (e.g., squamous cell carcinoma), breast cancer, colorectal cancer, epithelial cancer (e.g., squamous cell carcinoma), ovarian cancer, and prostate cancer.

[0495] In particular, the invention described herein will benefit patient populations at high risk of TKI resistance mutations. Based on the incidence of non-small cell lung cancer (approximately 160,000 new cases in the United States), response to erlotinib in the general population (approximately 10%, resulting in a susceptible population of 16,000), the presence of activating mutations (10-20% in Caucasian populations and 30-40% in Asian populations, resulting in a susceptible population of 16,000-32,000), acquisition of secondary resistance (most, if not all, patients, resulting in a susceptible population of 16,000-32,000), and the proportion of patients with the T790M point mutation (approximately 50%, resulting in a susceptible population of 8,000-16,000), approximately 8,000-16,000 new cases per year can be estimated. Patients with TKI resistance mutations include those whose cancer is resistant to one or more of the following: erlotinib, gefitinib, dacomitinib, afatinib, osimertinib, CL-387,785, BIBW 2992 (CAS Registry Number 439081-18-2), CI-1033, neratinib (HKI-272), MP-412 (AV-412), PF-299804, AEE78, and XL64.

[0496] Specifically, the present invention relates to the treatment of EGFR-driven cancers with T790M point mutation.In general, irreversible inhibitors (e.g., CI-1033, neratinib (HKI-272), and PF-299804) are less potent in cell lines with T790M mutation and do not inhibit T790M at clinically achievable concentrations.Since the ATP Km of T790M and WT are similar, the concentrations that inhibit the mutant inhibit WT, resulting in gastrointestinal and skin events.

[0497] EGFR mutants also include other amino acid and nucleotide sequences of EGFR with one or more deletions, substitutions, or additions, such as point mutations, that retain or increase tyrosine kinase or phosphorylation activity. When the mutant is a protein or polypeptide, preferred substitutions are conservative substitutions, which are substitutions between amino acids that have similar properties, such as structural, electrical, polar, or hydrophobic properties. For example, the substitutions can be made between basic amino acids (e.g., Lys, Arg, and His), or between acidic amino acids (e.g., Asp and Glu), or between amino acids with uncharged polar side chains (e.g., Gly, Asn, Gln, Ser, Thr, Tyr, and Cys), or between amino acids with hydrophobic side chains (e.g., Ala, Val, Leu, Ile, Pro, Phe, and Met), or between amino acids with branched side chains (e.g., Thr, Val, Leu, and Ile), or between amino acids with aromatic side chains (e.g., Tyr, Trp, Phe, and His).

[0498] When the variant is a nucleic acid, the DNA encoding the EGFR variant protein may comprise a nucleotide sequence capable of hybridizing under stringent conditions to a complementary sequence of a nucleotide sequence encoding the EGFR variant, as defined herein. As used herein, stringent conditions include low, medium, or high stringency conditions. Examples of stringent conditions include hybridization at about 42-55°C in about 2-6×SSC, followed by washing at about 50-65°C in about 0.1-1×SSC containing about 0.1-0.2% SDS, where 1×SSC is a solution containing 0.15 M NaCl and 0.015 M sodium citrate, pH 7.0. Washing may be performed one or more times. In general, stringent conditions may be set at a temperature approximately 5°C lower than the melting temperature (Tm) of a particular nucleotide sequence at a defined ionic strength and pH.

[0499] The amino acid and nucleotide sequences of EGFR, as well as the DNA encoding them, are available from public databases such as NCBI GenBank (USA), EMBL (Europe), etc. For example, GenBank accession numbers for EGFR [Homo sapiens] include MIM131550, AAI28420, NM_005228, NP_005219.2, and GeneID:1956.

[0500] Selective EGFR inhibition In some embodiments, a compound described herein (e.g., any compound of Formula (I)-(XXIII), such as any of compounds (1)-(169)), or any pharma- ceutically acceptable salt thereof, selectively inhibits EGFR (including any mutant EGFR described herein) over other kinases.

[0501] In some embodiments, the compounds described herein, or any pharma- ceutically acceptable salt thereof, selectively inhibit mutant EGFR (e.g., any mutant EGFR described herein) over wild-type EGFR. In embodiments, the compounds described herein selectively inhibit EGFR characterized by a mutation that is a deletion of exon 19 (del19), a T790M mutation, an L858R mutation, and / or a C797S mutation, or any combination thereof. Such inhibitors may be effective in ameliorating diseases and disorders associated with mutant EGFR activity.

[0502] As non-limiting examples, the selectivity ratio can be greater than about 10, greater than about 20, greater than about 30, greater than about 40, greater than about 50, greater than about 60, greater than about 70, greater than about 80, greater than about 100, greater than about 120, or greater than about 150, and the selectivity can be measured by in vitro assays known in the art. Non-limiting examples of assays for measuring selectivity include enzyme assays, cell proliferation assays, and EGFR phosphorylation assays. In one embodiment, the selectivity can be determined by a cell proliferation assay. In another embodiment, the selectivity can be determined by an EGFR phosphorylation assay. In some embodiments, the mutant EGFR inhibitory activity of the compounds disclosed herein can be less than about 1000 nM, less than about 100 nM, less than about 50 nM, less than about 30 nM, or less than about 10 nM.

[0503] In some embodiments, the IC of the subject compounds for mutant EGFR inhibition 50 can be less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, or less than about 1 pM.

[0504] Characterization of EGFR-driven cancers The compositions and methods of the present invention can be used to treat subjects with EGFR-driven cancers (i.e., cancers characterized by EGFR mutant expression or overexpression). EGFR mutant expression or overexpression can be determined in diagnostic or prognostic assays by assessing the level of EGFR mutants in a biological sample or by assessing the level of EGFR mutants secreted by cells (e.g., by immunohistochemistry assays using anti-EGFR or anti-p-EGFR antibodies, FACS analysis, etc.). Alternatively, or in addition, the level of nucleic acid or mRNA encoding EGFR mutants in cells can be measured by, for example, fluorescent in situ hybridization (FISH; see WO98 / 45479 published October 1998), Southern blotting, Northern blotting, or polymerase chain reaction (PCR) techniques, such as real-time quantitative PCR (RT-PCR), using a nucleic acid-based probe corresponding to the nucleic acid encoding the EGFR mutant or its complement. For example, antibody-based assays can be used to study EGFR mutant expression by measuring shed antigens in biological samples such as serum (see, for example, U.S. Pat. No. 4,933,294, issued Jun. 12, 1990; WO 91 / 05264, published Apr. 18, 1991; U.S. Pat. No. 5,401,638, issued Mar. 28, 1995; and Sias et al., J. Immunol. Methods 132:73 (1990)). In addition to the above assays, various in vivo assays are available to those skilled in the art. For example, cells in a mammalian body can be exposed to an antibody that is optionally labeled with a detectable label, e.g., a radioisotope, and binding of the antibody to the mammalian cells can be assessed, for example, by external scanning for radioactivity or by analyzing a biopsy taken from a mammal previously exposed to the antibody.

[0505] Examples of biological characteristics that can be measured in isolated cells include mRNA expression, protein expression, and DNA quantification.In addition, the DNA of cells isolated by the method of the present invention can be sequenced, or certain sequence features (e.g., polymorphisms and chromosomal abnormalities) can be identified using standard techniques, such as FISH or PCR.Cell chemical components and other analytes can also be assayed after isolation.Cells may also be assayed without lysis, for example, using extracellular or intracellular staining, or by other observations, such as morphology or growth characteristics in various media.

[0506] Although any hybridization technique can be used to detect gene rearrangements, one preferred technique is fluorescent in situ hybridization (FISH). FISH is a cytogenetic technique that can be used to detect and localize the presence or absence of specific DNA or RNA sequences on chromosomes. FISH incorporates the use of fluorescently labeled nucleic acid probes that only bind to parts of chromosomes with which they show a high degree of sequence similarity. Fluorescence microscopy can be used to find where the fluorescent probes bind on the chromosome. The basic steps of FISH are outlined below. Exemplary FISH probes include the Vysis EGFR SpectrumOrange / CEP SpectrumGreen Probe (Abbott, Downers Grove, IL), which hybridizes to band 7p12, and the ZytoLight SPEC EGFR / CEN 7 Dual Color Probe (ZytoVision), which hybridizes to the alpha satellite sequence of the centromere of chromosome 7.

[0507] In the case of FISH, a probe is constructed that is long enough to specifically hybridize to the target (not hybridize to similar sequences in the genome), but not too large to interfere with the hybridization process.The probe is generally labeled with a fluorophore, an antibody target, biotin, or any combination thereof.This can be done in a variety of ways, for example, using random priming, nick translation, and PCR using tagged nucleotides.

[0508] Generally, a sample or aliquot of a cell population is used for FISH analysis. For example, in one preparation method, cells are trypsinized to disperse into single cells, cytospun onto glass slides, and then fixed with paraformaldehyde and stored in 70% ethanol. In the case of preparation of chromosomes for FISH, the chromosomes are firmly attached to a substrate, usually glass. After preparation, a probe is applied to the chromosomal RNA and hybridization begins. In several washing steps, all unhybridized or partially hybridized probes are washed away. If signal amplification is required to exceed the detection threshold of the microscope (which depends on many factors such as probe labeling efficiency, probe type, and fluorescent dye), fluorescently labeled antibodies or strepavidin are bound to the tag molecules, and thus the fluorescence is amplified.

[0509] Epifluorescence microscopy can be used to observe the hybridized sequences. The white light of the source lamp is filtered so that only wavelengths associated with the excitation of the fluorescent molecules reach the sample. The emission of the fluorescent dyes generally occurs at larger wavelengths, which makes it possible to distinguish between the excitation light and the emission light using different optical filters. With more sophisticated filter sets it is possible to distinguish several excitation and emission bands and thus several fluorescent dyes, which allows the observation of many different probes on the same strand.

[0510] Depending on the probes used, FISH can have the resolution range of large chromosomes or small (approximately 100 kilobase) sequences. Probes can be quantified by simply counting dots or comparing colors.

[0511] Allele-specific quantitative real-time PCR can also be used to identify nucleic acids encoding mutant EGFR proteins (see, e.g., Diagnostic Innovations DxS BCR-ABL T3151 Mutation Test Kit, and Singer et al., Methods in Molec. Biol. 181:145 (2001)). This technique utilizes Taq DNA polymerase, which is highly effective at discriminating between matches and mismatches at the 3' end of the primer (if the 3' base is mismatched, efficient amplification does not occur). Using this technique, the 3' end of the primer can be designed to specifically hybridize to a nucleic acid sequence corresponding to a codon that codes for a mutant amino acid in an EGFR mutant, as described herein. In this way, a specific mutant sequence can be selectively amplified in a patient sample. This technique further utilizes a Scorpion probe molecule, which is a bifunctional molecule that includes a PCR primer, a fluorophore, and a quencher. The fluorophore in the probe interacts with the quencher, thereby reducing fluorescence. During the PCR reaction, when the Scorpion probe binds to the amplicon, the fluorophore and quencher in the Scorpion probe become separated, which results in an increase in fluorescence from the reaction tube. Any of the primers described herein can be used in allele-specific quantitative real-time PCR.

[0512] Biological samples can be analyzed to detect EGFR gene mutations or EGFR gene expression levels by methods known in the art. For example, methods such as direct nucleic acid sequencing, hybridization changes, abnormal electrophoretic gel migration, mismatch binding protein-mediated binding or cleavage, single-strand conformation polymorphism (SSCP) analysis, or restriction fragment length polymorphism (RFLP) analysis of PCR products from patient samples can be used to detect EGFR gene mutations, ELISA can be used to measure the level of EGFR polypeptides, and PCR can be used to measure the level of EGFR nucleic acid molecules.

[0513] Any of these techniques can be used to facilitate detection of mutations in candidate genes, each of which is well known in the art, with examples of specific techniques being described, but not limited to, Orita et al. (Proc. Natl. Acad. Sci. USA 86:2766 (1989)) and Sheffield et al. (Proc. Natl. Acad. Sci. USA 86:232 (1989)). Additionally, expression of candidate genes in biological samples (e.g., biopsies) can be monitored by standard Northern blot analysis or assisted by PCR (see, e.g., Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY (1995); PCR Technology: Principles and Applications for DNA Amplification, H.A. Ehrlich, Ed., Stockton Press, NY; Yap et al., Nucl. Acids. Res. 19:4294 (1991)).

[0514] A person skilled in the art can use several sequence alignment software programs (e.g., the NCBI BLAST website) to identify residues (e.g., amino acids or nucleotides) or codons in a nucleic acid or protein sequence that correspond to residues or codons in wild-type EGFR or EGFR mutants. Such software programs may allow for gaps in the alignment of the compared sequences. Using such software, a person skilled in the art can identify nucleotides, amino acids, or amino acids that correspond to specific nucleotides, amino acids, or codons in wild-type EGFR or EGFR mutants.

[0515] The level of EGFR expression (e.g., DNA, mRNA, or protein) in a biological sample can be determined by using any of several standard techniques well known in the art or described herein. Exemplary biological samples include plasma, blood, sputum, pleural fluid, bronchoalveolar lavage fluid, or biopsies such as lung biopsy and lymph node biopsy. For example, EGFR expression in a biological sample (e.g., blood sample or tissue sample) from a patient can be monitored by standard Northern blot analysis or quantitative PCR (see, for example, Ausubel et al., (see above); PCR Technology: Principles and Applications for DNA Amplification, H.A. Ehrlich, Ed., Stockton Press, NY; Yap et al., Nucl.Acids.Res.19:4294(1991)).

