PYRIMIDINE COMPOUNDS, COMPOSITIONS, AND MEDICINAL APPLICATIONS THEREOF

BACKGROUND OF THE DISCLOSURE

Lung cancer accounts for the greatest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors displaying specific oncogenic drivers, namely mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Three generations of tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations, however, other oncogenic drivers in the EGFR family of receptor tyrosine kinases have received less research and development focus and several oncogenic drivers, including insertions in the exon 20 gene of EGFR, have no currently approved therapeutics to treat their cancers.

The mutation, amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2), another member of the human epidermal growth factor receptor family of receptor tyrosine kinases, has been implicated in the oncogenesis of several cancers, including lung, breast, ovarian, and gastric cancers. Although targeted therapies such as trastuzumab and lapatinib have shown clinical efficacy especially in breast tumors, their utility in lung cancer has been limited. It is likely that this variation is due to tissue-specific factors, including the low potency of kinase inhibitors like lapatinib for the mutagenic alterations in HER2 that are observed in the lung cancer patient population, including insertions in the exon 20 gene of HER2.

Given that many patients with mutations in EGFR and HER2 do not derive clinical benefit from currently available therapies against these targets, there remains a significant unmet need for the development of novel therapies for the treatment of cancers associated with EGFR and HER2 mutations.

SUMMARY OF THE DISCLOSURE

In one aspect, provided herein is a compound of Formula I.

embedded image

- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
- X is —NH— or —O—;
- R¹is —(C(R⁴)₂)_nR⁵, wherein R⁵is unsubstituted or substituted with 2 or 3 R⁵;
  - n is 0, 1, 2, or 3;
  - each R⁴is independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;
  - R⁵is C_4-10cycloalkyl, aryl, or heteroaryl;
  - each R^5′ is independently deuterium, aryl, heteroaryl, alkyl, C₃-C₆cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —NH₂, —NHR⁶, —N(CH₃)R₆, —N(R⁶)₂, —C(═O)NH₂, —C(═O)NHR⁶, —C(═O)N(R⁶)₂, —NR⁶C(═O)R⁶, —NHC(═O)R⁶, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂NH₂, —S(═O)₂NHR⁶, —S(═O)₂N(R⁶)₂, —S(═O)₂heteroaryl, alkoxy, or haloalkoxy; or
  - two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is unsubstituted or substituted with alkyl; each R⁶is independently alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl;
- R²is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is substituted with at least one R⁷and 0, 1, or 2 R⁸;
  - each R⁷is independently

embedded image

- - - Y is —C(═O)—, —S(═O)—, or —S(═O)₂—;
    - R⁹, R^9′, and R^9″ are independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl;
    - R¹⁰is hydrogen, alkyl, haloalkyl, or cycloalkyl;
  - each R⁸is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy;
    - each R¹¹is independently alkyl, cycloalkyl, aryl, or heteroaryl;
- R³is heteroaryl substituted with 0, 1, 2, or 3 R¹²;
  - each R¹²is independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, —N(R¹³)₂, —S(═O)₂NH₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl are each independently unsubstituted or substituted with 0, 1, or 2 R¹⁴;
    - each R¹³is independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;
    - each R¹⁴is independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy; and
      - each R¹⁵is independently alkyl, cycloalkyl, aryl, or heteroaryl.

In some embodiments, X is —NH—.

In some embodiments, n is 0.

In some embodiments, R⁵is phenyl, naphthyl, anthracenyl, phenanthrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indolyl; wherein R⁵is substituted with 2 or 3 R^5′. In some embodiments, R⁵is substituted with 2 R^5′. In some embodiments, R⁵is substituted with 3 R^5′.

In some embodiments, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 or 3 R⁵. In some embodiments, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 R⁵. In some embodiments, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 3 R⁵. In some embodiments, two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle.

In some embodiments, each R^5′ is independently alkyl, haloalkyl, 3-8 membered heterocycloalkyl, halo, cyano, hydroxy, —N(R⁶)₂, —N(CH₃)R₆, —C(═O)NHR⁶, —NHC(═O)R⁶, —S(═O)₂NH₂, alkoxy, or haloalkoxy. In some embodiments, each R^5′ is independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, —N(R⁶)₂, —C(═O)NHR⁶, —NHC(═O)R⁶, —S(═O)₂NH₂, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R^5′ is independently methyl, morpholinyl, fluoro, chloro, cyano, —C(═O)NHMe, —NHC(═O)Me, —S(═O)₂NH₂, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

In some embodiments, each R⁶is independently alkyl or aryl. In some embodiments, each R⁶is independently methyl, ethyl, iso-propyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R⁶is independently methyl or phenyl.

In some embodiments, R²is monocyclic. In some embodiments, R²is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is phenyl, cyclohexyl, or pyrrolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸.

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is R¹⁰

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is R¹⁰

embedded image

In some embodiments, Y is —C(═O)—. In some embodiments, Y is —S(═O)₂—.

In some embodiments, R⁹, R^9′ and R^9″ are independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R⁹, R^9′ and R^9″ are independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R⁹and R^9′ are independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R⁹and R^9′ are independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl.

In some embodiments, R¹⁰is hydrogen, methyl, ethyl n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, or cyclopropyl. In some embodiments, R¹⁰is hydrogen or methyl.

In some embodiments, R²is substituted with 1 or 2 R⁸. In some embodiments, each R⁸is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R⁸is independently methyl, ethyl, iso-propyl, tert-butyl, fluoro, chloro, —N(R¹¹)₂, hydroxyethyl, methoxyethyl, or cyano.

In some embodiments, each R¹¹is independently alkyl or aryl. In some embodiments, each R¹¹is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, or phenanthrenyl. In some embodiments, each R¹¹is independently methyl, ethyl, iso-propyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R¹¹is independently methyl or phenyl.

In some embodiments, R²is not substituted with R⁸.

In some embodiments, R³is:

embedded image

wherein R³is substituted with 0 to 3 R¹².

In some embodiments, R³is:

embedded image

In some embodiments, R³is:

embedded image

In some embodiments, R³is unsubstituted. In some embodiments, R³is substituted with at least 1 R¹². In some embodiments, R³is substituted with at least 2 R¹².

In some embodiments, each R¹²is independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, —N(R¹³)₂, —S(═O)₂NH₂, or cycloalkyl. In some embodiments, each R¹²is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, —N(R¹³)₂, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹²is independently methyl, iso-propyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl. In some embodiments, each R¹²is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro. In some embodiments, each R¹²is independently methyl or chloro.

In some embodiments, each R¹³is independently alkyl or cycloalkyl. In some embodiments, each R¹³is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹³is independently methyl, ethyl, iso-propyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹³is independently methyl, cyclopropyl, or cyclohexyl.

In some embodiments, the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is unsubstituted. In some embodiments, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is substituted with 1 or 2 R¹⁴.

In some embodiments, each R¹⁴is independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, —N(R¹¹)₂, or alkoxy. In some embodiments, each R¹⁴is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, —N(R¹¹)₂methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R¹⁴is independently methyl, ethyl, iso-propyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, —N(R¹¹)₂, or methoxy.

In some embodiments, each R¹⁵is independently alkyl or cycloalkyl. In some embodiments, each R¹⁵is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, each R¹³is independently methyl, ethyl, iso-propyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹³is independently methyl, cyclopropyl, or cyclohexyl.

In some embodiments:

- X is —NH— or —O—;
- n is 0;
- R⁵is phenyl substituted with 2 or 3 R^5′;
- R²is phenyl substituted with at least one R⁷and 0, 1, or 2 R⁸; and
- R³is pyrazolyl substituted with 0, 1, 2, or 3 R¹².

In some embodiments, X is —NH—.

In some embodiments, R^5′ is fluoromethyl, difluoromethyl, or trifluoromethyl.

In some embodiments:

- R⁷is

embedded image

and

- R⁸is halo.

In some embodiments:

- R⁸is fluoro;
- Y is —C(═O)—;
- R⁹and R^9′ are hydrogen; and
- R¹⁰is hydrogen.

In some embodiments, R¹²is alkyl.

In some embodiments, R¹²is methyl.

In some embodiments, the compound is of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F or Formula I-G:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is of Formula I-B:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of Formula I-B, wherein R¹is R⁵. In some embodiments of the compound of Formula I-B, wherein R¹is R⁵; and R⁵is substituted with 2 R^5′. In some embodiments of the compound of Formula I-B, wherein R¹is R⁵; and R⁵is substituted with 3 R^5′. In some embodiments of the compound of Formula I-B, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 or 3 R^5′. In some embodiments of the compound of Formula I-B, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 R^5′. In some embodiments of the compound of Formula I-B, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 3 R^5′. In some embodiments of the compound of Formula I-B, two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle.

In some embodiments, the compound is of Formula I-C:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of Formula I-C, wherein R¹is R⁵. In some embodiments of the compound of Formula I-C, wherein R¹is R⁵; and R⁵is substituted with 2 R^5′. In some embodiments of the compound of Formula I-C, wherein R¹is R⁵; and R⁵is substituted with 3 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 or 3 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 3 R^5′. In some embodiments of the compound of Formula I-C, two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle.

In some embodiments, the compound is:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compounds described herein have improved potency and increased efficacy. In some embodiments, the compounds described herein are useful as inhibitors of both EGFR and HER2. In some embodiments, the compounds described herein are dual inhibitors of EGFR and HER2. In some embodiments, the compounds described herein are dual inhibitors of mutant forms of EGFR and HER2. In some embodiments, the compounds described herein are dual inhibitors of wild type EGFR and a mutant form of HER2. In some embodiments, the compounds described herein have improved potency and increased efficacy through the inhibition of both EGFR and HER2.

In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a method of inhibiting a human epidermal growth factor receptor 2 (HER2) mutant and an epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof.

In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, provided herein is a method of treating one or more cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the cancer in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, the present disclosure provides a method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the inflammatory disease is psoriasis, eczema, or atherosclerosis.

In some embodiments, the inflammatory disease in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR.

The present disclosure discloses a process of preparation of compounds of Formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, and to pharmaceutical compositions containing them.

The compounds of the present disclosure may be useful in the treatment, prevention or suppression of diseases and disorders mediated by epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2).

These and other features, aspects, and advantages of the present disclosure will become better understood with reference to the following description. This statement is provided to introduce a selection of concepts in simplified form. This statement is not intended to identify key features or essential features of the subject matter, nor is it intended to be used to limit the scope of the subject matter.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions

In the structural formulae given herein and throughout the present disclosure, the following terms have the indicated meaning, unless specifically stated otherwise.