[0516] Combination therapy In some embodiments, provided herein are methods for combination therapy in which agents known to regulate other pathways or other components of the same pathway, or even overlapping sets of target enzymes, are used in combination with a compound provided herein (e.g., any compound of Formula (I)-(XXIII), such as any of Compounds (1)-(169)), or a pharmaceutically acceptable form thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives). In one aspect, such therapy includes, but is not limited to, combinations of the subject compounds with chemotherapeutic agents, therapeutic antibodies, and radiation therapy, where synergistic or additive therapeutic effects are provided.

[0517] When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition. The phrase "combination therapy" when referring to the use of the disclosed compounds with another pharmaceutical agent means, in either case, the co-administration of each agent substantially simultaneously, as well as the sequential administration of each agent in a regimen that provides the beneficial effects of the drug combination. Co-administration includes, among others, the co-delivery in a single tablet, capsule, injection, or other dosage form having a fixed ratio of these active agents, as well as the co-delivery in multiple separate dosage forms, each for each agent. Thus, administration of the disclosed compounds can be combined with additional therapies known to those skilled in the art in the prevention or treatment of cancer, such as radiation therapy or cytostatic agents, cytotoxic agents, other anti-cancer agents, and other drugs to ameliorate the symptoms of cancer or the side effects of any of these drugs.

[0518] In some embodiments, the treatment can be provided in combination with one or more other cancer therapies, including surgery, radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy, biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF)), hyperthermia, cryotherapy, agents that attenuate any adverse effects (e.g., antiemetics), and other cancer chemotherapy agents. The other agents can be administered using the same or different formulations, routes of administration, and administration schedules as those used with the compounds provided herein.

[0519] In embodiments, the combination therapy includes administering a compound described herein, or any pharma- ceutically acceptable form thereof (e.g., any pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof, in combination with an anti-cancer agent (e.g., anti-proliferative agents, anti-angiogenic agents, and other chemotherapeutic agents).

[0520] In several embodiments, the combination therapy includes administering a compound described herein, or any pharma- ceutically acceptable form thereof (e.g., any pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof, in combination with an amount of an anti-cancer agent (e.g., a chemotherapeutic agent). EXAMPLES

[0521] Example 1: Preparation of compound (169) Synthesis of the inhibitor: 5,10-dimethyl-13-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (169)).

[0522] (I) Synthesis of intermediate A (INT-A) [ka]

[0523] Step 1: A mixture of 2-chloropyrimidin-4-amine (2 g, 15.4 mmol, 1 equiv.) and DMAP (188.6 mg, 1.54 mmol, 0.1 equiv.) in THF (20 mL) was degassed and purged with nitrogen three times and treated with TEA (6.25 g, 61.8 mmol, 4 equiv.) and Boc 2 O (10.11 g, 46.3 mmol, 3 equiv.) was added. The mixture was stirred under nitrogen at 15° C. for 16 h. The reaction mixture was diluted with H 2 The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-20%, flow rate = 20 mL / min) to give tert-butyl N-tert-butoxycarbonyl-N-(2-chloropyrimidin-4-yl)carbamate (4.5 g, 85.7% yield, 97% purity) as an off-white solid.

[0524] 1 H NMR(400 MHz,DMSO)δ 8.72(d, J=6.0 Hz,1H),7.73(d,J=6.0 Hz,1H),1.52(s,18 H).

[0525] Step 2: To a solution of 2-methylpyrazol-3-ol (3 g, 30.6 mmol, 1 equiv.) in MeCN (20 mL), SEMCl (11 mL, 62.2 mmol, 2.03 equiv.) and K 2 CO 3(18.0 g, 0.130 mol, 4.26 equiv) was added. The mixture was stirred at 20° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, DCM / MeOH, MeOH 0-8%, flow rate=40 mL / min) to give 2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (6.2 g, 70.1% yield, 79% purity) as a white solid.

[0526] 1 H NMR(400MHz,chloroform-d)δ 7.30(d,J=3.6 Hz,1H),5.49(d,J=3.6 Hz,1H),4.98(s,2H),3.43-3.47(m,5H),0.87(t,J=8.0 Hz,2H),-0.02(s,9H).

[0527] Step 3: To a mixture of 2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (1.7 g, 7.44 mmol, 1 equiv.) in MeCN (20 mL) was added NBS (1.99 g, 11.2 mmol, 1.5 equiv.) under nitrogen at 0° C. and the mixture was stirred at 15° C. under nitrogen for 1 h. The reaction mixture was diluted with saturated Na 2 S 2 O 3 The mixture was diluted with aqueous solution (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, petroleum ether / EtOAc, 50-100% EtOAc, flow rate = 30 mL / min) to give 4-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (1.2 g, 48.8% yield, 93% purity) as a yellow solid.

[0528] 1H NMR (400 MHz, chloroform-d) δ 7.42 (s, 1H), 4.97 (s, 2H), 3.48-3.52 (m, 5H), 0.89 (t, J = 8.0 Hz, 2H), -0.01 (s, 9H).

[0529] Step 4: MeCN (25 mL) and H 2 tert-Butyl N-tert-butoxycarbonyl-N-(2-chloropyrimidin-4-yl)carbamate (2.68 g, 8.14 mmol, 5 equiv.), 4-bromo-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (500 mg, 1.63 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.07 g, 8.14 mmol, 5 equiv.), 4-di-tert-butylphosphanyl-N,N-dimethyl-aniline in O (2.5 mL); dichloropalladium (230.4 mg, 0.325 mmol, 0.2 equiv.) and Na 2 CO 3 (862.4 mg, 8.14 mmol, 5 equiv) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 100° C. for 4 h. 2 The mixture was diluted with 200 mL of 2H2O and extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (200 mL) and anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, DCM / MeOH, MeOH 0-10%, flow rate = 30 mL / min) to give tert-butyl N-tert-butoxycarbonyl-N-[2-[2-methyl-3-oxo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrimidin-4-yl]carbamate (2 g, 55.4% yield, 47% purity) as a brown oil.

[0530] LCMS[M+H] +m / z: calculated 522.3, measured 522.4.

[0531] Step 5: To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-[2-methyl-3-oxo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrimidin-4-yl]carbamate (500 mg, 0.958 mmol, 1 equiv.) in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL), TFA (1 mL, 13.5 mmol, 14.09 equiv.) was added. The mixture was stirred at 15 °C for 3 h. The reaction mixture was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (silica, DCM / MeOH=10 / 1, 254 nm) to give 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (150 mg, 46.7% yield, 96% purity) as a red solid.

[0532] 1 H NMR (400MHz, methanol-d 4 )δ 8.38(br s,1H),8.02(br s,1H),6.34(br s,1H),5.40(s,2H),3.52-3.62(m,5H),0.92(t,J=8.0 Hz,2H),-0.00(s,9H).

[0533] (II) Synthesis of compound (169) [ka]

[0534] Step 1: To a solution of butane-1,3-diol (5 g, 55.5 mmol, 1.0 equiv) and imidazole (4.15 g, 61.0 mmol, 1.1 equiv) in DCM (80.0 mL) was added TBDMSCl (8.36 g, 55.5 mmol, 1.0 equiv) at 0° C. The mixture was stirred at 15° C. for 12 h. The reaction mixture was stirred at H 2 The mixture was diluted with 2×DCM (100 mL) and extracted with 2×DCM (100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was purified by flash / column chromatography (ISCO®, 40 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-30%, 100 mL / min, PMA) to give 4-[tert-butyl(dimethyl)silyl]oxybutan-2-ol (10 g, 88.2% yield) as a colorless oil.

[0535] 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.07-3.98(m,1H),3.92-3.86(m,1H),3.84-3.78(m,1H),1.70-1.60(m,2H),1.19(d,J=6.4 Hz,3H),0.90(s,9H),0.10-0.06(m,6H).

[0536] Step 2: 5-Bromo-2-chloro-pyridin-4-ol (1 g, 4.80 mmol, 1.0 equiv.) in THF (15.0 mL), PPh 3 (3.77 g, 14.4 mmol, 3.0 equiv.) and tert-butyl (NE)-N-tert-butoxycarbonyliminocarbamate (3.31 g, 14.4 mmol, 3.0 equiv.) were added to N 2 The mixture was stirred at 15 °C for 30 min under reduced pressure, then cooled to 0 °C and 4-[tert-butyl(dimethyl)silyl]oxybutan-2-ol (1.18 g, 5.76 mmol, 1.2 equiv) in THF (5.0 mL) was added dropwise at 0 °C and the mixture was cooled to 5 °C with N 2 The mixture was stirred at 15° C. for 12 hours under atmospheric conditions.2 The mixture was diluted with 2×O (30 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×1) and anhydrous Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-15%, 40 mL / min, 254 nm) to give 3-[(5-bromo-2-chloro-4-pyridyl)oxy]butoxy-tert-butyl-dimethyl-silane (1.1 g, 49.2% yield, 85% purity) as a yellow solid.

[0537] 1 H NMR (400 MHz, CDCl 3 )δ ppm 8.37-8.32(m,1H),6.91(s,1H),4.80-4.71(m,1H),3.80-3.69(m,2H),2.07-1.98(m,1H),1.88-1.79(m,1H),1.43(d,J=6.4 Hz,3H),0.90-0.87(m,9H),0.02(d,J=14.4 Hz,6H).

[0538] Step 3: Dioxane (15.0 mL) and H 2 3-[(5-bromo-2-chloro-4-pyridyl)oxy]butoxy-tert-butyl-dimethyl-silane (1.1 g, 2.79 mmol, 1.0 equiv.), 1-methyl-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine (1.06 g, 3.34 mmol, 1.2 equiv.), Pd(dppf)Cl in O (3.0 mL). 2 (204mg, 0.279mmol, 0.1eq), K 2 CO 3 A mixture of (1.16 g, 8.36 mmol, 3.0 equiv.) was degassed and flushed with N 2 Purge the mixture three times with N 2 The mixture was stirred at 90° C. for 12 hours under atmospheric conditions. 2The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×1) and anhydrous Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, EtOAc / MeOH, MeOH 0-15%, 40 mL / min, 254 nm) to give tert-butyl-[3-[[2-chloro-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (960 mg, 63.5% yield, 93% purity) as a yellow solid.

[0539] 1 H NMR (400 MHz, CDCl 3 )δ ppm 8.18(s,1H),7.44-7.40(m,2H),7.39-7.35(m,2H),6.98(s,1H),4.79-4.71(m,1H),3.65(t,J=5.6 Hz,2H),3.59(s,2H),3.50(s,1H),2.77-2.50(m,7H),2.42(br s,3H),1.99-1.91(m,1H),1.79-1.71(m,1H),1.37(d,J=6.0 Hz,3H),0.89(s,9H),0.01(d,J=5.6 Hz,6H).

[0540] LCMS(ESI)[M+H] + m / z: calculated 504.3, measured 504.1.

[0541] Step 4: tert-Butyl-[3-[[2-chloro-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (300 mg, 0.595 mmol, 1.0 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (192 mg, 0.595 mmol, 1.0 equiv.), Xantphos (104 mg, 0.179 mmol, 0.3 equiv.), Cs 2 CO3 (582 mg, 1.79 mmol, 3.0 equiv.), and Pd 2 (dba) 3 (82 mg, 0.0893 mmol, 0.15 equiv) was taken up in dioxane (10.0 mL) in a microwave tube. The sealed tube was heated in a microwave at 130 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 4 g SepaFlash® silica flash column, EtOAc / MeOH, MeOH 0-15%, 40 mL / min, 254 nm) to give 4-[4-[[4-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (350 mg, 69.5% yield, 93% purity) as a yellow solid.

[0542] LCMS(ESI)[M+H] + m / z: calculated 789.5, measured 789.4.

[0543] Step 5: To a solution of 4-[4-[[4-[3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (200 mg, 0.253 mmol, 1.0 equiv.) in THF (5.0 mL) was added 1 M TBAF / THF (0.5 mL, 0.5 mmol, 2.0 equiv.). The mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash chromatography (column: SepaFlash® Sphercial C18, 40 g, 40-60 μm, 120 Å, MeCN / water (0.5% NH 3 -H 2HO), MeCN 0-30%, 100 mL / min, 254 nm) to give 4-[4-[[4-(3-hydroxy-1-methyl-propoxy)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (130 mg, 71.5% yield, 76% purity) as a yellow solid.

[0544] LCMS(ESI)[M+H] + m / z: calculated 545.3, measured 545.1.

[0545] Step 6: To a solution of 4-[4-[[4-(3-hydroxy-1-methyl-propoxy)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (130 mg, 0.239 mmol, 1.0 equiv.) in toluene (10.0 mL), 2-(tributyl-λ5-phosphanylidene)acetonitrile (288 mg, 1.19 mmol, 5.0 equiv.) was added. The mixture was cooled to 50° C. for 2 hours. 2 The mixture was stirred at 130° C. for 12 h under reduced pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, EtOAc / MeOH, MeOH 0-20%, 40 mL / min, 254 nm) to give a crude product which was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40 mm×3 μm, mobile phase: [water (10 mM NH 4 HCO 3 )-ACN], B%: 32%-62%, 7.8 min) to give 5,10-dimethyl-13-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (20)) (49.0 mg, 38.6% yield) as a white solid.

[0546] 1 H NMR (400 MHz, CD 3 OD)δ ppm 8.77(s,1H),8.23(d,J=5.6 Hz,1H),8.03(d,J=8.8 Hz,2H),7.50(d,J=8.0 Hz,2H),7.38(d,J=8.0 Hz,2H),6.68(d,J=5.6 Hz,1H),5.18-5.09(m,1H),4.76-4.68(m,1H),4.24-4.17(m,1H),3.79(s,3H), 3.62(s,2H),2.97-2.52(m,8H),2.46(s,3H),2.32-2.22(m,2H),1.43(d,J=6.4 Hz,3H).

[0547] LCMS(ESI)[M+H] + m / z: calculated 527.3, measured 527.1.

[0548] The regiochemistry was confirmed by HSQC (-CH 2 The chemical shift of -O- is 71.932 ppm.

[0549] Example 2: Preparation of compound (48) Synthesis of inhibitor: (10S)-5,10-dimethyl-13-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 ]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (48)). (I) Synthesis of intermediate B (INT-B) [ka]

[0550] Step 1: To a solution of (3R)-butane-1,3-diol (20 g, 0.222 mol) in DCM (200 mL) was added imidazole (20 g, 0.294 mol) and tert-butyl-chloro-dimethyl-silane (34 g, 0.226 mol) at 0° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was washed with brine (200 mL×2) and added Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 220 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-30%, flow rate: 100 mL / min, PMA) to give (2R)-4-[tert-butyl(dimethyl)silyl]oxybutan-2-ol (39 g, 86%) as a colorless oil.

[0551] 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.04-3.90(m,1H),3.89-3.86(m,1H),3.84-3.80(m,1H),1.69-1.62(m,2H),1.19(d,J=6.4 Hz,2H),0.91(s,9H),0.08(s,6H).

[0552] Step 2: 2-Chloropyridin-4-ol (10 g, 0.0772 mol), (2R)-4-[tert-butyl(dimethyl)silyl]oxybutan-2-ol (19 g, 0.0930 mmol), and PPh in THF (200 mL) 3(30 g, 0.114 mol) was added dropwise to DIAD (23 mL, 0.118 mol) at 0° C., and the mixture was then stirred under nitrogen atmosphere at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (ISCO®, 330 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-15%, flow rate: 100 mL / min, 254 nm) to give tert-butyl-[(3S)-3-[(2-chloro-4-pyridyl)oxy]butoxy]-dimethyl-silane (25 g, 88.2% yield, 86% purity) as a yellow oil.

[0553] 1 H NMR (400 MHz, CDCl 3 )δ ppm 8.14(d,J=5.6 Hz,1H),6.84(d,J=2.0 Hz,1H),6.74(dd,J=5.6 Hz,2.0 Hz,2H),4.72-4.64(m,1H),3.72-3.65(m,1H),1.97-1.91(m,1H),1.78-1.72(m,1H),1.34(d,J=6.4 Hz,3H),0.87(s,9H),0.02(s,3H),-0.01(s,3H).

[0554] LCMS(ESI)[M+H] + m / z: calculated 316.1, measured 315.9.

[0555] Step 3: tert-Butyl-[(3S)-3-[(2-chloro-4-pyridyl)oxy]butoxy]-dimethyl-silane (13 g, 41.1 mmol), (Bpin) in hexane (250 mL) 2A mixture of (18 g, 70.9 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1 g, 3.73 mmol), and (1Z,5Z)-cycloocta-1,5-diene;2,4-dimethyl-BLAH bicyclo[1.1.0]butane (1 g, 1.51 mmol) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 90° C. for 48 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 330 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-24%, flow rate: 100 mL / min, 254 nm) to give tert-butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (10 g, 44.0% yield) as a yellow oil. The regiochemistry was confirmed by HSQC.

[0556] 1 H NMR (400 MHz, CDCl 3 )δ ppm 8.40(s,1H),6.82(s,1H),4.68-4.63(m,1H),3.83-3.78(m,1H),3.74-3.70(m,1H),1.99-1.93(m,1H),1.83-1.80(m,1H),1.61(d,J=6.0 Hz,3H),1.33(s,12H),0.87(s,9H),0.01(s,3H),-0.02(s,3H).

[0557] LCMS(ESI)[M+H] + m / z: calculated 442.2, found 442.1 (boronic acid observed by LCMS at different retention times). (II) Synthesis of compound (48) [ka]

[0558] Step 1: To a solution of methyl 3-hydroxy-1-methyl-pyrrole-2-carboxylate (1.5 g, 9.67 mmol, 1.0 equiv) in DCM (20.0 mL) was added NBS (2.06 g, 11.60 mmol, 1.2 equiv). The mixture was stirred at -78 °C for 3.5 h. The reaction mixture was cooled to -78 °C with saturated Na 2 SO 3 The reaction was quenched by the addition of aqueous solution (30 mL) of H 2 The mixture was diluted with O (10 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with saturated Na 2 SO 3 Wash with aqueous solution (40 mL x 3) and brine (40 mL x 2) and add Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave methyl 4-bromo-3-hydroxy-1-methyl-pyrrole-2-carboxylate (1.7 g, crude) as a white solid. LCMS [M+H] + m / z: calculated 233.9, measured 233.8.

[0559] Step 2: Methyl 4-bromo-3-hydroxy-1-methyl-pyrrole-2-carboxylate (1.7 g, 7.26 mmol, 1.0 equiv.) and K in DMF (20.0 mL). 2 CO 3 (3.1 g, 22.43 mmol, 3.1 equiv.) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.4 g, 14.65 mmol, 2.0 equiv.). The mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to 5° C. and cooled to 5° C. for 1 h. 2 The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (60 mL×5) and 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, 0-20% EtOAc, flow rate: 80 mL / min, 254 nm) to give methyl 4-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyrrole-2-carboxylate (1.7 g, 68.8% yield, 93% purity) as a white solid.

[0560] 1 H NMR (400 MHz, chloroform-d) δ ppm 6.68 (s, 1H), 4.37 (q, J = 8.4 Hz, 2H), 3.86 (d, J = 8.5 Hz, 6H). LCMS [M+H] + m / z: calculated 315.9, measured 317.8.

[0561] Step 3: To a solution of methyl 4-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyrrole-2-carboxylate (1.7 g, 5.38 mmol, 1.0 equiv) in MeOH (20.0 mL), H 2 NaOH (2.2 g, 55.00 mmol, 10.2 equiv) in 2O (4.0 mL) was added. The mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H 2 The mixture was diluted with 200 mL of HO (10 mL) and the pH was adjusted to <5 with 4 N HCl. The mixture was filtered and the filter cake was washed with H 2 The filter cake was concentrated under reduced pressure to give 4-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyrrole-2-carboxylic acid (1.7 g, crude) as a white solid.

[0562] 1 H NMR (400MHz, DMSO-d 6 )δ ppm 12.84(br s,1H),7.19(s,1H),4.53(q,J=9.0 Hz,2H),3.77(s,3H).LCMS [M+H] + m / z: calculated 301.9, measured 301.9.

[0563] Step 4: To a solution of 4-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyrrole-2-carboxylic acid (1.7 g, 5.63 mmol, 1.0 equiv) in DMSO (20.0 mL) was added NaCl (660 mg, 11.29 mmol, 2.0 equiv). The mixture was stirred at 140° C. for 4 h. The reaction mixture was stirred at H 2 The mixture was diluted with 20 mL of 2H2O (40 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (60 mL x 5) and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, 0-14% EtOAc, flow rate: 80 mL / min, 254 nm) to give 3-bromo-1-methyl-4-(2,2,2-trifluoroethoxy)pyrrole (1.2 g, 64.4% yield, 78% purity) as a yellow oil.

[0564] 1 H NMR (400 MHz, chloroform-d) δ ppm 6.44 (d, J = 2.6 Hz, 1H), 6.31 (d, J = 2.6 Hz, 1H), 4.25 (q, J = 8.4 Hz, 2H), 3.56 (s, 3H). LCMS [M+H] + m / z: calculated 257.9, measured 259.8.

[0565] Step 5: DMF (20.0 mL) and H 2 3-Bromo-1-methyl-4-(2,2,2-trifluoroethoxy)pyrrole (1.2 g, 4.65 mmol, 1.0 equiv.), tert-butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (2.9 g, 6.56 mmol, 1.4 equiv.), Cs in O (2.0 mL). 2 CO 3(4.6 g, 14.12 mmol, 3.0 equiv.), [2-(2-aminophenyl)phenyl]-chloro-palladium; and bis(1-adamantyl)-butyl-phosphane (310 mg, 0.463 mmol, 0.1 equiv.) were degassed and cooled with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 12 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (15 mL×4). The combined filtrate was extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine (50 mL×5) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-17%, flow rate: 80 mL / min, 254 nm) to give tert-butyl-[(3S)-3-[[2-chloro-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (1 g, 41.0% yield, 94% purity) as a yellow oil.

[0566] LCMS[M+H] + m / z: calculated 493.1, measured 493.1.

[0567] Step 6: tert-Butyl-[(3S)-3-[[2-chloro-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (1 g, 2.03 mmol, 1.0 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (700 mg, 2.18 mmol, 1.0 equiv.), Pd in ​​dioxane (20.0 mL) and DME (4.0 mL). 2 (dba) 3 (190 mg, 0.207 mmol, 0.1 equiv.), Xantphos (120 mg, 0.207 mmol, 0.1 equiv.) and Cs 2 CO 3A mixture of (2 g, 6.14 mmol, 3.0 equiv.) was degassed and diluted with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 130° C. under atmospheric pressure for 12 hours. The reaction mixture was filtered and the filter cake was washed with DCM (15 mL×4). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, MeOH (0.05% NH 3 H 2 O) / DCM, MeOH (0.05% NH 3 H 2 0-17%, flow rate: 80 mL / min, 254 nm) to give 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (700 mg, crude) as a brown oil.

[0568] LCMS[M+H] + m / z: calculated 778.3, measured 778.4.

[0569] Step 7: To a solution of 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (700 mg, 0.899 mmol, 1.0 equiv.) in THF (5.0 mL) was added 2.7 mL of 1 M TBAF / THF. The mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®, column: SepaFlash® Sphercial C18, 60 g, 40-60 μm, 120 Å, MeCN / water (0.05% NH 3 -H2 0H, MeCN 0-47%, 50 mL / min, 254 nm) to give 4-[4-[[4-[(1S)-3-hydroxy-1-methyl-propoxy]-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (830 mg, crude) as a brown solid.

[0570] LCMS[M+H] + m / z: calculated 534.2, measured 534.1.

[0571] Step 8: 4-[4-[[4-[(1S)-3-hydroxy-1-methyl-propoxy]-5-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (830 mg, 1.56 mmol, 1.0 equiv.), 2-(tributyl-lambda) in toluene (20.0 mL) 5 Degas a mixture of (-phosphanylidene)acetonitrile (1.9 g, 7.87 mmol, 5.0 equiv.) and N 2 Purge the mixture three times with N 2 The mixture was stirred at 130° C. for 12 hours under atmospheric pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, DCM / EtOAc, EtOAc 0-100%, then DCM / MeOH (0.05% NH 3 H 2 O), MeOH (0.05% NH 3 H 2The crude product was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75×40 mm×3 um, mobile phase: [water (ammonia hydroxide v / v)-ACN], B%: 40%-70%, 9.5 min. Column temperature: 30° C.) to give (10S)-5,10-dimethyl-13-[1-methyl-4-(2,2,2-trifluoroethoxy)pyrrol-3-yl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1] as a white solid. 12,16 .0 2,6 ] Tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (127.8 mg, 15.7% yield, 99% purity) was obtained.

[0572] 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.57(s,1H),8.48(s,1H),8.13(d,J=6.0 Hz,1H),7.97(s,1H),6.92(d,J=2.5 Hz,1H),6.58(d,J=5.8 Hz,1H),6.44(d,J=2.5 Hz,1H),5.07-4.99(m,1H),4.63(dt,J=3.0,9.5 Hz,1H),4.32(q,J=8.7 Hz,2H),4.10(td,J=4.5,9.3 Hz,1H),3.75(s,3H),3.59(s,3H),2.29-2.17(m,2H),1.48(d,J=6.3 Hz,3H)

[0573] 19 F NMR (377 MHz, methanol-d 4 ) δppm-75.77(s,1F)

[0574] LCMS [M+H] + m / z: calculated 516.1, measured 516.1.

[0575] The regiochemistry was confirmed by HMBC (-CH 2 The chemical shift of -O- is 71.853 ppm.

[0576] Example 3: Preparation of compounds (28) and (25) Synthesis of inhibitor: 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 〕tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (compound (28)) and 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 ]Tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (compound (25)) [ka]

[0577] Step 1: Cyclopropanecarbonitrile (10.0 g, 149 mmol, 1.0 equiv.) in THF (150.0 mL), Pin 2 B 2 A mixture of (34.0 g, 134 mmol, 0.9 equiv.), 2,9-dimethyl-1,10-phenanthroline (1.0 g, 4.80 mmol, 0.03 equiv.), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (1.0 g, 1.51 mmol, 0.02 equiv.) was degassed and cooled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 90° C. for 12 hours under atmospheric pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-15%, flow rate = 100 mL / min, KMnO 4) to give 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarbonitrile (3.3 g, 11.4% yield) as a white solid.