The term “optionally substituted” as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. In some embodiments, when the group in question is substituted with more than one substituent, the substituent is the same. In some embodiments, when the group in question is substituted with more than one substituent, the substituent is different. In some embodiments, the reference group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and —S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents are independently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CHF₂, —CF₃, —OCH₃, —OCHF₂, and —OCF₃. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (═O)

As used herein, C₁-C_xincludes C₁-C₂, C₁-C₃. . . C₁-C_x. By way of example only, a group designated as “C₁-C₆” indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C₁-C₄alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl

The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “cycloalkyl” refers to unless otherwise mentioned, carbocyclic groups of from 3 to 6 carbon atoms having a single cyclic ring or multiple condensed rings or spirocyclic rings or bridged rings. This definition encompasses rings that are saturated or partially unsaturated.

Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

“Halo” or “Halogen”, alone or in combination with any other term means halogens such as chloro (Cl), fluoro (F), bromo (Br) and iodo (I).

The term “aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. This definition encompasses monocyclic, bicyclic, tricyclic or tetracyclic ring system, as well as fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

The term “phenyl” refers to an aromatic carbocyclic group of 6 carbon atoms having a single ring.

The term “phenyl alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms substituted with an aromatic carbocyclic group of 6 carbon atoms having a single ring.

The term “heteroaryl” refers to an aromatic cyclic group having 5, or 6 carbon atoms and 1, 2, or 3 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. An “X-linked heteroaryl” refers to a heteroaryl connected to the rest of the molecule via an X atom. For example,

embedded image

is an N-linked imidazolyl, while

embedded image

is a C-linked imidazolyl.

The term “heterocycloalkyl” refers to a saturated, partially unsaturated, or unsaturated group having a single ring or multiple condensed rings or spirocyclic rings, or bridged rings unless otherwise mentioned, having from 2 to 10 carbon atoms and from 1 to 3 hetero atoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.

The term “alkenyl” refers to unsaturated aliphatic groups having at least one double bond.

The term “alkynyl” refers to unsaturated aliphatic groups having at least one triple bond.

The term “amino” refers to the —NH₂radical.

The term “cyano” refers to the —CN radical.

The term “hydroxy” or “hydroxyl” refers to the —OH radical.

The term “heteroalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with an O, N or S atom. Unless stated otherwise specifically in the specification, the heteroalkyl group is optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to —OCH₂CH₂OMe, —OCH₂CH₂OCH₂CH₂NH₂, and —OCH₂CH₂OCH₂CH₂OCH₂CH₂N(Me)₂.

A “hetercycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is a C₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “haloalkyl” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a halogen atom. In some embodiments, the haloalkyl group is optionally substituted as described below. Representative haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl.

The term “aminoalkyl” refers to an alkyl group substituted with an amino (NH2) group.

In some embodiments, the aminoalkyl group is unsubstituted or substituted with alkyl on the nitrogen atom.

The term “alkoxy” refers to the group R—O—, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Representative examples of alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, ²H, ³H, ¹³C, 14C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³²P and ³³P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, the compounds described herein exist as isotopic variants. In some embodiments, an isotopic variant of a compound described herein has one or more hydrogen atoms replaced by deuterium.

In some embodiments, the compounds described herein contain one or more chiral centers and/or double bonds and therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. In some embodiments, enantiomeric and stereoisomeric mixtures are resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. In some embodiments, the compounds also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.

In some embodiments, a compound disclosed herein is a free base, salt, hydrate, isomer, diastereomer, prodrug (e.g., ester), metabolite, ion pair complex, or chelate form. In some embodiments, compounds exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In some embodiments, compounds are hydrated, solvated or N-oxides. Also contemplated within the scope of the disclosure are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

“Pharmaceutically acceptable salt” embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines. In some embodiments, the compound is a pharmaceutically acceptable salt derived from acids including, but not limited to, the following: acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, or p-toluenesulfonic acid.

“Pharmaceutical composition” refers to one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

“Carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. In some embodiments, such pharmaceutical carriers are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, water is a carrier when the pharmaceutical composition is administered orally. In some embodiments, saline and aqueous dextrose are exemplary carriers when the pharmaceutical composition is administered intravenously. In some embodiments, saline solutions and aqueous dextrose and glycerol solutions are employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. In some embodiments, the composition comprises minor amounts of wetting or emulsifying agents, or pH buffering agents. In some embodiments, these compositions take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. In some embodiments, the composition is formulated as a suppository, with traditional binders and carriers such as triglycerides. In some embodiments, an oral formulation comprises carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, for example in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

“Combined” or “in combination” or “combination” should be understood as a functional coadministration, encompassing scenarios wherein compounds are administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration. In some embodiments, the individual compounds of such combinations are administered sequentially in separate pharmaceutical compositions. In some embodiments, the individual compounds of such combinations are administered simultaneously in combined pharmaceutical compositions.

Compounds

In one aspect, provided herein is a compound of Formula I.

embedded image

- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
- X is —NH— or —O—;
- R¹is —(C(R⁴)₂)_nR⁵, wherein R⁵is substituted with 2 or 3 R^5′;
  - n is 0, 1, 2, or 3;
  - each R⁴is independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;
  - R⁵is C_4-10cycloalkyl, C-linked heterocycloalkyl, aryl, or heteroaryl;
  - each R^5′ is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —NH₂, —NHR⁶, —N(R⁶)₂, —C(═O)NH₂, —C(═O)NR⁶, —C(═O)N(R⁶)₂, —NR⁶C(═O)R⁶, —NHC(═O)R⁶, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂NH₂, —S(═O)₂NHR⁶, —S(═O)₂N(R⁶)₂, —S(═O)₂heteroaryl, alkoxy, or haloalkoxy;
    - each R⁶is independently alkyl, cycloalkyl, aryl, or heteroaryl;
- R²is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is substituted with at least one R⁷and 0, 1, or 2 R⁸;
  - each R⁷is independently

embedded image

- - - Y is —C(═O)—, —S(═O)—, or —S(═O)₂—;
    - R⁹and R^9′ are independently hydrogen, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl;
    - R¹⁰is hydrogen, alkyl, haloalkyl, or cycloalkyl;
  - each R⁸is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy;
    - each R¹¹is independently alkyl, cycloalkyl, aryl, or heteroaryl;
- R³is heteroaryl substituted with 0, 1, 2, or 3 R¹²;
  - each R¹²is independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, —N(R¹³)₂, —S(═O)₂NH₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl are each independently substituted with 0, 1, or 2 R¹⁴;
    - each R¹³is independently alkyl, cycloalkyl, aryl, or heteroaryl;
    - each R¹⁴is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy; and
      - each R¹⁵is independently alkyl, cycloalkyl, aryl, or heteroaryl;
        
        provided that when X is —O—, R⁵is not C-linked heterocycloalkyl.

In one aspect, provided herein is a compound of Formula I:

embedded image

- or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
- X is —NH— or —O—;
- R¹is —(C(R⁴)₂)_nR⁵, wherein R⁵is 2 or 3 R^5′;
  - n is 0, 1, 2, or 3;
  - each R⁴is independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl;
  - R⁵is C_4-10cycloalkyl, aryl, or heteroaryl;
  - each R^5′ is independently deuterium, aryl, heteroaryl, alkyl, C₃-C₆cycloalkyl, 3-8 membered heterocycloalkyl, oxo, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —NH₂, —NHR⁶, —N(CH₃)R₆, —N(R⁶)₂, —C(═O)NH₂, —C(═O)NHR⁶, —C(═O)N(R⁶)₂, —NR⁶C(═O)R⁶, —NHC(═O)R⁶, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂NH₂, —S(═O)₂NHR⁶, —S(═O)₂N(R⁶)₂, —S(═O)₂heteroaryl, alkoxy, or haloalkoxy; or
  - two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is unsubstituted or substituted with alkyl; each R⁶is independently alkyl, aminoalkyl, cycloalkyl, aryl, or heteroaryl;
- R²is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is substituted with at least one R⁷and 0, 1, or 2 R⁸;
  - each R⁷is independently

embedded image

- - - Y is —C(═O)—, —S(═O)—, or —S(═O)₂—;
    - R⁹, R^9′, and R^9″ are independently hydrogen, deuterium, halo, alkyl, haloalkyl, cycloalkyl, heteroalkyl, or (alkyl)heterocycloalkyl;
    - R¹⁰is hydrogen, alkyl, haloalkyl, or cycloalkyl;
  - each R⁸is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy;
    - each R¹¹is independently alkyl, cycloalkyl, aryl, or heteroaryl;
- R³is heteroaryl substituted with 0, 1, 2, or 3 R¹²;
  - each R¹²is independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, —N(R¹³)₂, —S(═O)₂NH₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl are each independently unsubstituted or substituted with 0, 1, or 2 R¹⁴;
    - each R¹³is independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;
    - each R¹⁴is independently deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy; and
      - each R¹⁵is independently alkyl, cycloalkyl, aryl, or heteroaryl.

For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, X is —NH—. In some embodiments, X is —O—.

In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, or 3. In some embodiments, n is 0, 2, or 3. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0 or 2. In some embodiments, n is 0 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, R⁵is phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, pyrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, C-linked imidazolyl, or C-linked indolyl; wherein R⁵is substituted with 2 or 3 R^5′. In some embodiments, R⁵is phenyl, naphthyl, anthracenyl, phenanthrenyl, C-linked pyridyl, C-linked pyrimidinyl, C-linked pyrazolyl, or C-linked imidazolyl; wherein R⁵is substituted with 2 or 3 R^5′. In some embodiments, R⁵is phenyl; wherein the phenyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is naphthyl; wherein the naphthyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is anthracenyl; wherein the anthracenyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is phenanthrenyl; wherein the phenanthrenyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is chrysenyl; wherein the chrysenyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is pyrenyl; wherein the pyrenyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is C-linked pyridyl; wherein the pyridyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is C-linked pyrimidinyl; wherein the C-linked pyrimidinyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is C-linked pyrazolyl; wherein the C-linked pyrazolyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is C-linked imidazolyl; wherein C-linked imidazolyl is substituted with 2 or 3 R^5′. In some embodiments, R⁵is C-linked indolyl; wherein the C-linked indolyl is substituted with 2 or 3 R^5′.

In some embodiments, R⁵is substituted with 2 or 3 R^5′. In some embodiments, R⁵is substituted with 2 R^5′. In some embodiments, R⁵is substituted with 3 R^5′.

In some embodiments, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 or 3 R^5′. In some embodiments, two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle.