[0578] 1 H NMR(400MHz,chloroform-d)δ ppm 1.49(td,J=5.4,8.2 Hz,1H),1.30(td,J=4.6,10.4 Hz,1H),1.23(s,12H),1.09(dt,J=4.0,7.8 Hz,1H),0.63(ddd,J=5.8,7.6,10.2 Hz,1H)

[0579] Step 2: THF (8.0 mL) and H 2 To a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarbonitrile (1.0 g, 5.18 mmol, 1.0 equiv) in 2HO (2.0 mL) was added NaIO 4 (1.66 g, 7.76 mmol, 1.5 equiv.) and 1M HCl / H 2 O (6.2 mL, 1.2 equiv.) was added. The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with saturated Na 2 S 2 O 3 Wash with aqueous solution (30 mL x 2) and brine (30 mL x 2) and add Na 2 SO 4 Dry at 40° C., filter and concentrate under reduced pressure to give (2-cyanocyclopropyl)boronic acid (600 mg, crude) as a yellow solid.

[0580] 1 H NMR (400MHz, methanol-d 4 )δ ppm 1.52(br s,1H),1.27-1.17(m,1H),1.04(dt,J=3.6,7.8 Hz,1H),0.70(br s,1H)

[0581] Step 3: 4-Bromo-3-ethoxy-1H-pyrazole (400 mg, 2.09 mmol, 1.0 equiv), (2-cyanocyclopropyl)boronic acid (600 mg, 5.41 mmol, 2.6 equiv), Cu(OAc) in DCE (10.0 mL) 2 (380mg, 2.09mmol, 1.0eq), Na 2 CO 3 A mixture of 2-(2-pyridyl)pyridine (440 mg, 4.15 mmol, 2.0 equiv.) and 2-(2-pyridyl)pyridine (340 mg, 2.18 mmol, 1.0 equiv.) was added to O 2 The mixture was stirred at 70° C. under atmospheric pressure for 2 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (100 mL). The combined organic layer was washed with brine (50 mL×2) and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-24%, flow rate = 80 mL / min, 254 nm) to give 2-(4-bromo-3-ethoxy-pyrazol-1-yl)cyclopropanecarbonitrile (400 mg, 65.6% yield, 88% purity) as a yellow solid.

[0582] LCMS(ESI)[M+H] + m / z: calculated 256.1, measured 258.1.

[0583] 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.66(s,1H),4.21(q,J=7.0 Hz,2H),4.16(dt,J=2.4,5.4 Hz,1H),2.15(ddd,J=3.2,6.6,10.0 Hz,1H),1.91(ddd,J=5.0,6.2,10.0 Hz,1H),1.65(td,J=6.4,8.2 Hz,1H),1.36(t,J=7.0 Hz,3H)

[0584] The regiochemistry was confirmed by NOE.

[0585] Step 4: DMF (20.0 mL) and H 2 2-(4-Bromo-3-ethoxy-pyrazol-1-yl)cyclopropanecarbonitrile (600 mg, 2.34 mmol, 1.0 equiv.), tert-butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (1.35 g, 3.05 mmol, 1.3 equiv.), [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (160 mg, 0.239 mmol, 0.1 equiv.) and Cs in 2O (2.0 mL). 2 CO 3 A mixture of (2.3 g, 7.06 mmol, 3.0 equiv.) was degassed and flushed with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 12 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The combined organic layer was washed with brine (30 mL×4) and diluted with Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 40 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-20%, flow rate: 100 mL / min, 254 nm) to give 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-chloro-3-pyridyl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (300 mg, 21.6% yield, 83% purity) as a yellow oil.

[0586] LCMS(ESI)[M+H] + m / z: calculated 491.2, measured 491.1.

[0587] 1H NMR(400MHz,chloroform-d)δ ppm 8.85(s,1H),7.84(s,1H),6.95(s,1H),4.86-4.77(m,1H),4.27(q,J=7.0 Hz,2H),3.77-3.71(m,2H),2.08-1.97(m,4H),1.67-1.62(m,2H),1.46(dd,J=2.2,6.2 Hz,3H),1.42-1.39(m,3H),0.91(d,J=1.6 Hz,9H),0.04(dd,J=2.8,7.8 Hz,6H).

[0588] Step 5: 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-chloro-3-pyridyl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (300 mg, 0.611 mmol, 1.0 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (200 mg, 0.622 mmol, 1.0 equiv.), Xantphos (100 mg, 0.173 mmol, 0.3 equiv.), Pd in ​​dioxane (20.0 mL) and DME (4.0 mL). 2 (dba) 3 (120 mg, 0.131 mmol, 0.2 equiv.) and Cs 2 CO 3 (600 mg, 1.84 mmol, 3.0 equiv.) was degassed and diluted with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 130° C. under atmospheric pressure for 12 h. The reaction mixture was filtered and the filter cake was washed with DCM (100 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-100%, to DCM / MeOH (0.05% NH 3 H 2HO, MeOH 0-15%, flow rate = 80 mL / min, 254 nm) to give 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-[[2-[2-methyl-3-oxo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrimidin-4-yl]amino]-3-pyridyl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (400 mg, 75.0% yield, 89% purity) as a yellow solid.

[0589] LCMS(ESI)[M+H] + m / z: calculated 776.4, measured 776.4.

[0590] Step 6: To a mixture of 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-[[2-[2-methyl-3-oxo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]pyrimidin-4-yl]amino]-3-pyridyl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (400 mg, 0.515 mmol, 1.0 equiv.) in THF (10.0 mL), 1M TBAF / THF (1.5 mL, 2.9 equiv.) was added and the mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®, column: SepaFlash® Sphercial C18, 60 g, 40-60 μm, 120 Å, MeCN / water (0.05% NH 3 -H 2 HO, MeCN 0-38%, 50 mL / min, 254 nm) to give 2-[3-ethoxy-4-[4-[(1S)-3-hydroxy-1-methyl-propoxy]-6-[[2-(5-hydroxy-1-methyl-pyrazol-4-yl)pyrimidin-4-yl]amino]-3-pyridyl]pyrazol-1-yl]cyclopropanecarbonitrile (200 mg, 64.2% yield, 88% purity) as a yellow solid.

[0591] LCMS [M+H] +m / z: calculated 532.2, measured 532.3.

[0592] Step 7: 2-[3-ethoxy-4-[4-[(1S)-3-hydroxy-1-methyl-propoxy]-6-[[2-(5-hydroxy-1-methyl-pyrazol-4-yl)pyrimidin-4-yl]amino]-3-pyridyl]pyrazol-1-yl]cyclopropanecarbonitrile (200 mg, 0.376 mmol, 1.0 equiv.) and 2-(tributyl-λ) in toluene (20.0 mL). 5 A mixture of (450 mg, 1.86 mmol, 5.0 equiv.)-phosphanylideneacetonitrile was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 130° C. for 12 hours under atmospheric pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-100%, DCM / MeOH (0.05% NH 3 H 2 The crude product was purified by preparative HPLC (column: Welch Xtimate C18 100×25 mm×3 um, mobile phase: [water (FA)-ACN], B%: 16%-46%, 8 min, column temperature: 30° C.) to give 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1]H2O as a white solid. 12,16 .0 2,6 ]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (44.3 mg, 22.6% yield) as a white solid, and 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6[tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-3-ethoxy-pyrazol-1-yl]cyclopropanecarbonitrile (7.2 mg, 3.6% yield). The major isomer was determined by 2D NMR to be the trans-substituted cyclopropane (relative configuration), i.e., compound (28).

[0593] LCMS [M+H] + m / z: calculated 514.2, measured 514.1.

[0594] Compound (28): 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.74(s,1H),8.63(d,J=2.4 Hz,1H),8.24(d,J=6.0 Hz,1H),8.03(s,1H),8.02(d,J=4.4 Hz,1H),6.70(d,J=6.0 Hz,1H),5.19(br d,J=3.8 Hz,1H),4.78-4.72(m,1H),4.34-4.23(m,4H),3.83(s,3H),2.45-2.28(m,2H),2.21(ddd,J=3.4,6.4,9.8 Hz,1H),2.01-1.93(m,1H),1.73-1.67(m,1H),1.60(d,J=6.2 Hz,3H),1.43(t,J=7.0 Hz,3H).

[0595] Compound (25): 1 H NMR (400MHz, methanol-d 4)δ ppm 8.69(d,J=2.0 Hz,1H),8.67(br d,J=3.6 Hz,1H),8.19(d,J=6.2 Hz,1H),8.04(s,1H),8.02(s,1H),6.68(d,J=6.0 Hz,1H),5.16-5.09(m,1H),4.68(dt,J=2.8,9.8 Hz,1H),4.37(q,J=7.0 Hz,2H),4.26-4.19(m,1H),4.07-4.00(m,1H),3.81(s,3H),2.43-2.22(m,2H),2.15(td,J=6.8,8.8 Hz,1H),2.08-2.00(m,1H),1.78-1.70(m,1H),1.58(d,J=6.2 Hz,3H),1.45(t,J=7.0 Hz,3H).

[0596] Example 4: Preparation of compound (58) Synthesis of inhibitor: 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 ]Tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-5-ethoxy-pyrazol-1-yl]-N,N-dimethyl-ethanamine (compound (58)) [ka]

[0597] Step 1: tert-Butyl N-(1,3-dioxoisoindolin-2-yl)carbamate (5 g, 19.06 mmol, 1.0 equiv.), 2-chloro-N,N-dimethyl-ethanamine; hydrochloride (5.5 g, 38.18 mmol, 2.0 equiv.) and K in DMF (80.0 mL). 2 CO 3 (8 g, 57.88 mmol, 3.0 equiv.) was stirred at 50° C. for 12 h. The reaction mixture was diluted with saturated Na 2 CO 3The mixture was quenched by the addition of aqueous solution (50 mL) and then extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine (40 mL×3) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave tert-butyl N-[2-(dimethylamino)ethyl]-N-(1,3-dioxoisoindolin-2-yl)carbamate (4 g, 47.8% yield, 76% purity) as a yellow oil. LCMS [M+H] + m / z: Calculated value 334.2, Measured value 334.2

[0598] Step 2: tert-Butyl N-[2-(dimethylamino)ethyl]-N-(1,3-dioxoisoindolin-2-yl)carbamate (4 g, 12.00 mmol, 1.0 equiv.) and N 2 H 4 -H 2 A mixture of O (6.46 g, 126.46 mmol, 98% purity, 10.5 equiv) was stirred for 2.5 h at 70° C. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-amino-N-[2-(dimethylamino)ethyl]carbamate (2 g, 82.0% yield) as a yellow oil.

[0599] 1 H NMR(400MHz,chloroform-d)δ ppm 3.83(br s,2H),3.48(t,J=6.7 Hz,2H),2.48(br t,J=6.5 Hz,2H),2.26(s,6H),1.46(s,9H).

[0600] LCMS[M+H] + m / z: Calculated 204.2, Measured 204.3

[0601] Step 3: A mixture of tert-butyl N-amino-N-[2-(dimethylamino)ethyl]carbamate (2 g, 9.84 mmol, 1.0 equiv) in MeOH (10.0 mL) and (50.0 mL) 4M HCl / MeOH was stirred for 1 h at 20° C. The reaction mixture was concentrated under reduced pressure to give 2-hydrazino-N,N-dimethyl-ethanamine; dihydrochloride (2 g, crude) as a yellow solid.

[0602] 1 H NMR (400MHz, methanol-d 4 )δ ppm 3.41-3.36(m, 2H),3.36-3.34(m,2H),2.94(s,6H)

[0603] Step 4: A mixture of 2-hydrazino-N,N-dimethyl-ethanamine; dihydrochloride (1.9 g, 10.79 mmol, 1.0 equiv.), ethyl (E)-3-ethoxyprop-2-enoate (4.0 mL, 27.69 mmol, 2.6 equiv.) and (30.0 mL) 1M HCl / H2O (2.8 equiv.) in EtOH (50.0 mL) was stirred at 80 °C for 4 h. The mixture was adjusted to pH > 10 with 1N aqueous NaOH and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, MeOH (0.05 v% TEA) / DCM, MeOH (0.05 v% TEA) 0-20%, flow rate: 80 mL / min, 254 nm) to give 2-(5-ethoxypyrazol-1-yl)-N,N-dimethyl-ethanamine (0.63 g, 31.9% yield) as a yellow oil.

[0604] 1H NMR(400MHz,chloroform-d)δ ppm 7.31(d,J=1.8 Hz,1H),5.47(d,J=1.6 Hz,1H),4.17-4.08(m,4H),2.89(t,J=6.8 Hz,2H),2.38(s,6H),1.42(t,J=7.1 Hz,3H)

[0605] LCMS [M+H] + m / z: calculated 184.1, measured 184.0.

[0606] Step 5: To a mixture of 2-(5-ethoxypyrazol-1-yl)-N,N-dimethyl-ethanamine (0.63 g, 3.44 mmol, 1.0 equiv) in THF (15.0 mL) was added NBS (700 mg, 3.93 mmol, 1.1 equiv) at -30° C. and the mixture was stirred at -30° C. for 1 h. The reaction mixture was cooled to 20° C. with saturated Na 2 SO 3 The mixture was quenched by the addition of aqueous solution (20 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (30 mL×3) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 2-(4-bromo-5-ethoxy-pyrazol-1-yl)-N,N-dimethyl-ethanamine (700 mg, 59.0% yield, 76% purity) as a yellow oil.

[0607] 1 H NMR(400MHz,chloroform-d)δ ppm 7.31(s,1H),4.39(q,J=7.0 Hz,2H),4.13(t,J=6.9 Hz,2H),2.82(t,J=6.9 Hz,2H),2.36(s,6H),1.42(t,J=7.0 Hz,3H)

[0608] LCMS [M+H] + m / z: Calculated value 262.0, Measured value 262.0

[0609] Step 6: DMF (15.0 mL) and H 2A mixture of 2-(4-bromo-5-ethoxy-pyrazol-1-yl)-N,N-dimethyl-ethanamine (700 mg, 2.67 mmol, 1.0 equiv.), tert-butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (3 g, 6.78 mmol, 2.5 equiv.), [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (180 mg, 0.269 mmol, 0.1 equiv.), and Cs in 2O (1.5 mL). 2 CO 3 (2.6 g, 7.98 mmol, 3.0 equiv.) was degassed and the mixture was then flushed with N 2 The mixture was stirred at 80° C. for 12 hours under reduced pressure. The reaction mixture was filtered. The filtrate was diluted with saturated Na 2 CO 3 The mixture was diluted with aqueous solution (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (60 mL×3) and diluted with Na 2 SO 4 The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, MeOH (0.05 v% TEA) / DCM, MeOH (0.05 v% TEA) 0-15%, flow rate: 80 mL / min, 254 nm) to give 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-chloro-3-pyridyl]-5-ethoxy-pyrazol-1-yl]-N,N-dimethyl-ethanamine (1.1 g, 34.0% yield, 41% purity) as a yellow oil.

[0610] LCMS [M+H] + m / z: calculated 497.3, measured 497.2.

[0611] Step 7: 2-[4-[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-6-chloro-3-pyridyl]-5-ethoxy-pyrazol-1-yl]-N,N-dimethyl-ethanamine (1.1 g, 2.21 mmol, 1.0 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (560 mg, 1.74 mmol, 0.8 equiv.), Xantphos (130 mg, 0.225 mmol, 0.1 equiv.), Cs in dioxane (25.0 mL) and DME (2.5 mL). 2 CO 3 (2 g, 6.14 mmol, 2.8 equiv.), and Pd 2 (dba) 3 (202 mg, 0.221 mmol, 0.1 equiv.) was degassed and then diluted with N 2 The mixture was stirred at 130° C. for 12 hours under atmospheric pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, MeOH (0.05 v% NH 3 .H 2 O) / DCM, MeOH (0.05v% NH 3 .H 2 HCl (0-12%, flow rate: 80 mL / min, 254 nm) to give 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[1-[2-(dimethylamino)ethyl]-5-ethoxy-pyrazol-4-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (900 mg, 24.4% yield, 47% purity) as a yellow oil.

[0612] LCMS [M+H] + m / z: calculated 782.4, measured 782.5.

[0613] Step 8: A mixture of 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[1-[2-(dimethylamino)ethyl]-5-ethoxy-pyrazol-4-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (900 mg, 1.15 mmol, 1.0 equiv.) in THF (15.0 mL) and (4.0 mL) 1M TBAF / THF was stirred at 70° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®, column: SepaFlash® Sphercial C18, 60 g, 40-60 μm, 120 Å, MeCN / water (0.05% NH 3 -H 2 0, MeCN 0-31%, 50 mL / min, 254 nm) to give 4-[4-[[5-[1-[2-(dimethylamino)ethyl]-5-ethoxy-pyrazol-4-yl]-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (700 mg, crude) as a yellow oil.

[0614] LCMS [M+H] + m / z: calculated 538.3, measured 538.3.

[0615] Step 9: 4-[4-[[5-[1-[2-(dimethylamino)ethyl]-5-ethoxy-pyrazol-4-yl]-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (700 mg, 1.30 mmol, 1.0 equiv.) and 2-(tributyl-lambda) in Tol (30.0 mL). 5 A mixture of (1.57 g, 6.51 mmol, 5.0 equiv.)-phosphanylidene)acetonitrile was added to N 2The mixture was stirred at 130° C. for 12 h under reduced pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 12 g SepaFlash® silica flash column, DCM / MeOH (0.05% NH 3 .H 2 O), MeOH (0.05% NH 3 .H 2 The crude product was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75×40mm×3um, mobile phase: [water (NH 4 HCO 3 )-ACN], B%: 30%~60%, 7.8 min, column temperature 30 °C) to give 2-[4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 ]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-5-ethoxy-pyrazol-1-yl]-N,N-dimethyl-ethanamine (54.6 mg, yield 7.9%, purity 97.35%) was obtained.

[0616] 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.69(s,1H),8.19-8.16(m,2H),7.99(s,1H),7.58(s,1H),6.63(d,J=5.8 Hz,1H),5.13-5.05(m,1H),4.65(dt,J=3.4,9.5 Hz,1H),4.22-4.13(m,3H),4.05-3.95(m,2H),3.77(s,3H),2.79(t,J=6.8 Hz,2H),2.31(s,6H),2.29-2.20(m,2H),1.47(d,J=6.3 Hz,3H),1.30(t,J=7.0 Hz,3H)

[0617] LCMS [M+H] + m / z: calculated 520.3, measured 520.2.

[0618] Example 5: Preparation of compound (96) Synthesis of inhibitor: (10S)-13-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (96)) [ka]

[0619] Step 1: To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5 g, 24.8 mmol, 1.0 equiv) in DCM (50.0 mL) was added Et 3 N (99.4 mmol, 13.8 mL, 4.0 equiv.) and 4-methylbenzenesulfonyl chloride (9.47 g, 49.7 mmol, 2.0 equiv.) were added. The mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated. The residue was purified by H 2 The mixture was diluted with 2×O (100 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (150 mL×1) and anhydrous Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 80 g SepaFlash® silica flash column, petroleum ether gradient / EtOAc, EtOAc 0-50%, 100 mL / min, 254 nm) to give tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (6.9 g, 77.3% yield, 99% purity) as an off-white solid.

[0620] 1 H NMR (400 MHz, CDCl 3)δ ppm 7.80(d,J=8.4 Hz,2H),7.35(d,J=8.0 Hz,2H),4.68(tt,J=3.6,7.2 Hz,1H),3.63-3.56(m,2H),3.29-3.21(m,2H),2.46(s,3H),1.81-1.66(m,4H),1.46-1.42(m,9H).

[0621] LCMS(ESI)[M+H] + m / z: calculated 378.1, measured 378.0.

[0622] Step 2: To a solution of 3-ethoxy-1H-pyrazole (1 g, 8.92 mmol, 1.0 equiv) in DMF (20.0 mL) was added NBS (2.38 g, 13.4 mmol, 1.5 equiv). The mixture was stirred at -25 °C for 2 h. The reaction mixture was diluted with saturated Na 2 CO 3 The mixture was diluted with aqueous solution (50.0 mL) and extracted with EtOAc (80 mL×2). The combined organic layers were washed with brine (80 mL×1) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-20%, 40 mL / min, 254 nm) to give 4-bromo-3-ethoxy-1H-pyrazole (1.5 g, 88.1% yield, 100% purity) as a white solid.

[0623] 1 H NMR(400 MHz,MeOD)δ ppm 7.52(s,1H),4.21(q,J=7.2 Hz,2H),1.37(t,J=7.2 Hz,3H).

[0624] LCMS(ESI)[M+H] + m / z: calculated 191.0, measured 190.8.

[0625] Step 3: To a solution of 4-bromo-3-ethoxy-1H-pyrazole (850 mg, 4.45 mmol, 1.0 equiv) in DMF (10.0 mL) was added NaH (534 mg, 13.4 mmol, 60 wt% in mineral oil, 3.0 equiv) at 20° C. for 30 min. Then tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (2.05 g, 5.77 mmol, 1.30 equiv) was added and the mixture was stirred at 90° C. for 12 h. The reaction mixture was cooled to 0° C. and cooled to 5° C. with H 2 The mixture was quenched by the addition of 2H2O (50 mL) and then extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (50 mL x 2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 12 g SepaFlash® silica flash column, petroleum ether gradient / EtOAc, EtOAc 0-5%, 40 mL / min, 254 nm). The crude was purified by preparative HPLC (column: Welch Xtimate C18 100×40 mm×3 μm; mobile phase: [water (TFA)-ACN]; B%: 40%-70%, 10 min) to give tert-butyl 4-(4-bromo-3-ethoxy-pyrazol-1-yl)piperidine-1-carboxylate (380 mg, 21.5% yield, 94% purity) as a colorless oil.

[0626] 1 H NMR(400 MHz,MeOD)δ ppm 7.55(s,1H),4.25-4.08(m,5H),3.02-2.81(m,2H),2.04-1.95(m,2H),1.82(dq,J=4.4,12.0 Hz,2H),1.47(s,9H),1.35(t,J=7.2 Hz,3H).

[0627] LCMS(ESI)[M+H] + m / z: calculated 374.1, measured 375.9.

[0628] Step 4: To a solution of tert-butyl 4-(4-bromo-3-ethoxy-pyrazol-1-yl)piperidine-1-carboxylate (380 mg, 1.02 mmol, 1.0 equiv) in MeOH (5.0 mL) was added 4M HCl / MeOH (5.0 mL, 20 mmol, 19.70 equiv). The mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated. The residue was diluted with MeOH (10 mL) and washed with saturated Na 2 CO 3 The pH was adjusted to about 8 by addition of aqueous solution and concentrated under reduced pressure to give 4-(4-bromo-3-ethoxy-pyrazol-1-yl)piperidine (270 mg, crude) as a yellow oil.

[0629] LCMS(ESI)[M+H] + m / z: calculated 274.0, measured 275.8.

[0630] Step 5: A solution of 4-(4-bromo-3-ethoxy-pyrazol-1-yl)piperidine (260 mg, 0.948 mmol, 1.0 equiv.) and formaldehyde (154 mg, 1.90 mmol, 37% purity, 2.0 equiv.) in DCE (10.0 mL) was added to CH 3 COOH (285 mg, 4.74 mmol, 5.0 equiv.) was added. The mixture was stirred at 20° C. for 30 min. Then, NaBH(OAc) 3 (1.0 g, 4.74 mmol, 5.0 equiv) was added and the mixture was stirred at 20° C. for 1 h. 2 The mixture was diluted with 2×O (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL×1) and anhydrous Na 2 SO 4 The residue was purified by flash chromatography (ISCO®, 4 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-100%, then EtOAc / MeOH, MeOH 0-20%, 18 mL / min, 254 nm) to give 4-(4-bromo-3-ethoxy-pyrazol-1-yl)-1-methyl-piperidine (260 mg, 95.1% yield, 100% purity) as a yellow oil.

[0631] 1 H NMR (400 MHz, CD 3 OD)δ ppm 7.55(s,1H),4.20(q,J=7.2 Hz,2H),3.97(tt,J=5.2,10.4 Hz,1H),2.98(br d,J=12.0 Hz,2H),2.33(s,3H),2.23(dt,J=3.6,11.6 Hz,2H),2.06-1.96(m,4H),1.35(t,J=7.2 Hz,3H).

[0632] LCMS(ESI)[M+H] + m / z: calculated 288.1, measured 287.9.

[0633] Step 6: Dioxane (5.0 mL) and H 2 4-(4-Bromo-3-ethoxy-pyrazol-1-yl)-1-methyl-piperidine (250 mg, 0.868 mmol, 1.0 equiv.), tert-Butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (498 mg, 1.13 mmol, 1.3 equiv.), Pd(dppf)Cl in O (1.0 mL). 2 (127mg, 0.174mmol, 0.2eq), Na 2 CO 3 A mixture of (184 mg, 1.74 mmol, 2.0 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. for 4 hours under atmospheric conditions. 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 1) and anhydrous Na 2 SO 4The residue was purified by flash chromatography (ISCO®, 4 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-100%, then EtOAc / MeOH, MeOH 0-20%, 18 mL / min, 254 nm) to give tert-butyl-[(3S)-3-[[2-chloro-5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (140 mg, 19.4% yield, 63% purity) as a yellow oil.

[0634] LCMS(ESI)[M+H] + m / z: calculated 523.3, measured 523.3.

[0635] Step 7: tert-Butyl-[(3S)-3-[[2-chloro-5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-pyridyl]oxy]butoxy]-dimethyl-silane (90 mg, 0.172 mmol, 1.0 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (61 mg, 0.189 mmol, 1.1 equiv.), Pd 2 (dba) 3 (32mg, 0.0344mmol, 0.2eq), Cs 2 CO 3(168 mg, 0.516 mmol, 3.0 equiv.) and Xantphos (40 mg, 0.0688 mmol, 0.4 equiv.) were taken in dioxane (2.0 mL) in a microwave tube. The sealed tube was heated in a microwave at 130° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 4 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-100%, EtOAc / MeOH, MeOH 0-20%, 18 mL / min, 254 nm) to give 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (80 mg, 28.8% yield, 50% purity) as a pale yellow solid.

[0636] LCMS(ESI)[M+H] + m / z: calculated 808.5, measured 808.7.