In some embodiments, each R⁴is independently hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, or heteroalkyl. In some embodiments, each R⁴is independently hydrogen, alkyl, halo, haloalkyl, or alkoxy. In some embodiments, each R⁴is independently hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, trifluoromethyl, trifluoroethyl, pentafluoroethyl, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R⁴is independently hydrogen, methyl, fluoro, trifluoromethyl, methoxy, or trifluoromethoxy. In some embodiments, each R⁴is hydrogen. In some embodiments, each R⁴is independently alkyl. In some embodiments, each R⁴is independently halo. In some embodiments, each R⁴is independently haloalkyl. In some embodiments, each R⁴is hydroxy. In some embodiments, each R⁴is independently alkoxy. In some embodiments, each R⁴is independently heteroalkyl. In some embodiments, each R⁴is methyl. In some embodiments, each R⁴is ethyl. In some embodiments, each R⁴is n-propyl. In some embodiments, each R⁴is iso-propyl. In some embodiments, each R⁴is n-butyl. In some embodiments, each R⁴is iso-butyl. In some embodiments, each R⁴is sec-butyl. In some embodiments, each R⁴is tert-butyl.

In some embodiments, each R⁴is fluoro. In some embodiments, each R⁴is chloro. In some embodiments, each R⁴is trifluoromethyl. In some embodiments, each R⁴is trifluoroethyl. In some embodiments, each R⁴is pentafluoroethyl. In some embodiments, each R⁴is methoxy. In some embodiments, each R⁴is ethoxy. In some embodiments, each R⁴is trifluoromethoxy.

In some embodiments, each R^5′ is independently alkyl, haloalkyl, heterocycloalkyl, halo, cyano, hydroxy, —N(R⁶)₂, —C(═O)NR⁶, —NHC(═O)R⁶, —S(═O)₂NH₂, alkoxy, or haloalkoxy. In some embodiments, each R^5′ is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R⁶)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy. In some embodiments, each R^5′ is independently aryl, heteroaryl, alkyl, heterocycloalkyl, halo, cyano, hydroxy, —N(R⁶)₂, or alkoxy. In some embodiments, each R^5′ is independently aryl. In some embodiments, each R^5′ is independently heteroaryl. In some embodiments, each R^5′ is independently alkyl. In some embodiments, each R^5′ is independently cycloalkyl. In some embodiments, each R^5′ is independently heterocycloalkyl. In some embodiments, each R^5′ is independently halo. In some embodiments, each R^5′ is independently heteroalkyl. In some embodiments, each R^5′ is independently haloalkyl. In some embodiments, each R^5′ is cyano. In some embodiments, each R^5′ is hydroxy.

In some embodiments, each R^5′ is amino. In some embodiments, each R^5′ is independently —N(R⁶)₂. In some embodiments, each R^5′ is independently —S(═O)₂alkyl. In some embodiments, each R^5′ is independently —S(═O)₂aryl. In some embodiments, each R^5′ is independently-S(═O)₂heteroaryl. In some embodiments, each R^5′ is independently alkoxy. In some embodiments, each R^5′ is independently phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, pyrenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, hydroxy, —N(R⁶)₂, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R^5′ is independently phenyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, —N(R⁶)₂, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R^5′ is independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, cyano, hydroxy, —N(R⁶)₂, —C(═O)NR⁶, —NHC(═O)R⁶, —S(═O)₂NH₂, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R^5′ is independently methyl, morpholinyl, fluoro, chloro, cyano, —C(═O)NHMe, —NHC(═O)Me, —S(═O)₂NH₂, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy. In some embodiments, each R^5′ is independently phenyl, imidazolyl, pyridinyl, methyl, tert-butyl, pyrrolidinyl, morpholinyl, fluoro, cyano, hydroxy, —N(R⁶)₂, or methoxy. In some embodiments, each R^5′ is phenyl. In some embodiments, each R^5′ is naphthyl. In some embodiments, each R^5′ is anthracenyl. In some embodiments, each R^5′ is phenanthrenyl. In some embodiments, each R^5′ is chrysenyl. In some embodiments, each R^5′ is pyrenyl. In some embodiments, each R^5′ is pyrrolyl. In some embodiments, each R^5′ is imidazolyl. In some embodiments, each R^5′ is pyrazolyl. In some embodiments, each R^5′ is triazolyl. In some embodiments, each R^5′ is tetrazolyl. In some embodiments, each R^5′ is indolyl. In some embodiments, each R^5′ is indazolyl. In some embodiments, each R^5′ is benzimidazolyl. In some embodiments, each R^5′ is azaindolyl. In some embodiments, each R^5′ is thiazolyl. In some embodiments, each R^5′ is isothiazolyl. In some embodiments, each R^5′ is oxazolyl. In some embodiments, each R^5′ is isoxazolyl. In some embodiments, each R^5′ is pyridinyl. In some embodiments, each R^5′ is pyrimidinyl. In some embodiments, each R^5′ is pyridazinyl. In some embodiments, each R^5′ is pyrazinyl. In some embodiments, each R^5′ is triazinyl. In some embodiments, each R^5′ is quinolinyl. In some embodiments, each R^5′ is isoquinolinyl. In some embodiments, each R^5′ is quinoxalinyl. In some embodiments, each R^5′ is quinazolinyl. In some embodiments, each R^5′ is cinnolinyl. In some embodiments, each R^5′ is naphthyridinyl. In some embodiments, each R^5′ is methyl. In some embodiments, each R^5′ is ethyl. In some embodiments, each R^5′ is n-propyl. In some embodiments, each R^5′ is iso-propyl. In some embodiments, each R^5′ is n-butyl. In some embodiments, each R^5′ is iso-butyl. In some embodiments, each R^5′ is sec-butyl. In some embodiments, each R^5′ is tert-butyl. In some embodiments, each R^5′ is azetidinyl. In some embodiments, each R^5′ is oxetanyl. In some embodiments, each R^5′ is pyrrolidinyl. In some embodiments, each R^5′ is imidazolidinyl. In some embodiments, each R^5′ is tetrahydrofuranyl. In some embodiments, each R^5′ is piperidinyl. In some embodiments, each R^5′ is piperazinyl. In some embodiments, each R^5′ is tetrahydropyranyl. In some embodiments, each R^5′ is morpholinyl. In some embodiments, each R^5′ is fluoro. In some embodiments, each R^5′ is chloro.

In some embodiments, each R^5′ is methoxy. In some embodiments, each R^5′ is ethoxy. In some embodiments, each R^5′ is trifluoromethoxy. In some embodiments, each R^5′ is —C(═O)NHMe. In some embodiments, each R^5′ is —NHC(═O)Me. In some embodiments, each R^5′ is —S(═O)₂NH₂. In some embodiments, each R^5′ is difluoromethoxy.

In some embodiments, each R⁶is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R⁶is independently alkyl or aryl. In some embodiments, each R⁶is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, or pyrenyl. In some embodiments, each R⁶is independently methyl, ethyl, iso-propyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R⁶is independently methyl or phenyl. In some embodiments, each R⁶is methyl. In some embodiments, each R⁶is ethyl. In some embodiments, each R⁶is n-propyl. In some embodiments, each R⁶is iso-propyl. In some embodiments, each R⁶is n-butyl. In some embodiments, each R⁶is iso-butyl. In some embodiments, each R⁶is sec-butyl. In some embodiments, each R⁶is tert-butyl. In some embodiments, each R⁶is phenyl. In some embodiments, each R⁶is naphthyl. In some embodiments, each R⁶is anthracenyl. In some embodiments, each R⁶is phenanthrenyl. In some embodiments, each R⁶is chrysenyl. In some embodiments, each R⁶is pyrenyl.

In some embodiments, R²is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is aryl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is heteroaryl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is cycloalkyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is heterocycloalkyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is monocyclic. In some embodiments, R²is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is phenyl, cyclohexyl, or pyrrolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is phenyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is cyclopropyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is cyclobutyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is cyclopentyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is cyclohexyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyrrolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is imidazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyrazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is triazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is tetrazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is thiazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is isothiazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is oxazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is isoxazolyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyridinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyrimidinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyridazinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is pyrazinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸. In some embodiments, R²is triazinyl; wherein R²is substituted with at least one R⁷and 0, 1, or 2 R⁸.

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

embodiments, R⁷is

embedded image

In some embodiments, Y is —C(═O)—. In some embodiments, Y is —S(═O)—. In some embodiments, Y is —S(═O)₂—.

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

embodiments, R⁷is

embedded image

In some embodiments, R⁷is

embedded image

In some embodiments, R⁹and R^9′ are independently hydrogen, halo, alkyl, heteroalkyl, haloalkyl, or (alkyl)heterocycloalkyl. In some embodiments, R⁹is hydrogen, halo, alkyl, cycloalkyl, or heteroalkyl. In some embodiments, R⁹is hydrogen, halo, or heteroalkyl. In some embodiments, R⁹and R^9′ are independently hydrogen, fluoro, chloro, methyl, hydroxyethyl, methoxyethyl, methoxymethyl, dimethylaminomethyl, 1-piperidinylmethyl, 1-morpholinylmethyl, or fluoromethyl. In some embodiments, R⁹is hydrogen, fluoro, chloro, hydroxyethyl, or methoxyethyl. In some embodiments, R⁹is hydrogen. In some embodiments, R⁹is fluoro. In some embodiments, R⁹is chloro. In some embodiments, R⁹is hydroxyethyl. In some embodiments, R⁹is methoxyethyl. In some embodiments, R⁹is methyl. In some embodiments, R⁹is methoxymethyl. In some embodiments, R⁹is dimethylaminomethyl. In some embodiments, R⁹is 1-piperidinylmethyl. In some embodiments, R⁹is 1-morpholinomethyl. In some embodiments, R⁹is fluoromethyl. In some embodiments, R^9′ is hydrogen. In some embodiments, R^9′ is fluoro. In some embodiments, R^9′ is chloro. In some embodiments, R^9′ is hydroxyethyl. In some embodiments, R^9′ is methoxyethyl. In some embodiments, R^9′ is methyl. In some embodiments, R^9′ is methoxymethyl. In some embodiments, R^9′ is dimethylaminomethyl. In some embodiments, R^9′ is 1-piperidinylmethyl. In some embodiments, R^9′ is 1-morpholinomethyl. In some embodiments, R^9′ is fluoromethyl.

In some embodiments, R¹⁰is hydrogen or alkyl. In some embodiments, R¹⁰is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In some embodiments, R¹⁰is hydrogen. In some embodiments, R¹⁰is methyl. In some embodiments, R¹⁰is ethyl. In some embodiments, R¹⁰is n-propyl. In some embodiments, R¹⁰is iso-propyl. In some embodiments, R¹⁰is n-butyl. In some embodiments, R¹⁰is iso-butyl. In some embodiments, R¹⁰is sec-butyl. In some embodiments, R¹⁰is tert-butyl.