[0637] Step 8: To a solution of 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (80 mg, 0.0496 mmol, 50% purity, 1.0 equiv.) in THF (5.0 mL) was added 1M TBAF / THF (0.1 mL, 0.1 mmol, 2.0 equiv.). The mixture was stirred at 75° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: SepaFlash® Sphercial C18, 40 g, 40-60 μm, 120 Å, MeCN / water (0.5% NH 3 -H 2HO), MeCN 0-30%, 50 mL / min, 254 nm) to give 4-[4-[[5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (25 mg, 83.3% yield, 93% purity) as a yellow solid.

[0638] LCMS(ESI)[M+H] + m / z: calculated 564.3, measured 564.3.

[0639] Step 9: To a solution of 4-[4-[[5-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (25 mg, 0.0444 mmol, 1.0 equiv.) in toluene (15.0 mL) was added 2-(tributyl-λ5-phosphanylidene)acetonitrile (54 mg, 0.222 mmol, 5.0 equiv.). The mixture was cooled to 50° C. for 2 hours at 4° C. for 1 hour. 2 The mixture was stirred at 130° C. for 12 h under reduced pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 4 g SepaFlash® silica flash column, DCM / EtOAc, EtOAc 0-100%, DCM / MeOH, MeOH 0-20%, 18 mL / min, 254 nm). The crude product was purified by preparative HPLC (column: 2_Phenomenex Gemini C18 75×40 mm×3 μm, mobile phase: [water (NH 4 HCO 3)-ACN], B%: 37%-67%, 9.5 min) to give (10S)-13-[3-ethoxy-1-(1-methyl-4-piperidyl)pyrazol-4-yl]-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (4.3 mg, 17.7% yield, 99% purity) as a white solid.

[0640] 1 H NMR (400 MHz, CD 3 OD)δ ppm 8.73(s,1H),8.65(s,1H),8.22(d,J=6.0 Hz,1H),8.02(s,1H),7.94(s,1H),6.68(d,J=6.0 Hz,1H),5.22-5.12(m,1H),4.77-4.72(m,1H),4.31(q,J=7.2 Hz,2H),4.27-4.21(m,1H),4.11-4.00(m,1H),3.82(s,3H),3.05(br d,J=12.0 Hz,2H),2.42-2.28(m,7H),2.16-2.02(m,4H),1.58(d,J=6.4 Hz,3H),1.43(t,J=7.2 Hz,3H).

[0641] LCMS(ESI)[M+Na] + m / z: calculated 568.3, measured 568.2.

[0642] Example 6: Preparation of compound (105) Synthesis of inhibitor: (10S)-13-(3-ethoxy-1-methyl-pyrazol-4-yl)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (105)) [ka]

[0643] Step 1: To a solution of 2-methyl-1H-pyrazol-5-one (2 g, 20.4 mmol, 1 equiv.) in DCM (100 mL), add NaHCO 3 (2.06g, 24.5mmol, 1.2eq), Br 2 (1.20 mL, 23.2 mmol, 1.14 equiv.) was added. The mixture was stirred at 0° C. for 2 h. The resulting mixture was diluted with saturated Na 2 SO 3 The mixture was quenched by the addition of aqueous solution (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 4-bromo-2-methyl-1H-pyrazol-5-one (2 g, crude) as a pale yellow solid.

[0644] LCMS(ESI)[M+H] + m / z calculated 178.9, measured 178.7.

[0645] Step 2: To a solution of 4-bromo-2-methyl-1H-pyrazol-5-one (2 g, 11.3 mmol, 1 equiv.) in DMF (20 mL), 2 CO 3 (4.0 g, 28.9 mmol, 2.56 equiv) was added. The mixture was stirred at 50° C. for 1 h. Iodoethane (2.20 g, 14.1 mmol, 1.25 equiv) was added and the mixture was stirred at 50° C. for 1 h. The resulting mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL) and anhydrous Na 2 Drying over SO4, filtration and concentration under reduced pressure gave 4-bromo-3-ethoxy-1-methyl-pyrazole (2.0 g, crude) as a yellow oil.

[0646] LCMS(ESI)[M+H] + m / z calculated 205.0, measured 204.9.

[0647] Step 3: Dioxane (50 mL) / H 2To a solution of tert-butyl-[(3S)-3-[[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (3.5 g, 7.92 mmol, 1.62 equiv.), 4-bromo-3-ethoxy-1-methyl-pyrazole (1 g, 4.88 mmol, 1 equiv.) in 2H2O (10 mL), Pd(dppf)Cl 2 (400 mg, 0.547 mmol, 0.11 equiv), K3PO4 (3.50 g, 16.5 mmol, 3.38 equiv) were added. The mixture was stirred at 80 °C under nitrogen for 2 h. The resulting mixture was quenched by the addition of water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated NH 4 Wash with aqueous Cl (100 mL × 2), brine (100 mL), and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave tert-butyl-[(3S)-3-[[2-chloro-5-(3-ethoxy-1-methyl-pyrazol-4-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (800 mg, 37.3% yield) as a yellow oil.

[0648] LCMS(ESI)[M+H] + m / z calculated 440.2, measured 440.2.

[0649] Step 4: To a solution of tert-butyl-[(3S)-3-[[2-chloro-5-(3-ethoxy-1-methyl-pyrazol-4-yl)-4-pyridyl]oxy]butoxy]-dimethyl-silane (450 mg, 1.02 mmol, 1 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (430 mg, 1.34 mmol, 1.31 equiv.) in dioxane (15 mL), Pd 2 (dba) 3 (130mg, 0.142mmol, 0.14eq), Cs 2 CO 3(1.01 g, 3.11 mmol, 3.04 equiv) and Xantphos (178 mg, 0.308 mmol, 0.30 equiv) were added. The mixture was stirred at 130° C. for 2 h in a microwave. The resulting mixture was filtered and washed with DCM / MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue (combined with ES17560-230-P1) was purified by flash chromatography (ISCO®; 40 g SepaFlash® silica flash column, DCM / MeOH, MeOH 0-15%, 30 mL / min flow rate, 254 nm) to give 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-(3-ethoxy-1-methyl-pyrazol-4-yl)-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (700 mg, 65.4% yield) as a yellow solid.

[0650] LCMS(ESI)[M+H] + m / z calculated 725.4, measured 725.4.

[0651] Step 5: To a solution of 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-(3-ethoxy-1-methyl-pyrazol-4-yl)-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (700 mg, 0.965 mmol, 1 equiv.) in MeOH (5 mL) was added 4M HCl / MeOH (5 mL, 20 mmol). The mixture was stirred at 40° C. for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by H 2The mixture was diluted with 2H2O (5 mL), adjusted to pH = 9 with saturated aqueous Na2CO3, and then extracted with DCM / i-PrOH (60 mL x 3, v / v = 20 / 1). The combined organic layers were concentrated under reduced pressure to give 4-[4-[[5-(3-ethoxy-1-methyl-pyrazol-4-yl)-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1H-pyrazol-3-one (360 mg, crude) as a yellow solid.

[0652] LCMS(ESI)[M+H] + m / z calculated 481.2, measured 481.1.

[0653] Step 6: To a solution of 4-[4-[[5-(3-ethoxy-1-methyl-pyrazol-4-yl)-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1H-pyrazol-3-one (360 mg, 0.749 mmol, 1 equiv.) in toluene (50 mL) was added CMBP (900 mg, 3.73 mmol, 4.98 equiv.). The mixture was stirred at 130° C. for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 12 g SepaFlash® silica flash column, DCM / EtOAc, EtOAc 0-100%, then DCM / MeOH, MeOH 0-18%, flow rate 50 mL / min, 254 nm) to give the crude product (200 mg, yellow solid). The crude product was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector, Column: 2_Phenomenex Gemini C18 75×40mm×3um, Mobile Phase A: 0.05% NH 3 -H 2 H with O(v%) 2HO, mobile phase B: MeCN, gradient: 35% to 68% B in 7.8 min, 100% B held for 2 min, flow rate: 25 mL / min, column temperature: 30 °C, wavelength: 220 nm, 254 nm) to give (10S)-13-(3-ethoxy-1-methyl-pyrazol-4-yl)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (123 mg, 35.5% yield).

[0654] 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.67-8.71(m,1 H),8.65(s,1 H),8.18-8.23(m,1 H),8.02(s,1 H),7.83(s,1 H),6.64-6.69(m,1 H),5.11-5.20(m,1 H),4.73(br d,J=3.0 Hz,1 H),4.30(q,J=7.0 Hz,2 H),4.17-4.25(m,1 H),3.80(d,J=12.0 Hz,6 H),2.24-2.41(m,2 H),1.58(d,J=6.3 Hz,3 H),1.44(t,J=7.0 Hz,3 H).

[0655] LCMS(ESI)[M+H] + m / z calculated 463.2, measured 463.2.

[0656] Example 7: Preparation of compound (151) Synthesis of inhibitor: (10S)-13-chloro-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (151)) [ka]

[0657] Step 1: 2-Bromo-5-chloro-pyridin-4-ol (1 g, 4.80 mmol, 1 equiv.), PPh 3 A mixture of (3.77 g, 14.4 mmol, 3 equiv.) and THF (20 mL) was cooled to 0° C., then di-tert-butyl azodicarboxylate (3.31 g, 14.4 mmol, 3 equiv.) in THF (5 mL) was added at 0° C. The mixture was stirred at 0° C. for 1 h, then (2R)-4-[tert-butyl(dimethyl)silyl]oxybutan-2-ol (1.20 g, 5.87 mmol, 1.22 equiv.) was added at 0° C. The mixture was stirred at 20° C. for 11 h. The resulting mixture was quenched by the addition of water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated NH 4 Wash with aqueous Cl (100 mL × 2), brine (100 mL), and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 24 g AgelaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-10%, flow rate: 30 mL / min) to give [(3S)-3-[(2-bromo-5-chloro-4-pyridyl)oxy]butoxy]-tert-butyl-dimethyl-silane (1.11 g, 58.6% yield) as a yellow oil.

[0658] 1 H NMR(400MHz,chloroform-d)δ ppm 8.13-8.19(m,1 H),7.04(s,1 H),4.71(sxt,J=6.2 Hz,1 H),3.64-3.75(m,2 H),1.92-2.03(m,1 H),1.73-1.82(m,1 H),1.58(d,J=4.5 Hz,1 H),1.38(d,J=6.0 Hz,3 H),0.80-0.86(m,9 H),-0.02(d,J=13.8 Hz,6 H).

[0659] Step 2: [(3S)-3-[(2-bromo-5-chloro-4-pyridyl)oxy]butoxy]-tert-butyl-dimethyl-silane (1 g, 2.53 mmol, 1 equiv.), 4-(4-aminopyrimidin-2-yl)-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (900 mg, 2.80 mmol, 1.11 equiv.), Pd 2 (dba) 3 (260mg, 0.284mmol, 1.12e-1eq), Xantphos (300mg, 0.518mmol, 0.205eq), Cs 2 CO 3 A mixture of (1.66 g, 5.09 mmol, 2.01 equiv) and dioxane (15 mL) was stirred in a microwave at 130 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 24 g AgelaFlash® silica flash column, DCM / MeOH, MeOH 0-20%, flow rate: 30 mL / min) to give the crude product, which was purified by flash chromatography (Column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120 Å, MeCN / water (0.5% NH 3 -H 2 HO, MeCN 0-89%, 25 mL / min, 220 nm) to give 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-chloro-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (320 mg, 18.9% yield, 95% purity) as a yellow oil.

[0660] LCMS(ESI)[M+H] + m / z: calculated 635.3, measured 635.3.

[0661] Step 3: A mixture of 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-chloro-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol-3-one (320 mg, 0.504 mmol, 1 eq.), 4-[4-[[4-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-methyl-propoxy]-5-chloro-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-1H-pyrazol-3-one (320 mg, 0.634 mmol, 1 eq.), and 1M TBAF / THF (2.0 mL, 2.0 mmol, 2.12 eq.) and THF (4 mL) was stirred at 70 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography (column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120 Å, MeCN / water (0.5% NH 3 -H 2 0, MeCN 0-45%, 25 mL / min, 220 nm) to give 4-[4-[[5-chloro-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (500 mg, crude) as a yellow oil. LCMS (ESI) [M+H] + m / z: calculated 391.1, measured 391.0.

[0662] Step 4: A mixture of 4-[4-[[5-chloro-4-[(1S)-3-hydroxy-1-methyl-propoxy]-2-pyridyl]amino]pyrimidin-2-yl]-2-methyl-pyrazol-3-ol (400 mg, 1.02 mmol, 1 eq.), 2-(tributyl-λ5-phosphanylidene)acetonitrile (1.24 g, 5.14 mmol, 5.02 eq.) and toluene (20 mL) was stirred for 12 h at 130° C. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 24 g AgelaFlash® silica flash column, DCM / MeOH, MeOH 0–10%, flow rate: 30 mL / min, 254 nm) to give (10S)-13-chloro-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (700 mg, crude) as a yellow solid. 20 mg of this crude product was separated by preparative HPLC (instrument: Gilson GX-281 liquid handler, Gilson 322 pump, Gilson 156 UV detector, column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase A: 0.05% NH 3 -H 2 H containing O (v%) 2 HO, mobile phase B: MeCN, gradient: 52% to 82% B in 9.5 min, 100% B held for 2.5 min, flow rate: 25 mL / min, column temperature: 30 °C, wavelength: 220 nm, 254 nm) to give (10S)-13-chloro-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.112,16.02,6]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (5 mg) as a white solid.