In some embodiments, R²is not substituted with R⁸. In some embodiments, R²is substituted with 1 or 2 R⁸. In some embodiments, R²is substituted with 1 R⁸. In some embodiments, R²is substituted with 2 R⁸.

In some embodiments, each R⁸is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, heteroalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R⁸is independently methyl, ethyl, iso-propyl, tert-butyl, fluoro, chloro, —N(R¹¹)₂, hydroxyethyl, methoxyethyl, or cyano. In some embodiments, each R⁸is methyl. In some embodiments, each R⁸is ethyl. In some embodiments, each R⁸is n-propyl. In some embodiments, each R⁸is iso-propyl. In some embodiments, each R⁸is n-butyl. In some embodiments, each R⁸is iso-butyl. In some embodiments, each R⁸is sec-butyl. In some embodiments, each R⁸is tert-butyl. In some embodiments, each R⁸is fluoro. In some embodiments, each R⁸is chloro. In some embodiments, each R⁸is independently —N(R¹¹)₂. In some embodiments, each R⁸is hydroxyethyl. In some embodiments, each R⁸is methoxyethyl. In some embodiments, each R⁸is cyano.

In some embodiments, each R¹¹is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R¹¹is independently alkyl or aryl. In some embodiments, each R¹¹is independently alkyl. In some embodiments, each R¹¹is independently cycloalkyl. In some embodiments, each R¹¹is independently aryl. In some embodiments, each R¹¹is independently heteroaryl. In some embodiments, each R¹¹is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, chrysenyl, or pyrenyl. In some embodiments, each R¹¹is independently methyl, ethyl, iso-propyl, tert-butyl, phenyl, or naphthyl. In some embodiments, each R¹¹is independently methyl or phenyl.

In some embodiments, each R¹¹is methyl. In some embodiments, each R¹¹is ethyl. In some embodiments, each R¹¹is n-propyl. In some embodiments, each R¹¹is iso-propyl. In some embodiments, each R¹¹is n-butyl. In some embodiments, each R¹¹is iso-butyl. In some embodiments, each R¹¹is sec-butyl. In some embodiments, each R¹¹is tert-butyl. In some embodiments, each R¹¹is phenyl. In some embodiments, each R¹¹is naphthyl. In some embodiments, each R¹¹is anthracenyl. In some embodiments, each R¹¹is phenanthrenyl. In some embodiments, each R¹¹is chrysenyl. In some embodiments, each R¹¹is pyrenyl.

In some embodiments, R³is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, azaindolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, or naphthyridinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is imidazolyl, pyrazolyl, triazolyl, indolyl, indazolyl, thiazolyl, isothiazolyl, or pyridinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyrrolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is imidazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyrazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is triazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is tetrazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is indolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is indazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is benzimidazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is azaindolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is thiazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is isothiazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is oxazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is isoxazolyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyridinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyrimidinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyridazinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is pyrazinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is triazinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is quinolinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is isoquinolinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is quinoxalinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is quinazolinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is cinnolinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹². In some embodiments, R³is naphthyridinyl; wherein R³is substituted with 0, 1, 2, or 3 R¹².

In some embodiments, R³is unsubstituted. In some embodiments, R³is substituted with at least 1 R¹². In some embodiments, R³is substituted with at least 2 R¹². In some embodiments, R³is substituted with 1 R¹². In some embodiments, R³is substituted with 2 R¹². In some embodiments, R³is substituted with 3 R¹².

In some embodiments, R³is

embedded image

wherein R³is substituted with 0 to 3 R¹². In some embodiments, R³is

embedded image

wherein R³is substituted with 1 or 2 R¹².

In some embodiments, R³is:

embedded image

In some embodiments, R³is:

embedded image

In some embodiments, R³is:

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, R³is

embedded image

In some embodiments, each R¹²is independently aryl, heteroaryl, alkyl, heteroalkyl, haloalkyl, halo, cyano, alkoxy, heterocycloalkyl, —N(R¹³)₂, —S(═O)₂NH₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or cycloalkyl. In some embodiments, each R¹²is independently alkyl, heteroalkyl, haloalkyl, halo, cyano, heterocycloalkyl, —N(R¹³)₂, or cycloalkyl. In some embodiments, each R¹²is independently aryl. In some embodiments, each R¹²is independently heteroaryl. In some embodiments, each R¹²is independently alkyl. In some embodiments, each R¹²is independently heteroalkyl. In some embodiments, each R¹²is independently haloalkyl. In some embodiments, each R¹²is independently halo. In some embodiments, each R¹²is cyano. In some embodiments, each R¹²is independently alkoxy. In some embodiments, each R¹²is independently heterocycloalkyl. In some embodiments, each R¹²is independently —N(R¹³)₂. In some embodiments, each R¹²is independently —S(═O)₂NH₂. In some embodiments, each R¹²is independently —S(═O)₂alkyl. In some embodiments, each R¹²is independently —S(═O)₂aryl. In some embodiments, each R¹²is independently —S(═O)₂heteroaryl. In some embodiments, each R¹²is independently cycloalkyl. In some embodiments, each R¹²is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, fluoro, chloro, cyano, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, —N(R¹³)₂, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹²is independently methyl, iso-propyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl. In some embodiments, each R¹²is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro. In some embodiments, each R¹²is independently methyl or chloro. In some embodiments, each R¹²is methyl. In some embodiments, each R¹²is ethyl. In some embodiments, each R¹²is n-propyl. In some embodiments, each R¹²is iso-propyl. In some embodiments, each R¹²is n-butyl. In some embodiments, each R¹²is iso-butyl. In some embodiments, each R¹²is sec-butyl. In some embodiments, each R¹²is tert-butyl. In some embodiments, each R¹²is hydroxyethyl. In some embodiments, each R¹²is methoxyethyl. In some embodiments, each R¹²is trifluoromethyl. In some embodiments, each R¹²is trifluoroethyl. In some embodiments, each R¹²is pentafluoroethyl. In some embodiments, each R¹²is fluoro. In some embodiments, each R¹²is chloro. In some embodiments, each R¹²is azetidinyl. In some embodiments, each R¹²is oxetanyl. In some embodiments, each R¹²is pyrrolidinyl. In some embodiments, each R¹²is imidazolidinyl. In some embodiments, each R¹²is tetrahydrofuranyl. In some embodiments, each R¹²is piperidinyl. In some embodiments, each R¹²is piperazinyl. In some embodiments, each R¹²is tetrahydropyranyl. In some embodiments, each R¹²is morpholinyl. In some embodiments, each R¹²is cyclopropyl. In some embodiments, each R¹²is cyclobutyl. In some embodiments, each R¹²is cyclopentyl. In some embodiments, each R¹²is cyclohexyl.

In some embodiments, each R¹³is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R¹³is independently alkyl or cycloalkyl. In some embodiments, each R¹³is independently alkyl. In some embodiments, each R¹³is independently cycloalkyl. In some embodiments, each R¹³is independently aryl. In some embodiments, each R¹³is independently heteroaryl. In some embodiments, each R¹³is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹³is independently methyl, ethyl, iso-propyl, tert-butyl, cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹³is independently methyl, cyclopropyl, or cyclohexyl. In some embodiments, each R¹³is methyl. In some embodiments, each R¹³is ethyl. In some embodiments, each R¹³is n-propyl. In some embodiments, each R¹³is iso-propyl. In some embodiments, each R¹³is n-butyl. In some embodiments, each R¹³is iso-butyl. In some embodiments, each R¹³is sec-butyl. In some embodiments, each R¹³is tert-butyl.

In some embodiments, each R¹³is cyclopropyl. In some embodiments, each R¹³is cyclobutyl. In some embodiments, each R¹³is cyclopentyl. In some embodiments, each R¹³is cyclohexyl.

In some embodiments, the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is unsubstituted. In some embodiments, the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is substituted with 1 or 2 R¹⁴. In some embodiments, the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is substituted with 1 R¹⁴. In some embodiments, the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl of R¹²is substituted with 2 R¹⁴.

In some embodiments, each R¹⁴is independently aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, halo, heteroalkyl, haloalkyl, cyano, hydroxy, amino, —N(R¹¹)₂, —S(═O)₂alkyl, —S(═O)₂aryl, —S(═O)₂heteroaryl, or alkoxy. In some embodiments, each R¹⁴is independently alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, —N(R¹¹)₂, or alkoxy. In some embodiments, each R¹⁴is independently aryl. In some embodiments, each R¹⁴is independently heteroaryl. In some embodiments, each R¹⁴is independently alkyl. In some embodiments, each R¹⁴is independently cycloalkyl. In some embodiments, each R¹⁴is independently heterocycloalkyl. In some embodiments, each R¹⁴is independently halo. In some embodiments, each R¹⁴is independently heteroalkyl. In some embodiments, each R¹⁴is independently haloalkyl. In some embodiments, each R¹⁴is cyano. In some embodiments, each R¹⁴is hydroxy. In some embodiments, each R¹⁴is amino. In some embodiments, each R¹⁴is independently —N(R¹⁵)₂. In some embodiments, each R¹⁴is independently —S(═O)₂alkyl. In some embodiments, each R¹⁴is independently —S(═O)₂aryl. In some embodiments, each R¹⁴is independently —S(═O)₂heteroaryl. In some embodiments, each R¹⁴is independently alkoxy. In some embodiments, each R¹⁴is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, fluoro, chloro, cyano, —N(R¹¹)₂, methoxy, ethoxy, or trifluoromethoxy. In some embodiments, each R¹⁴is independently methyl, ethyl, iso-propyl, tert-butyl, pyrrolidinyl, piperidinyl, morpholinyl, fluoro, chloro, —N(R¹¹)₂, or methoxy. In some embodiments, each R¹⁴is methyl. In some embodiments, each R¹⁴is ethyl. In some embodiments, each R¹⁴is n-propyl. In some embodiments, each R¹⁴is iso-propyl. In some embodiments, each R¹⁴is n-butyl. In some embodiments, each R¹⁴is iso-butyl. In some embodiments, each R¹⁴is sec-butyl. In some embodiments, each R¹⁴is tert-butyl. In some embodiments, each R¹⁴is cyclopropyl. In some embodiments, each R¹⁴is cyclobutyl. In some embodiments, each R¹⁴is cyclopentyl. In some embodiments, each R¹⁴is cyclohexyl. In some embodiments, each R¹⁴is azetidinyl. In some embodiments, each R¹⁴is oxetanyl. In some embodiments, each R¹⁴is pyrrolidinyl. In some embodiments, each R¹⁴is imidazolidinyl. In some embodiments, each R¹⁴is tetrahydrofuranyl. In some embodiments, each R¹⁴is piperidinyl. In some embodiments, each R¹⁴is piperazinyl. In some embodiments, each R¹⁴is tetrahydropyranyl. In some embodiments, each R¹⁴is morpholinyl. In some embodiments, each R¹⁴is fluoro. In some embodiments, each R¹⁴is chloro. In some embodiments, each R¹⁴is methoxy. In some embodiments, each R¹⁴is ethoxy. In some embodiments, each R¹⁴is trifluoromethoxy.

In some embodiments, each R¹¹is independently alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, each R¹¹is independently alkyl or cycloalkyl. In some embodiments, each R¹¹is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R¹¹is methyl. In some embodiments, each R¹¹is ethyl. In some embodiments, each R¹¹is n-propyl. In some embodiments, each R¹¹is iso-propyl. In some embodiments, each R¹¹is n-butyl. In some embodiments, each R¹¹is iso-butyl. In some embodiments, each R¹¹is sec-butyl. In some embodiments, each R¹⁵is tert-butyl. In some embodiments, each R¹⁵is cyclopropyl. In some embodiments, each R¹⁵is cyclobutyl. In some embodiments, each R¹⁵is cyclopentyl. In some embodiments, each R¹⁵is cyclohexyl.

In some embodiments:

- X is —NH— or —O—;
- n is 0;
- R⁵is phenyl substituted with 2 or 3 R^5′;
- R²is phenyl substituted with at least one R⁷and 0, 1, or 2 R⁸; and
- R³is pyrazolyl substituted with 0, 1, 2, or 3 R¹².

In some embodiments, X is —NH—.

In some embodiments, R^5′ is fluoromethyl, difluoromethyl, or trifluoromethyl.

In some embodiments:

- R⁷is

embedded image

and

- R⁸is halo.

In some embodiments:

- R⁸is fluoro;
- Y is —C(═O)—;
- R⁹and R^9′ are hydrogen; and
- R¹⁰is hydrogen.

In some embodiments, R¹²is alkyl.

In some embodiments, R¹²is methyl.

In some embodiments, the compound is of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, or Formula I-G:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound is of Formula I-B:

embedded image

In some embodiments, the compound is of Formula I-C:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments of the compound of Formula I-C, wherein R¹is R⁵; and R⁵is substituted with 2 R^5′. In some embodiments of the compound of Formula I-C, wherein R¹is R⁵; and R⁵is substituted with 3 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 or 3 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 2 R^5′. In some embodiments of the compound of Formula I-C, R⁵is phenyl or C-linked pyridyl; wherein the phenyl or C-linked pyridyl is substituted with 3 R^5′. In some embodiments of the compound of Formula I-C, two adjacent R^5′ groups come together to form a 5- to 10-membered heterocycle.

In some embodiments, the compound of Formula I is:

embedded image

or a pharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

Particular embodiments of the present disclosure are compounds of Formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, selected from the group consisting of,

N-(4-fluoro-3-((5-(3-fluoro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 1),
N-(3-((5-(3,4-dimethoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 2)
N-(3-((5-(3-chloro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 3),
N-(4-fluoro-3-((5-(4-fluoro-3-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 4),
N-(3-((5-(3,4-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 5),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 6),
N-(4-fluoro-3-((5-(2-fluoro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 7),
N-(3-((5-(2-chloro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 8),
N-(4-fluoro-3-((5-(5-fluoro-2-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 9),
N-(4-fluoro-3-((5-(2-methoxy-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 10),
N-(3-((5-(2-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 11),
N-(3-((5-(2-chloro-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 12),
N-(4-fluoro-3-((5-(3-fluoro-4-methylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 13),
N-(4-fluoro-3-((5-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 14),
N-(3-((5-(3-(difluoromethyl)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 15),
N-(3-((5-(4-(difluoromethoxy)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 16),
N-(3-((5-(5,6-dichloropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 17),
N-(3-((5-(3-bromo-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (Compound 18),
N-(4-fluoro-3-((5-(5-fluoro-6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide trifluoroacetate (Compound 19),
N-(3-((5-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (Compound 20),
N-(4-fluoro-3-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 21),
N-(4-fluoro-3-((5-(4-methoxy-3-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 22),
N-(3-((5-(5-chloro-2-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 23),
N-(4-fluoro-3-((5-(2-fluoro-5-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 24),
N-(4-fluoro-3-((5-(4-fluoro-3-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 25),
N-(3-((5-(3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 26),
N-(4-fluoro-3-((5-(3-fluoro-5-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 27),
N-(3-((5-(4-(dimethylamino)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 28),
N-(3-((5-(5,6-difluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 29),
N-(3-((5-(4-(dimethylamino)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 30),
N-(3-((5-(5-chloro-6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide trifluoroacetate (Compound 31),
N-(3-((5-(3,5-dichlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 32),
N-(3-((5-(4-chloro-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 33),
N-(3-((5-(3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 34),
N-(4-fluoro-3-((5-(3-fluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 35),
N-(3-((5-(3,4-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 36),
N-(3-((5-(4-(difluoromethyl)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 37),
N-(3-((5-(3-fluoro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 38),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 39),
N-(3-((5-(4-chloro-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 40),
N-(3-((5-(3-fluoro-4-methylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 41),
N-(3-((5-(3-(dimethylamino)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 42),
N-(3-((5-(3-(difluoromethyl)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 43),
N-(3-((5-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamidet (Compound 44),
N-(3-((5-(6-chloro-5-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 45),
N-(3-((5-(5-chloro-6-methylpyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 46),
N-(4-fluoro-3-((5-(6-fluoro-5-(trifluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 47),
N-(3-((5-(6-chloro-5-methylpyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 48),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 49),
N-(3-((5-(3,4-dichlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 50),
N-(3-((5-(3,4-dichlorophenyl)-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 51),
N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3-chloro-4-fluorophenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 52),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 53),
N-(3-((5-(3-chloro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 54),
N-(4-fluoro-3-((5-(3-fluoro-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 55),
N-(3-((5-(3,4-dichlorophenyl)-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 56),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 57),
N-(3-((5-(3,4-dichlorophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 58),
N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(1-methylindolin-5-yl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 59),
N-(3-((5-(4-((dimethylamino)methyl)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 60),
N-(4-fluoro-3-((5-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 61),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 62),
N-(4-fluoro-3-((5-(2-fluoro-6-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 63),
N-(4-fluoro-3-((5-(3-fluoro-5-methylphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 64),
N-(4-fluoro-3-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 65),
N-(3-((5-(3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 66),
N-(3-((5-(3,4-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 67),
N-(3-((5-(4-chloro-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 68),
N-(3-((5-(3-fluoro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 69),
N-(3-((5-(6-chloro-5-fluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 70),
N-(3-((5-(5-fluoro-6-methoxypyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 71),
N-(3-((5-(6-chloro-5-methylpyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 72),
N-(3-((5-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 73),
N-(3-((5-(4-(dimethylamino)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 74),
N-(3-((5-(5,6-difluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 75),
N-(4-fluoro-3-((5-(3-fluoro-4-morpholinophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 76),
N-(4-fluoro-3-((5-(3-fluoro-4-(pyrrolidin-1-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 77),
N-(4-fluoro-3-((5-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 78),
N-(4-fluoro-3-((5-(3-fluoro-4-(3-methoxyazetidin-1-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 79),
N-(3-((5-(4-(azetidin-1-yl)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 80),
N-(4-fluoro-3-((5-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 81),
N-(3-((2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(3-fluoro-4-(piperidin-1-yl)phenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 82),
N-(3-((5-(4-(3-(dimethylamino)azetidin-1-yl)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 83),
N-(4-fluoro-3-((5-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 84),
N-(3-((5-(4-(azepan-1-yl)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 85),
N-(3-((5-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 86),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 87),
N-(3-((5-(4-bromo-3-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 88),
N-(3-((5-(4-bromo-3-chlorophenyl)-2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 89),
N-(3-((5-(3-bromo-4-chlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 90),
N-(3-((5-(4-bromo-3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 91),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 92),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 93),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 94),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 95),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 96),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (Compound 97),
N-(3-((5-(4-chloro-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide (Compound 98),
N-(3-((5-(3,4-dichlorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (Compound 99),
N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 100),
N-(3-((5-(5,6-difluoropyridin-3-yl)-2-((1-(methyl-d₃)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 101),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide-3,3-d₂(Compound 102),
N-(3-((5-(5,6-difluoropyridin-3-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide-3,3-d₂(Compound 103),
N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3,5-difluorophenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 104),
(E)-N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 105),
N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3-fluoro-5-methoxyphenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 106),
N-(4-fluoro-3-((5-(4-fluoro-2-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 107),
N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3-(difluoromethyl)-5-fluorophenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 108),
N-(3-((5-(3-bromo-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 109),
N-(3-((2-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 110),
N-(3-((5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 111),
N-(3-((5-(4-bromo-2-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 112),
N-(3-((5-(3-bromo-2-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 113),
N-(3-((5-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 114),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 115),
N-(3-((5-(3,5-dimethoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 116),
(E)-N-(3-((5-(3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 117),
N-(3-((5-(4-bromo-3-(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 118),
N-(3-((5-(4-bromo-3-(dimethylamino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 119),
N-(3-((5-(3-(azetidin-1-yl)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 120),
N-(4-fluoro-3-((5-(3-fluoro-5-(pyrrolidin-1-yl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 121),
N-(3-((5-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 122),
N-(3-((5-(4-bromo-3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 123),
N-(3-((5-(4-(difluoromethoxy)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 124),
N-(3-((5-(3,4-difluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 126),
N-(3-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 127),
N-(3-((5-(3-ethoxy-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 128),
N-(4-fluoro-3-((5-(3-fluoro-5-isopropoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 129),
N-(3-((5-(3-(cyclopropylmethoxy)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 130),
N-(3-bromo-5-((5-(3-fluoro-4-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 131)
N-(3-bromo-5-((5-(4-(difluoromethoxy)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 132)
N-(4-fluoro-3-((5-(3-fluoro-5-methoxy-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 133),
N-(3-((5-(4-bromo-3-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 134),
N-(3-((5-(3,4-difluoro-5-(trifluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 135),
N-(3-((5-(3-(difluoromethoxy)-4,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 136),
N-(3-((5-(4-bromo-3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 137),
N-(3-((5-(4-bromo-3-(difluoromethyl)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 138),
N-(3-((5-(3-(dimethylamino)-4,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 139),
N-(3-((5-(4-bromo-3-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 140),
N-(3-((5-(3-(difluoromethyl)-4,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 141),
(E)-N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(piperidin-1-yl)but-2-enamide (Compound 142),
N-(4-fluoro-3-((5-(3-fluoro-5-methoxyphenyl-4-d)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 143),
(E)-4-(dimethylamino)-N-(4-fluoro-3-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)but-2-enamide (Compound 144),
N-(3-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl-4-d)acrylamide (Compound 145),
N-(3-((5-(4-bromo-3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 146),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-chlorophenyl)acrylamide (Compound 147),
N-(3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3,4,5-trifluorophenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 148),
N-(4-fluoro-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(3,4,5-trifluorophenyl)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 149),
(E)-N-(3-((5-(3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide (Compound 150),
(E)-N-(3-((5-(3,5-difluorophenyl-4-d)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 151),
N-(3-((5-(4-bromo-3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 152),
N-(3-((5-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 153),
N-(3-((5-(4-bromo-3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 154),
N-(3-((5-(3,5-bis(difluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 155),
N-(3-((5-(4-(dimethylamino)-3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 156),
N-(3-((5-(3,5-difluorophenyl-4-d)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 157)
N-(3-((5-(4-chloro-3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 158),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-chlorophenyl)acrylamide (Compound 159),
N-(3-((5-(3-(difluoromethoxy)-4,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 160),
(E)-N-(3-((5-(3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 161),
N-(3-((5-(2,3-dihydrobenzofuran-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 162),
N-(3-((5-(4-bromo-3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (Compound 163),
N-(3-((5-(3,5-difluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (Compound 164),
N-(4-fluoro-3-((5-(3-fluoro-5-(methoxy-d3)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 165),
(E)-4-(azetidin-1-yl)-N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)but-2-enamide (Compound 166),
(E)-N-(3-((5-(3,5-difluorophenyl)-2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 167),
N-(3-((5-(3-(difluoromethoxy)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 168),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 169),
N-(3,4-difluoro-5-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 170),
(E)-N-(3-((5-(4-bromo-3,5-difluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 171),
N-(4-fluoro-3-((5-(3-fluoro-5-(trifluoromethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 172),
N-(3-bromo-5-((5-(3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 173),
N-(3-bromo-5-((5-(3-(difluoromethyl)-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 174),
(E)-N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-fluorobut-2-enamide (Compound 175),
N-(4-fluoro-3-((5-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 176),
N-(3-((5-(4-bromo-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-2-fluoroacrylamide (Compound 177), and
(E)-N-(3-((5-(2,3-dihydrobenzofuran-6-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)-4-(dimethylamino)but-2-enamide (Compound 178).