[0663] 1 H NMR (400MHz, methanol-d 4)δ ppm 8.83(s,1 H),8.25(d,J=6.4 Hz,1 H),8.17(s,1 H),8.10(s,1 H),6.82(d,J=6.4 Hz,1 H),5.13-5.19(m,1 H),4.68-4.74(m,1 H),4.32-4.41(m,2 H),3.88(s,3 H),2.33-2.41(m,2 H),1.59(d,J=6.3 Hz,3 H).

[0664] LCMS(ESI)[M+H] + m / z: calculated 373.1, measured 373.1.

[0665] Example 8: Preparation of compound (127) Synthesis of inhibitor: (10S)-5,10-dimethyl-13-[1-methyl-5-[(4-methylpiperazin-1-yl)methyl]pyrrol-3-yl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1 12,16 .0 2,6 ]Tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (compound (127)) [ka]

[0666] Step 1: To a solution of (4-bromo-1H-pyrrole-2-carbaldehyde (1 g, 5.75 mmol, 1.0 equiv.) in DMF (20.0 mL), NaH (500 mg, 12.5 mmol, 60 wt% purity in mineral oil, 2.2 equiv.) was added at 0° C. After the addition, the mixture was stirred at 0° C. for 30 min, and then MeI (1.82 g, 12.9 mmol, 2.2 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into ice water (3 mL) and stirred for 3 min. The aqueous phase was extracted with EtOAc (20 mL×2) and the combined organic phase was washed with brine (15 mL×3) and anhydrous Na 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 20 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-15%, flow rate: 80 mL / min, 254 nm) to give 4-bromo-1-methyl-pyrrole-2-carbaldehyde (1 g, 74.3% yield, 80% purity) as a pale yellow oil.

[0667] LCMS [M+H] + m / z: calculated 187.9, measured 189.7.

[0668] Step 2: 4-Bromo-1-methyl-pyrrole-2-carbaldehyde (300 mg, 1.60 mmol, 1.0 equiv.) in dioxane (10.0 mL), (Bpin) 2 (810mg, 3.19mmol, 2.0eq), Pd(dppf)Cl 2 -DCM (130 mg, 0.159 mmol, 0.1 equiv.) and KOAc (314 mg, 3.20 mmol, 2.0 equiv.) were degassed and then diluted with N 2 The mixture was heated to 100° C. under reduced pressure for 12 h. The reaction mixture was filtered, the filter cake was washed with EtOAc (10 mL×2), and then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®, 12 g SepaFlash® silica flash column, petroleum ether / EtOAc, EtOAc 0-20%, flow rate: 80 mL / min, 254 nm) to give 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-2-carbaldehyde (190 mg, 42.0% yield, 83% purity) as a pale yellow solid.

[0669] LCMS [M+H] + m / z: Calculated value 236.1, measured value 236.0

[0670] Step 3: Dioxane (5.0 mL) and H 2Compound (151) (50 mg, 0.134 mmol, 1.0 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-2-carbaldehyde (90 mg, 0.382 mmol, 2.9 equiv.), XPhos-Pd-G2 (11 mg, 0.013 mmol, 0.1 equiv.), XPhos (7 mg, 0.014 mmol, 1.0 equiv.), and Cs in O (1.0 mL). 2 CO 3 A mixture of (90 mg, 0.276 mmol, 2.0 equiv.) was degassed and then washed with N 2 The mixture was heated at 95° C. for 12 h under reduced pressure. The mixture was filtered, the filter cake was washed with DCM (10 mL×2), and then the combined filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, MeOH (0.05% TEA) / DCM, MeOH (0.05% TEA) 0-20%, flow rate: 30 mL / min, 254 nm) to give compound 4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1] as a pale yellow solid. 12,16 .0 2,6 ]tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-1-methyl-pyrrole-2-carbaldehyde (89 mg, crude).

[0671] LCMS [M+H] + m / z: calculated 446.2, measured 446.0.

[0672] Step 4: 4-[(10S)-5,10-dimethyl-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo-[16.3.1.1 12,16 .0 2,6]-tricosa-1(22),2(6),3,12(23),13,15,18,20-octaen-13-yl]-1-methyl-pyrrole-2-carbaldehyde (89 mg, 0.199 mmol, 1.0 equiv.), 1-methylpiperazine (105 mg, 1.05 mmol, 5.3 equiv.) and Ti(OEt) 4 (240 mg, 1.05 mmol, 5.3 equiv.) was stirred at 70 °C for 12 h. Then, NaBH 3 CN (73 mg, 1.16 mmol, 5.8 equiv) was added and the mixture was stirred at 30° C. for 30 min. The reaction mixture was diluted with H 2 O (0.2 mL) and saturated Na 2 CO 3 The mixture was quenched by the addition of aqueous solution (0.2 mL), then silica gel was added and the mixture was diluted with Na 2 SO 4 The mixture was stirred at 20° C. for 15 min. The mixture was filtered, the filter cake was washed with DCM / MeOH (15 mL×5, v / v:10 / 1), and the combined filtrate was washed with Na 2 SO 4 The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 30%~60%, 9.5 min. Temperature: 30°C) to give (10S)-5,10-dimethyl-13-[1-methyl-5-[(4-methylpiperazin-1-yl)methyl]pyrrol-3-yl]-7,11-dioxa-4,5,15,17,21,22-hexaazatetracyclo[16.3.1.1] as a white solid. 12,16 .0 2,6 ] Tricosa-1(22),2(6),3,12(23),13,15,18,20-octaene (44.1 mg, yield 39.4%, purity 95%) was obtained.

[0673] 1 H NMR (400MHz, methanol-d 4)δ ppm 8.67(s,1H),8.24(s,1H),8.20(d,J=6.0 Hz,1H),8.02(s,1H),7.19(d,J=1.8 Hz,1H),6.66(d,J=6.0 Hz,1H),6.41(d,J=1.8 Hz,1H),5.20-5.10(m,1H),4.79-4.68(m,1H),4.25-4.14(m,1H),3.80(s,3H),3.68(s,3H),3.51(s,2H),2.54(br s,7H),2.33(br d,J=4.5 Hz,2H),2.31(s,3H),2.29-2.15(m,1H),1.57(d,J=6.3 Hz,3H).

[0674] LCMS [M+H] + m / z: calculated value 530.3, measured value 530.1.

[0675] Example 9: In vitro assay The biological activity of the compounds described herein can be tested according to standard methods known in the art. Methods can be used to test the inhibition of EGFR, including mutant forms of EGFR that include L858R, T790M, C797S, and / or Del19 mutations, or any combination thereof (e.g., L858R single, double, or triple mutants). Exemplary, non-limiting methods are described herein.

[0676] Kinase assay The assay using an in vitro kinase assay kit (HTRF KinEASE-TK kit) is L858R , EGFR L858R / T790M , and EGFR L858R / T790M / C797S The present invention can be used to test the inhibitory activity of the compounds described herein against EGFR mutants such as EGFR1, EGFR2, EGFR3, EGFR4, EGFR5, EGFR6, EGFR7, EGFR8, EGFR9, EGFR10, EGFR11, EGFR12, EGFR13, EGFR14, EGFR15, EGFR16, EGFR17, EGFR18, EGFR19, EGFR20, EGFR21, EGFR22, EGFR23, EGFR24, EGFR25, EGFR26, EGFR27, EGFR28, EGFR29, EGFR29, EGFR21, EGFR25, EGFR26, EGFR27, EGFR28, EGFR29, EGFR30, EGFR31, EGFR32, EGFR33 Ba / F3 viability assay

[0677] Inhibition of cell proliferation can be tested using Ba / F3 viability assays, including the Promega CellTiter-Glo cell viability assay, which can test the effect of compounds described herein in the following assays: (1) Ba / F3 parental, (2) Ba / F3 EGFR-Del19 / T790M, (3) Ba / F3 EGFR-Del19 / C797S, and (4) Ba / F3 EGFR-Del19 / T790M / C797S.

[0678] P-EGFR signaling assay Phosphorylation of EGFR can be tested using a multiplex immunoassay kit such as the Phospho-EGFR(Tyr1068) Total EGFR MULTI-SPOT® 96 HB 4-Spot Custom EGFR Duplex ANALYTES assay.

[0679] 136 compounds were tested using the kinase (EGFR) and BA / F3 assays described herein, and in all six assays, 60% or more of the compounds tested had IC values ​​less than 50 nM. 50 The compounds of the present invention thus represent a new general class of kinase inhibitors that includes potent EGFR mutant inhibitors.

[0680] Exemplary kinase inhibition (Kinase) and antiproliferative activity (Ba / F3) data for certain compounds of the invention are presented in Table 1 and are categorized according to the following descriptions. Description: A=IC 50 <50nM B=IC 50 50nM or more but less than 100nM C=IC 50 100nM or more but less than 1000nM D=IC 50 1000nM or more [Table 1]

[0681] From the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various usages and conditions without departing from the spirit and scope thereof.

[0682] All U.S. or foreign references, patents, or applications cited in this application are hereby incorporated by reference as if set forth herein in their entirety. In the event of any conflict, the material disclosed verbatim herein will control.

Claims

1. A compound of formula I, 【Chemistry 171】 or a pharma- ceutically acceptable salt thereof, wherein: X ２ are independently N or CR ５ and X ３ and X ４ each independently represents a covalent bond, O, S, NR ６ , C(O)NR ６ , N.R. ６ C(O), NR ６ C(O)NR ６ , or (C(R ７ ) ２ ) ｑ and L １ are independently a covalent bond, C heteroalkylene, C alkylene, C alkenylene, C alkynylene, C ３－６ cycloalkylene, 3- to 10-membered heterocyclylene, phenylene, or 5- to 10-membered heteroarylene; Each R １ and R ２ is independent, 【Chemistry 172】 OH, CN, halogen, C1-6 aliphatic, C1-6 alkoxy, NR ８ R ９ , C(O)R １０ , CO ２ R １０ , C(O)NR ８ R ９ , N.R. １１ C(O)R １０ , N.R. １１ CO ２ R １０ , N.R. １１ C(O)NR ８ R ９ , or (CH ２ ) ｒ R １２ or two R １ Or two R's ２ form a 5- to 10-membered ring together with the atoms to which they are attached, L ２ are independently a covalent bond, O, NR Ｌ , C(O), C(O)NR Ｌ , N.R. Ｌ C(O), CR Ｌ ２ and R Ｌ are independently H or C １－６ is alkyl, A is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C ３ -C １０ alicyclic or 3- to 10-membered heterocyclyl; B is independently phenyl, naphthyl, 5- to 13-membered heteroaryl, C ３ -C １０ alicyclic or 3- to 10-membered heterocyclyl; C is independently a 5- or 6-membered heteroaryl; Each R ３ are independently OH, CN, halogen, C1-6 aliphatic, C1-6 alkoxy, NR ８ R ９ , C(O)R １０ , CO ２ R １０ , C(O)NR ８ R ９ , N.R. １１ C(O)R １０ , N.R. １１ CO ２ R １０ , N.R. １１ C(O)NR ８ R ９ , or (CH ２ ) ｒ R １２ and Each R ４ are independently H, OH, CN, halogen, C1-6 aliphatic, C1-6 alkoxy, NR ８ R ９ , C(O)R １０ , CO ２ R １０ , C(O)NR ８ R ９ , N.R. １１ C(O)R １０ , N.R. １１ CO ２ R １０ , N.R. １１ C(O)NR ８ R ９ , N.R. １１ (CH ２ ) ｓ N.R. ８ R ９ , (CH ２ ) ｔ N.R. ８ R ９ , (CH ２ ) ｔ OH, (CH ２ ) ｔ OCH ３ , O(CH ２ ) ｔ OH, O(CH ２ ) ｔ OCH ３ , O(CH ２ ) ｒ R １２ , or (CH ２ ) ｒ R １２ or R ４ and R ６ , or R ４ and R ７ form a 5- or 6-membered ring together with the atoms to which they are attached, Each R ５ are independently H, OH, CN, halogen, C1-6 aliphatic, C1-6 alkoxy, NR ８ R ９ , C(O)R １０ , CO ２ R １０ , C(O)NR ８ R ９ , N.R. １１ C(O)R １０ , N.R. １１ CO ２ R １０ , N.R. １１ C(O)NR ８ R ９ , or (CH ２ ) ｒ R １２ and Each R ６ are independently H, an N-protecting group, or C １－６ alkyl or R ６ and R ４ form, together with the atoms to which they are attached, a 5- or 6-membered ring, Each R ７ are independently H or C １－６ alkyl or two R on the same carbon ７ may be linked to form an oxo (=O) group, or R ７ and R ４ form, together with the atoms to which they are attached, a 5- or 6-membered ring, Each R ８ , R ９ , and R １１ are independently H or C １－６ alkyl or R ８ and R ９ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, or R ８ and R １１ together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R １０ is independent, C １－６ aliphatic, C ３ -C １０ alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl, or R １０ and R １１ together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl; Each R １２ is independent, C ３ -C １０ alicyclic, 3- to 10-membered heterocyclyl, phenyl, naphthyl, or 5- to 12-membered heteroaryl; each m, n, and o is independently 0, 1, or 2; each p is independently 0, 1, 2, 3, or 4; each q is independently 1 or 2; each r is independently an integer from 0 to 4; each s is independently an integer from 2 to 6; A compound, or a pharma- ceutically acceptable salt thereof, wherein each t is independently an integer from 1 to 6.