An embodiment of the present disclosure relates to a compound of Formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for treating disease associated with epidermal growth factor receptor (EGFR) family kinases and HER family kinases.

Another embodiment of the present disclosure relates to a compound of Formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for treating cancer.

Another embodiment of the present disclosure relates to a compound Formula I, or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof, for treating disease or condition associated with non-small cell or small cell lung cancer or prostate cancer or head and neck cancer or breast cancer or colorectal cancer.

The present disclosure relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

The present disclosure further relates to the process of preparation of compounds of Formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof.

Uses

Some embodiments provided herein describe a class of compounds that are useful as epidermal growth factor receptor (EGFR) family kinase inhibitors and/or HER family kinase inhibitors. Some embodiments provided herein describe a class of compounds that are useful as as dual HER2 and EGFR kinase inhibitors.

Some embodiments provided herein describe a method of inhibiting a human epidermal growth factor receptor 2 (HER2) mutant and an epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

Some embodiments provided herein describe a class of compounds that are useful as epidermal growth factor receptor (EGFR) family kinase inhibitors. Some embodiments provided herein describe a class of compounds that are useful as HER2 inhibitors. Some embodiments provided herein describe a class of compounds that are useful as EGFR inhibitors. Some embodiments provided herein describe a class of compounds that are useful as EGFR del19/T790M inhibitors. Some embodiments provided herein describe a class of compounds that are useful as EGFR L858R/T790M inhibitors. In some embodiments, the compounds described herein have improved potency and/or beneficial activity profiles and/or beneficial selectivity profiles and/or increased efficacy and/or improved safety profiles (such as reduced side effects) and/or improved pharmacokinetic properties. In some embodiments, the compounds described herein have improved potency and increased efficacy. In some embodiments, the compounds described herein are selective inhibitors of EGFR del19/T790M over WT EGFR. In some embodiments, the compounds described herein are selective inhibitors of EGFR L858R/T790M over WT EGFR.

In some embodiments, the compounds described herein are useful as inhibitors of both EGFR and HER2. In some embodiments, the compounds described herein have improved potency and increased efficacy through the inhibition of both EGFR and HER2.

In some embodiments, the compounds described herein are useful to treat, prevent or ameliorate a disease or condition which displays drug resistance associated with EGFR del19/T790M activation. In some embodiments, the compounds described herein are useful to treat, prevent or ameliorate a disease or condition which displays drug resistance associated with EGFR L858R/T790M activation.

In some embodiments, EGFR family kinase mutants are detected with a commercially available test kit. In some embodiments, EGFR family kinase mutants are detected with a reverse transcription polymerase chain reaction (RT-PCR)-based method. In some embodiments, EGFR family kinase mutants are detected with a sequencing-based method. In some embodiments, EGFR family kinase mutants are detected with a mass spectrometry genotyping-based method. In some embodiments, EGFR family kinase mutants are detected with an immunohistochemistry-based method. In some embodiments, EGFR family kinase mutants are detected with a molecular diagnostics panel. In some embodiments, EGFR family kinase mutants are detected from a tumor sample. In some embodiments, EGFR family kinase mutants are detected from circulating DNA. In some embodiments, EGFR family kinase mutants are detected from tumor cells.

In one aspect, provided herein is a method of inhibiting an epidermal growth factor receptor (EGFR) family kinase mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, provided herein is a method of inhibiting a human epidermal growth factor receptor 2 (HER2) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775 G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutant is A775_G776insYVMA. In some embodiments, the HER2 mutant is A775 G776insSVMA. In some embodiments, the HER2 mutant is A775_G776insVVMA. In some embodiments, the HER2 mutant is G776del insVC. In some embodiments, the HER2 mutant is G776del insLC. In some embodiments, the HER2 mutant is G776del insAV. In some embodiments, the HER2 mutant is G776del insAVGC. In some embodiments, the HER2 mutant is S310F. In some embodiments, the HER2 mutant is S310Y. In some embodiments, the HER2 mutant is p95. In some embodiments, the HER2 mutant is V842I. In some embodiments, the HER2 mutant is P780_Y781insGSP.

In another aspect, provided herein is a method of inhibiting an epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, provided herein is a method of inhibiting a drug-resistant epidermal growth factor receptor (EGFR) mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the drug-resistant EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR.

In another aspect, provided herein is a method of inhibiting human epidermal growth factor receptor 2 (HER2) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits greater inhibition of a HER2 mutant relative to wild-type EGFR. In some embodiments, the HER2 mutant comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutant is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutant is A775_G776insYVMA. In some embodiments, the HER2 mutant is A775_G776insSVMA. In some embodiments, the HER2 mutant is A775_G776insVVMA. In some embodiments, the HER2 mutant is G776del insVC. In some embodiments, the HER2 mutant is G776del insLC. In some embodiments, the HER2 mutant is G776del insAV. In some embodiments, the HER2 mutant is G776del insAVGC. In some embodiments, the HER2 mutant is S310F. In some embodiments, the HER2 mutant is S310Y. In some embodiments, the HER2 mutant is p95. In some embodiments, the HER2 mutant is V842I. In some embodiments, the HER2 mutant is P780_Y781insGSP.

In another aspect, provided herein is a method of inhibiting epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound exhibits greater inhibition of an EGFR mutant relative to wild-type EGFR.

In some embodiments, the EGFR mutant comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutant is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutant is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutant is del19/T790M EGFR. In some embodiments, the EGFR mutant is L858R/T790M EGFR.

In another aspect, provided herein is a method of treating a disease or disorder associated with epidermal growth factor receptor (EGFR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the disease or disorder in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and a combination thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775_G776insSVMA. In some embodiments, the HER2 mutation is A775_G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

In some embodiments, the disease or disorder in the subject comprises an EGFR mutation. In some embodiments, the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21. In some embodiments, the EGFR mutation is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR (or D770_N771insSVD EGFR), 770insNPG EGFR (or D770_N771insNPG EGFR), 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR (or H773insNPH EGFR), 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof. In some embodiments, the EGFR mutation is del19/T790M EGFR or L858R/T790M EGFR. In some embodiments, the EGFR mutation is del19/T790M EGFR. In some embodiments, the EGFR mutation is L858R/T790M EGFR.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the cancer displays drug resistance associated with EGFR del19/T790M activation. In some embodiments, the cancer displays drug resistance associated with EGFR L858R/T790M activation. Other embodiments provided herein describe the use of the compounds described herein for treating cancer.

In some embodiments, the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer, prostate cancer, head and neck cancer, breast cancer, colorectal cancer, or glioblastoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is glioblastoma.

In some embodiments, the cancer in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and a combination thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775_G776insSVMA. In some embodiments, the HER2 mutation is A775_G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

In another aspect, provided herein is a method of treating inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. Also described herein is the use of the compounds described herein for treating inflammatory diseases associated with EGFR del19/T790M activation. Also described herein is the use of the compounds described herein for treating inflammatory diseases associated with EGFR L858R/T790M activation.

In some embodiments, the inflammatory disease is psoriasis, eczema, or atherosclerosis. In some embodiments, the inflammatory disease is psoriasis. In some embodiments, the inflammatory disease is eczema. In some embodiments, the inflammatory disease is atherosclerosis.

In some embodiments, the inflammatory disease in the subject comprises a HER2 mutation. In some embodiments, the HER2 mutation comprises an insertion in exon 20, an in-frame deletion and insertion in exon 20, a substitution in the extracellular domain, an extracellular truncation, or a substitution in exon 30. In some embodiments, the HER2 mutation is selected from A775_G776insYVMA, A775 G776insSVMA, A775_G776insVVMA, G776del insVC, G776del insLC, G776del insAV, G776del insAVGC, S310F, S310Y, p95, V842I, P780_Y781insGSP, and any combination thereof. In some embodiments, the HER2 mutation is A775_G776insYVMA. In some embodiments, the HER2 mutation is A775 G776insSVMA. In some embodiments, the HER2 mutation is A775 G776insVVMA. In some embodiments, the HER2 mutation is G776del insVC. In some embodiments, the HER2 mutation is G776del insLC. In some embodiments, the HER2 mutation is G776del insAV. In some embodiments, the HER2 mutation is G776del insAVGC. In some embodiments, the HER2 mutation is S310F. In some embodiments, the HER2 mutation is S310Y. In some embodiments, the HER2 mutation is p95. In some embodiments, the HER2 mutation is V842I. In some embodiments, the HER2 mutation is P780_Y781insGSP.

Administration and Pharmaceutical Composition

In certain embodiments, the EGFR and/or HER2 inhibitory compound as described herein is administered as a pure chemical. In other embodiments, the EGFR and/or HER2 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one EGFR and/or HER2 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.

One embodiment provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the EGFR and/or HER2 inhibitory compound disclosed herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

The dose of the composition comprising at least one EGFR and/or HER inhibitory compound as described herein differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

EXAMPLES
Example 1: Synthetic Procedures

Yields reported herein refer to purified products (unless specified) and are not optimised. Analytical TLC was performed on Merck silica gel 60 F₂₅₄aluminum-backed plates. Compounds were visualised by UV light and/or stained either with iodine, potassium permanganate or ninhydrin solution. Flash column chromatography was performed on silica gel (100-200 M) or flash chromatography. ¹H-NMR spectra were recorded on a Bruker Avance-400 MHz spectrometer with a BBO (Broad Band Observe) and BBFO (Broad Band Fluorine Observe) probe. Chemical shifts (δ) are expressed in parts per million (ppm) downfield by reference to tetramethylsilane (TMS) as the internal standard. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and bs (broad singlet). Coupling constants (J) are given in hertz (Hz). LC-MS analyses were performed on either an Acquity BEH C-18 column (2.10×100 mm, 1.70 μm) or on a Acquity HSS-T3 column (2.10×100 mm, 1.80 μm) using the Electrospray Ionisation (ESI) technique.

The following solvents, reagents or scientific terminology may be referred to by their abbreviations:

TLC Thin Layer Chromatography
DCM Dichloromethane
THF Tetrahydrofuran
MeOH Methanol
EtOH Ethanol

IPA Isopropyl alcohol

EtOAc Ethyl acetate

Et₂O Diethyl ether

DMA N,N-Dimethylacetamide
DMF N,N-Dimethylformamide
TEA/Et₃N Triethylamine
DMSO Dimethylsulfoxide

DIPEA Diisopropylethylamine (Hunig's base)

Mel Methyliodide
NBS N-Bromosuccinimide

TBAB Tetrabutylammonium bromide

TBAI Tetrabutylammonium iodide

DIBAL-H Diisobutylaluminum hydride

TFA Trifluoroacetic acid

AcOH Acetic acid

Boc tert-butoxycarbonyl

Cat Catalytic

mL milliliters

mmol millimoles

h hour or hours

min minute or minutes

g grams

mg milligrams

μl Microlitres
eq Equivalents

rt or RT Room temperature, ambient, about 27° C.

MS Mass spectrometry

Boc tert-Butyloxycarbonyl

m-CPBA meta-Chloroperbenzoic acid

T3P Propane phosphonic acid anhydride

BH₃-DMS Borane dimethylsulfide complex

LiBH₄Lithium aluminum hydride

NaBH₄Sodium borohydride

H₂Hydrogen

Pd/C Palladium on charcoal

1,2-DCE 1,2-Dichloroethane
General Procedure A:

To an ice cold solution of aryl amines (1.0 eq) in tetrahydrofuran was added sodium hydride (60% dispersion in mineral oil, 3.0 eq) portion-wise. The resulting reaction mixture was stirred at room temperature for 30 minutes and followed by the addition of 2,4,5-trichloropyrimidine or 2,4-dichloro-5-bromopyrimidine (1.0 eq). The resulting reaction mixture was heated at 60° C. for 16 hours. After completion (TLC monitoring), quenched with ice, extracted with ethyl acetate (3 times). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was triturated with diethyl ether, filtered and dried under vacuum to get desired products.

General Procedure B:

To a solution of aryl halo (1.0 eq) in 1,4-dioxane or toluene were added cesium carbonate (3.0 eq) and aryl amines (1.2 eq). The resulting reaction mixture degassed under nitrogen for 15 minutes, followed by addition of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 0.1 eq) and tris(dibenzylideneacetone)dipalladium(0) (0.1 eq) under nitrogen atmosphere. The resulting reaction mixture was again degassed for 15 minutes and then heated at 100° C. for 16 hours. After completion of reaction (TLC monitoring), reaction mixture was cooled, diluted with water, extracted with dichloromethane (3 times). The combined organic layers were washed with brine dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography using 4-8% methanol in dichloromethane as eluent, desired fractions were concentrated under reduced pressure afforded the desired products.

General Procedure C:

To an ice-cold solution of primary or secondary aryl amines (1.0 eq)) in dichloromethane were added triethylamine (3.0 eq) and acetyl chloride (1.2 eq) drop wise. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combiflash, eluted with 4-5% methanol in dichloromethane, desired fractions were concentrated under reduced pressure to afforded desired products.

General Procedure D:

To a solution of aldehydes (1.0 eq) in methanol were added respective amines (3.0 eq) and sodium acetate (5.0 eq). The resultant reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (monitored by TLC), the reaction mixture was poured in ice-cold water and resulted solid was filtered. The solid was dried under vacuum to get the desired products.

General Procedure E:

To a solution of products (1.0 eq) obtained from General Procedure D in methanol (2.5 vol) was added acetic acid (1.0 vol) and followed by addition of sodium borohydride (1.0 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was quenched with ice-cold water and resultant solid was filtered, washed with water. The solid was dried under vacuum to get the desired products.

General Procedure F:

To an ice-cold solution of products (1.0 eq) obtained from General Procedure E in tetrahydrofuran added di-isopropyl ethylamine (4.0 eq) followed by addition of triphosgene (0.4 eq). The resultant reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (TLC monitoring) saturated sodium bicarbonate solution was added and extracted with dichloromethane (3 times). The organic layer was washed with brine dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude was triturated with diethyl ether to get the desired products.

General Procedure G:

To an ice-cold solution of products (1.0 eq) obtained from General Procedure F in dichloromethane was added m-chloroperbenzoic acid (2.0 eq). The resulting reaction mixture was stirred at room temperature for 4 hours. After completion of reaction (TLC monitoring) saturated solution of sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was triturated with diethyl ether to get the desired products.

General Procedure H:

To an ice-cold solution of products (1.0 eq) obtained from General Procedure G in isopropanol was added respective amines (1.2 eq) and trifluoroacetic acid (2.0 eq). The reaction mixture was heated at 110° C. for 16 hours. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, added saturated solution of sodium bicarbonate and extracted with dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue was triturated with diethyl ether to get the desired products which was used directly for the next step.

General Procedure I:

An ice-cold solution of products (1.0 eq) obtained from General Procedure H in 20% trifluoroacetic acid in dichloromethane was stirred at room temperature for 3-16 hours. After completion of the reaction (TLC monitoring) the solvent was evaporated. The reaction mass diluted with saturated solution of sodium bicarbonate and extracted with 5% methanol in dichloromethane (3 times). The combined organic layers were washed with brine solution, dried over sodium sulfate and evaporated under reduced pressure. The crude was triturated with ether or purified over combiflash, elution with 5-10% methanol in dichloromethane to get the desired products.

General Procedure J:

To an ice-cold solution of products (1.0 eq) obtained from General Procedure I in dichloromethane was added triethylamine (3-5 eq) and respective acids (1.1 eq), followed by propylphosphonic anhydride (T₃P, 50% in ethyl acetate, 2.5 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (TLC monitoring), reaction mass diluted with saturated solution of sodium bicarbonate and extracted with 5% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crudes were purified over combiflash or Prep-TLC or Prep-HPLC purification to get the final compounds.

General Procedure K:

To a solution of products (1.0 eq) obtained from General Procedure I in dichloromethane:tetrahydrofuran (1:1) was cooled to −40° C. followed by triethylamine (3-5 eq) and acryloyl chloride (1.0 eq) were added. The mixture was stirred at the same temperature for 2 hours. After completion of reaction (monitored by TLC), added water and extracted with dichloromethane (3 times). The combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crudes were purified by Prep-HPLC purification to get the final compounds.

General Procedure K₁:

To a solution of products (1.0 eq) obtained from General Procedure I in tetrahydrofuran and water (3:1) at −0° C. were added triethylamine (5 eq) and acryloyl chloride (1.0 eq). The reaction mixture was stirred at the same temperature for 2 hours. After completion of reaction (monitored by TLC), added water and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC purification to get the final compounds.

General Procedure K₂:

To a solution of products (1.0 eq) obtained from General Procedure I in tetrahydrofuran and water (3:1) at −0° C. were added triethylamine (5 eq) and 3-Chloropropionyl chloride (1.2 to 1.5 eq). The reaction mixture was stirred at the same temperature for 20 minutes to one hour. After completion of reaction (monitored by LCMS), added water and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC purification to get the final compounds.

General Procedure L:

To an ice cold solution of nitro derivatives (1.0 eq) in methanol:tetrahydrofuran:water (2:2:1) were added zinc-dust or iron powder (5 eq) and ammonium chloride (5 eq). The resultant reaction mixture was stirred at room temperature for 2 hours. After completion of reaction (TLC monitoring), reaction mixture passed through celite bed washed with 5% methanol in dichloromethane. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to get the amino derivatives.

General Procedure L₁:

To a solution of nitro derivatives (1.0 eq) in methanol or ethanol (10 vol) was added 10% palladium on carbon (20% w/w). The reaction mixture was stirred under hydrogen atmosphere for 16 hours. After completion of reaction (TLC monitoring), reaction mixture was filtered through the celite bed and washed with methanol. The combined filtrate was concentrated under reduced pressure to get amino derivatives.

General Procedure M₁: (Suzuki Coupling):

To a solution of halo derivatives (1.0 eq) in acetonitrile was added respective boronate acid/ester derivatives (1.0 eq), followed by aqueous solution of potassium carbonate (2.0 eq) under argon purging. The resulting reaction mixture was degassed for 15 minutes, followed by [1,1′-Bis (diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (0.1 eq) was added and the reaction mixture was heated at 80° C. for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was diluted with ice water and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude was purified over combiflash, eluted with 40-60% ethyl acetate in hexane, desired fractions were concentrated under reduced pressure to get the desired products.

General Procedure M2:

To a solution of halo derivatives (1.0 eq) and respective boronic acids (1.1 eq) in toluene:ethanol (1:1) or dimethylformamide or dimethoxyethane and water (4:1) was added potassium carbonate (2.0 eq) or sodium bicarbonate (2.0 eq). The resulting reaction mixture was degassed with argon for 15 minutes, followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.05 eq). The resulting reaction mixture was heated at 90° C. for 5-16 hours. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified over combiflash, elution with 30-50% ethyl acetate in hexane, desired fractions were concentrated under reduced pressure to the desired products.