2. (a) at least one m or n is not 0; and / or (b) one of R 1 and R 2 is present and is moiety A or halogen; and / or (c) one of R 1 and R 2 is present and is moiety A; and / or (d) no more than one moiety A is present; and / or (e) The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein C is a 5- or 6-membered N-containing heteroaryl, optionally wherein C is pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl. (a) The compound represented by formula (IA) 【Chemistry 173】 having a structure according to During the ceremony, X １ is N or CR ５ or (b) the compound has the formula (IB) 【Chemistry 174】 having a structure according to During the ceremony, m is 0 or 1; or (c) The compound has the formula (IC) 【Chemistry 175】 having a structure according to During the ceremony, m is 0 or 1; or (d) the compound has the formula (II) 【Chemistry 176】 having a structure according to During the ceremony, each R 1 is independently OH, CN, halogen, C 1-6 aliphatic, C 1-6 alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , NR 11 C(O)R 10 , NR 11 CO 2 R 10 , NR 11 C(O)NR 8 R 9 , or R 12 , optionally (i) the compound has the formula (II-A) 【Chemistry 177】 and / or having a structure according to (ii) m is 0; or (e) the compound has the formula (III) 【Chemistry 178】 having a structure according to During the ceremony, each R 2 is independently OH, CN, halogen, C 1-6 aliphatic, C 1-6 alkoxy, NR 8 R 9 , C(O)R 10 , CO 2 R 10 , C(O)NR 8 R 9 , NR 11 C(O)R 10 , NR 11 CO 2 R 10 , NR 11 C(O)NR 8 R 9 , or R 12 , optionally (i) the compound has the formula (III-A) 【Chemistry 179】 and / or having a structure according to (ii) The compound according to claim 1 or 2, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

4. (a)X １ and X ２ each is independently N or CH; and / or (b) The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein X1 is N.

5. (a)X ２ is CH; and / or (b) The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein X3 is O.

6. X ４ But, N.R. ６ and R ２ is a partial structure A, and R ４ and R ６ 13. The compound of claim 1, wherein, together with the atoms to which they are attached, form a 5-membered ring, or a pharma- ceutically acceptable salt thereof.

7. X ４ is O, or a pharma- ceutically acceptable salt thereof.

8. Each X ３ and X ４ each independently represents a covalent bond, O, S, or NR ６ , C(O), CH ２ , CHCH ３ , or C(CH ３ ) ２ 2. The compound of claim 1, wherein:

9. (a)X ２ is CH, and X ３ is O and X ４ is O and optionally X 1 is N; and / or (b) L 1 is unsubstituted C 1-6 alkylene or C 1-6 alkylene containing one or two oxo (═O) substituents, optionally (i) L 1 is unsubstituted linear C 4-6 alkylene or unsubstituted branched C 4-6 alkylene; and / or (ii) L 1 is 【Chemistry 180】 where * indicates the point of covalent attachment to X 4 and ** indicates the point of covalent attachment to X 3 ; or (c) L 1 is unsubstituted C 1-6 heteroalkylene or C 1-6 heteroalkylene containing one or two oxo (═O) substituents, optionally (i) said C 1-6 heteroalkylene contains 1, 2, or 3 heteroatoms which are independently oxygen or nitrogen; and / or (ii) the C 1-6 heteroalkylene is -O(CH 2 ) u -, -(CH 2 ) u O-, -O(CH 2 ) u O-, -OCH 2 OCH 2 CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 -, -NH(CH 2 ) u -, -(CH 2 ) u NH-, or -NH(CH 2 ) u NH-, where u is an integer from 1 to 4; and / or (d) B is phenyl or 5-6 membered heteroaryl, optionally (i) B is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl; and / or (ii) R 3 is methyl, halogen, or CN and o is 0 or 1; and / or (iii) B is 【Chemistry 181】 where * indicates the point of covalent attachment to C and ** indicates the point of covalent attachment to X 3 ; and / or (e) The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl or 5-6 membered heteroaryl, and optionally A is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl.

10. The compound of claim 1, wherein the compound has the formula (IV) 【Chemistry 182】 having a structure according to During the ceremony, L １ is an unsubstituted linear or branched C2-6 alkylene; B is phenyl or 5-6 membered heteroaryl; R ３ is methyl, halogen, or CN; o is 0 or 1; R １ and R ２ is present as moiety A, and optionally the compound has formula (V): 【Chemistry 183】 having a structure according to During the ceremony, L 1 is —(CH 2 ) 3 — or —CH(CH 3 )CH 2 CH 2 —, preferably (a) The compound is represented by formula (VI-1) or formula (VI-2): 【Chemistry 184】 or having a structure according to (b) the compound is represented by formula (VI-3) or formula (VI-4): 【Chemistry 185】 or having a structure according to (c) the compound represented by formula (VII-1) or formula (VII-2) 【Chemistry 186】 or having a structure according to (d) the compound represented by formula (VII-3) or (VII-4) 【Chemistry 187】 2. The compound of claim 1 having a structure according to: or a pharma- ceutically acceptable salt thereof.

11. 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl or 5- or 6-membered heteroaryl.

12. (a) L ２ is a covalent bond; or (b) 【Chemistry 188】 but, 【Chemistry 189】 2. The compound of claim 1, selected from the group consisting of:

13. (a) The compound is a saturated linear or branched C aryl group containing -C≡N, -C≡CH, 0 to 4 fluoro substituents. １－６ Aliphatic or C1-6 alkoxy, NR １１ (CH ２ ) ｓ N.R. ８ R ９ , (CH ２ ) ｔ N.R. ８ R ９ , O(CH ２ ) ｔ OCH ３ , O(CH ２ ) ｒ R １２ , and (CH ２ ) ｒ R １２ and optionally one or more R 4 groups selected from (i) R 12 is selected from the group consisting of C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl containing 1-3 heteroatoms selected from O, N, and S, and 5- to 6-membered heteroaryl; and / or (ii) R 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino; and / or (iii) R 12 is substituted with 0-4 R 14 , each R 14 being independently selected from -CN, oxo (=O), halogen, -OH, -NH 2 , monoalkylamino, dialkylamino, unsubstituted C 3-6 cycloalkyl, or unsubstituted 3-4 membered heterocyclyl, preferably each R 14 is independently -CN, -F, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -CH 3 , -CH 2 F, -CHF2, -CF3, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -COCH 3 , selected from -COCH2CH3, -CH2COCH3, -CH2COCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; or (iv) the compound is -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH 2 CFH 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C≡CH, 【Chemistry 190】 【Chemistry 191】 【Chemistry 192】 an R 4 group selected from and / or -CH 2 OCH 3 , -OCH 3 , -OCH 2 F, -OCH 2 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -OCH 2 CH2OCH3, 【Chemistry 193】 an R 4 group selected from —CO 2 CH 3 , and CH 3 ; Contains; or (b) R 4 is unsubstituted C 1-6 alkyl, CO 2 (unsubstituted C 1-6 alkyl), O—(unsubstituted C 1-6 alkyl), O—(C 1-6 haloalkyl), NH(CH 2 ) s NMe 2 , (CH 2 ) t NMe 2 , or 【Chemistry 194】 is selected from the group consisting of X 5 is independently CH or N; X 6 is independently O, CHR 13 , or NR 13 ; R 13 is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl; r is 0 or 1; s is an integer from 2 to 4; t is an integer from 1 to 6, and optionally one R 4 is 【Chemistry 195】 and if present, the second R 4 is selected from unsubstituted C 1-6 alkyl, CO 2 (unsubstituted C 1-6 alkyl), O—(unsubstituted C 1-6 alkyl), O—(C 1-6 haloalkyl), NH(CH 2 ) s NMe 2 , and (CH 2 ) t NMe 2 ; or (c) 【Chemistry 196】 but, 【Chemistry 197】 where: A is phenyl or 5-6 membered heteroaryl; X 5 is independently CH or N; X 6 is independently O, CHR 13 , or NR 13 ; R 13 is independently H, unsubstituted C 1-6 alkyl, or unsubstituted C 3-6 cycloalkyl; r is 0 or 1; R 4 is selected from unsubstituted C 1-6 alkyl, CO 2 (unsubstituted C 1-6 alkyl), O—(unsubstituted C 1-6 alkyl), O—(C 1-6 haloalkyl), or NH(CH 2 ) s NMe 2 ; p is 0 or 1; s is an integer from 2 to 6; optionally 【Chemistry 198】 but, 【Chemistry 199】 and X 6 is O, NCH 3 , or N(cyclopropyl), or a pharma- ceutically acceptable salt thereof.

14. 13. The compound according to claim 13, wherein r is 0 or r is 1, or a pharma- ceutically acceptable salt thereof.

15. -CO ２ CH ３ , -OCH ２ CF ３ , -CH ３ , -CH ２ CH ３ , -OCH ３ , -OCH ２ CH ３ , -NHCH ２ CH ２ N (CH ３ ) ２ , or -CH ２ N (CH ３ ) ２ R ４ 13. The compound of claim 12, comprising a group, or a pharma- ceutically acceptable salt thereof.

16. 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, or imidazolyl. (a) the compound has a structure according to formula (VIII): 【Chemistry 200】 During the ceremony, R ４Ａ is the first R ４ It is based on R ４Ｂ is the second R ４ It is based on p is 0 or 1; or (b) the compound has a structure according to formula (IX): 【Chemistry 201】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; or (c) the compound has a structure according to formula (X): 【Chemistry 202】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; R 4D is an R 4 group that is unsubstituted C 1-6 alkyl; or (d) the compound has a structure according to formula (XI): 【Chemistry 203】 During the ceremony, R 4A is the first R 4 group; R 4D is an R 4 group that is unsubstituted C 1-6 alkyl; or (e) the compound has a structure according to formula (XII): 【Chemistry 204】 During the ceremony, R 4A is the first R 4 group; or (f) the compound has a structure according to formula (XIII): 【Chemistry 205】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; or (g) the compound has a structure according to formula (XIV): 【Chemistry 206】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; or (h) the compound has a structure according to formula (XV): 【Chemistry 207】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; R 4C is a third R 4 group; or (i) the compound has a structure according to formula (XVI): 【Chemistry 208】 During the ceremony, R 4C is the first R 4 group; or (j) the compound has a structure according to formula (XVII): 【Chemistry 209】 During the ceremony, R 4D is an R 4 group that is unsubstituted C 1-6 alkyl; or (k) the compound has a structure according to formula (XVIII): 【Chemistry 210】 During the ceremony, R 4C is the first R 4 group; or (l) the compound has a structure according to formula (XIX): 【Chemistry 211】 During the ceremony, R 4D is an R 4 group that is unsubstituted C 1-6 alkyl; or (m) the compound has a structure according to formula (XX): 【Chemistry 212】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; or (n) the compound has a structure according to formula (XXI): 【Chemistry 213】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; or (o) the compound has a structure according to formula (XXII): 【Chemistry 214】 During the ceremony, R 4A is the first R 4 group; R 4B is a second R 4 group; p is 0 or 1; R 4D is an R 4 group that is unsubstituted C 1-6 alkyl; or (p) the compound has a structure according to formula (XXIII): 【Chemistry 215】 During the ceremony, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R4A is the first R4 group.

18. (a) Each R ４Ａ , R ４Ｂ , and R ４Ｃ When present, each independently represents one of the following: -C≡N, -C≡CH, saturated linear or branched C １－６ Aliphatic or C1-6 alkoxy, NR １１ (CH ２ ) ｓ N.R. ８ R ９ , (CH ２ ) ｔ N.R. ８ R ９ , O(CH ２ ) ｔ OCH ３ , O(CH ２ ) ｒ R １２ , and (CH ２ ) ｒ R １２ and optionally an R 4 group selected from (i) R 12 is selected from the group consisting of C 3-6 cycloalkyl, 3- to 9-membered heterocyclyl containing 1-3 heteroatoms selected from O, N, and S, and 5- to 6-membered heteroaryl; and / or (ii) R 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino; and / or (iii) R 12 is substituted with 0-4 R 14 , wherein each R 14 is independently selected from -CN, oxo (=O), halogen, -OH, -NH 2 , monoalkylamino, dialkylamino, unsubstituted C 3-6 cycloalkyl, or unsubstituted 3-4 membered heterocyclyl, preferably each R 14 is independently -CN, -F, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -CH 3 , -CH 2 F, -CHF2, -CF3, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 OCH 3 , -COCH 3 , selected from -COCH2CH3, -CH2COCH3, -CH2COCH2CH3, cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl; and / or (b) the R 4A and / or R 4C groups, when present, are -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CFH 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C≡CH, 【Chemistry 216】 【Chemistry 217】 is selected from and / or R 4B groups, when present, are -CH 2 OCH 3 , -OCH 3 , -OCH 2 F, -OCH 2 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -OCH 2 CH2OCH3, 【Chemistry 218】 18. The compound of claim 17, or a pharma- ceutically acceptable salt thereof, wherein -CO2CH3, and CH3 are selected from the group consisting of:

19. The compound according to claim 1, which is selected from the group consisting of compounds (1) to (169), or a pharma- ceutically acceptable salt thereof.

20. 13. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof.

21. 21. A composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use in a method of treating cancer, the method comprising administering the composition or pharmaceutical composition to a human in need thereof, and optionally wherein the cancer is (a) lung cancer; and / or (b) non-small cell lung cancer; and / or (c) EGFR-driven cancer; and / or (d) cancer characterized by EGFR mutations A composition or pharmaceutical composition,

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