General Procedure M3:

To a solution of halo derivatives (1.0 eq) and respective boronate acid/ester derivatives (1.1 eq) in N,N-dimethylformamide:water (4:1) was added sodium carbonate or sodium bicarbonate (2.0 eq). The resulting reaction mixture was degassed under argon atmosphere for 15 minutes, followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.1 eq). The resulting reaction mixture was heated at 90° C. for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by using combiflash, desired fractions were concentrated under reduced pressure to afford the desired products.

General Procedure N:

To an ice-cold solution of N-(3-(2-chloro-6-fluoroquinazolin-8-yl)phenyl)acrylamide (1.0 eq) in dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 10 eq) portion-wise and stirred at room temperature for 30 minutes, followed by addition of respective amines (1.2 eq). The resultant reaction mixture was stirred at room temperature for 16 hours. After completion of reaction (as per TLC monitoring), reaction mixture was diluted with ice-cold water and extracted with 5% methanol/dichloromethane (3 times). The combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified over combiflash or Prep HPLC purification to get desired products.

General Procedure O:

To a solution of primary or secondary alcohols (1.0 eq) in dichloromethane was added activated manganese dioxide (10 eq) at room temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at same temperature for 16 hours. After completion of reaction (TLC monitoring), the reaction mixture was filtered through celite bed and washed with dichloromethane (3 times). The combined filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get desired products.

embedded image

Step 1: Synthesis of 5-(2-fluoro-4-(trifluoromethyl) phenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (3)

To a solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (1) (0.3 g, 0.73 mmol), [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (2) (0.18 g, 0.88 mmol) in 1,4-dioxane (3.00 mL) and water (1.00 mL) was added sodium hydrogen carbonate (0.18 g, 2.20 mmol). Then the reaction mixture was purged with nitrogen for 10 minutes, added bis(triphenylphosphine)palladium(II) dichloride (0.05 g, 0.73 mmol) and the reaction mixture was heated at 100° C. for 16 hours. Progress of the reaction was monitored by LCMS. After completion of the reaction the reaction mixture was cooled to room temperature and diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under vacuo. The crude product was purified by flash column chromatography with 80% ethyl acetate in hexane as eluent to give the title compound (3) (0.27 g, 74.76% yield) as yellow solid. LCMS: [M+H]⁺ 492.4

Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (4)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure Li to afford desired product (4) brown liquid (0.2 g, crude). LCMS: [M+H]⁺ 462.4.

Step 3: Synthesis of N-(4-fluoro-3-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 21)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K₁to afford off white solid (0.02 g, 17.9% yield). ¹H NMR (400 MHz, DMSO-d6): δ10.19 (s, 1H), 9.24 (s, 1H), 8.44 (s, 2H), 7.92 (s, 1H), 7.72-7.56 (m, 4H), 7.26-7.16 (m, 3H), 6.42-6.35 (m, 1H), 6.22 (d, J=15.2 Hz, 1H), 5.72 (d, J=11.6 Hz, 1H), 3.53 (s, 3H). LCMS: [M+H]⁺ 516.4.

TABLE 1

The following compounds were prepared using the procedures described above:

Cmpd.

General
LCMS

No.
Structure
Procedure
[M + H]

¹H-NMR (400 MHZ, DMSO-d₆)

1

embedded image

K
478.17
δ 10.25 (s, 1H), 9.11 (bs, 1H), 8.27 (bs, 1H), 7.89 (s, 1H), 7.61-7.79 (m, 2H), 7.16-7.30 (m, 6H), 6.39- 6.46 (m, 1H), 6.22-6.26 (m, 1H), 5.73 (dd, J = 12.0 Hz & 1.6 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 3H).

2

embedded image

K
490.15
δ 10.21 (s, 1H), 9.07 (bs, 1H), 8.13 (bs, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 6.98-7.18 (m, 6H), 6.38-6.45 (m, 1H), 6.22 (dd, J = 15.2 Hz & 2.0 Hz, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.56 (s, 3H).

3

embedded image

K
494.09
δ 10.21 (s, 1H), 9.12 (bs, 1H), 8.32 (bs, 1H), 7.88 (s, 1H), 7.75-7.76 (m, 1H), 7.49-7.58 (m, 2H), 7.38- 7.41 (m, 1H), 7.16-7.28 (m, 4H), 6.37-6.44 (m, 1H), 6.22 (d, J = 15.2 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.89 (s, 3H), 3.55 (s, 3H).

4

embedded image

K
478.21
δ 10.31 (s, 1H), 9.95 (bs, 1H), 9.22 (bs, 1H), 7.95 (s, 1H), 7.86-7.87 (m, 1H), 7.58 (s, 1H), 7.06-7.37 (m, 6H), 6.38-6.45 (m, 1H), 6.22 (dd, J = 16.8 Hz & 2.0 Hz, 1H), 5.75 (dd, J = 10.0 Hz & 2.0 Hz, 1H), 3.90 (s, 3H), 3.57 (s, 3H).

5

embedded image

K
466.16
δ 10.23 (s, 1H), 9.20 (bs, 1H), 8.40 (bs, 1H), 7.92 (s, 1H), 7.75-7.77 (m, 1H), 7.47-7.56 (m, 3H), 7.08- 7.30 (m, 4H), 6.37-6.44 (m, 1H), 6.22 (d, J = 16.8 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 3.54 (s, 3H).

6

embedded image

K
482.16
δ 10.23 (s, 1H), 9.20 (bs, 1H), 8.44 (bs, 1H), 7.92 (s, 1H), 7.75-7.76 (m, 1H), 7.64-7.66 (m, 1H), 7.57 (s, 1H), 7.44-7.49 (m, 2H), 7.10- 7.22 (m, 3H), 6.38-6.44 (m, 1H), 6.22 (d, J = 15.2 Hz, 1H), 5.73 (d, J = 10.4 Hz, 1H), 3.47 (s, 3H).

7

embedded image

K
478.17
δ 10.20 (s, 1H), 9.12 (bs, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.75-7.77 (m, 1H), 7.58 (s, 1H), 7.32-7.36 (m, 1H), 7.17-7.26 (m, 3H), 6.87- 6.94 (m, 2H), 6.37-6.44 (m, 1H), 6.21 (d, J = 15.2 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.81 (s, 3H), 3.55 (s, 3H).

8

embedded image

K
494.3
δ 10.17 (s, 1H), 9.10 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.73-7.71 (m, 1H), 7.58 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.30-7.10 (m, 3H), 6.99-6.96 (m, 2H), 6.42-6.35 (m, 1H), 6.24-6.20 (m, 1H), 5.74-5.71 (m, 1H), 3.78 (s, 3H), 3.54 (s, 3H).

9

embedded image

K
478.3
δ 10.19 (s, 1H), 9.12 (s, 2H), 7.89- 7.75 (m, 3H), 7.56 (s, 1H), 7.24- 7.05 (m, 4H), 6.50-6.35 (m, 1H), 6.24-6.20 (m, 1H), 5.73 (d, J = 12.0 Hz, 2H), 3.78 (s, 3H), 3.53 (s, 3H).

10

embedded image

K
528.3
δ 10.17 (s, 1H), 9.08 (s, 1H) ,7.97 (s, 1H), 7.82 (s, 1H) 7.73-7.72 (m, 1H), 7.56 (s, 1H), 7.49-7.47 (m, 1H), 7.37-7.31 (m, 2H), 7.23-7.21 (m, 3H), 6.42-6.40 (m, 1H), 6.25- 6.20 (m, 1H), 5.74-5.72 (m, 1H), 3.88 (s, 3H), 3.54 (s, 3H).

11

embedded image

K
482.08
δ 10.22 (bs, 1H), 9.21 (bs, 1H), 8.24 (bs, 1H), 7.83 (s, 1H), 7.72- 7.73 (m, 1H), 7.59-7.62 (m, 2H), 7.32-7.36 (m, 1H), 7.27-7.30 (m, 2H), 7.08-7.17 (m, 2H), 6.37-6.47 (m, 1H), 6.21-6.26 (m, 1H), 5.72 (d, J = 10.0 Hz, 1H), 3.54 (s, 3H).

12

embedded image

K
482.09
δ 10.25 (bs, 1H), 9.16 (bs, 1H), 8.16 (bs, 1H), 7.79 (s, 1H), 7.73- 7.74 (m, 1H), 7.54-7.60 (m, 3H), 7.29-7.33 (m, 2H), 7.17-7.26 (m, 2H), 6.38-6.44 (m, 1H), 6.21-6.25 (m, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.54 (s, 3H).

13

embedded image

K
462.13
δ 10.21 (bs, 1H), 9.15 (bs, 1H), 8.34 (bs, 1H), 7.92 (s, 1H), 7.75- 7.77 (m, 1H), 7.58 (s, 1H), 7.35- 7.39 (m, 1H), 7.09-7.25 (m, 5H), 6.38-6.44 (m, 1H), 6.22-6.26 (m, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.35 (s, 3H), 2.28 (s, 3H).

14

embedded image

K₁
532.2
δ 10.23 (s, 1H), 9.23 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 7.78-7.64 (m, 4H), 7.42 (d, J = 8.4 Hz, 1H), 7.30-7.11 (m, 3H), 6.46-6.39 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H)

15

embedded image

K₁
498.1
δ 10.32 (s, 1H), 10.23 (s, 1H), 9.48 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.60-7.51 (m, 4H), 7.38 (s, 1H), 7.25-6.98 (m, 3H), 6.46-6.39 (m, 1H), 6.26 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 3.60 (s, 3H).

16

embedded image

K₁
514.4
δ 10.30 (s, 1H), 10.03 (s, 1H), 9.36 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.59-7.12 (m, 9H), 6.43-6.36 (m, 1H), 6.24 (d, J = 17.2 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H)

17

embedded image

K₁
499.1
δ 10.32 (s, 1H), 9.35 (s, 1H), 8.70 (s, 1H), 8.48-8.47 (d, J = 5.2 Hz, 1H), 8.22-8.21 (s, 1H), 7.95 (m, 1H), 7.81-7.78 (m, 1H), 7.65- 7.53 (s, 2H), 7.32 (s, 1H), 7.17- 7.12 (d, J = 17.6 Hz, 1H), 6.47- 6.41 (m, 1H), 6.27-6.22 (m, 1H), 5.77-5.74 (d, J = 12.0 Hz, 1H), 3.54 (s, 3H)

18

embedded image

K₁
526.2
δ 10.31 (s, 1H), 10.05 (s, 1H), 9.34 (bs, 1H), 7.95 (s, 1H), 7.84-7.83 (m, 2H), 7.55-7.48 (m, 3H), 7.40- 7.30 (m, 1H), 7.21 (bs, 1H), 7.13 (bs, 1H), 7.08-6.95 (m, 1H), 6.43- 6.36 (m, 1H), 6.24 (dd, J = 16.4 Hz, 1.6 Hz, 1H), 5.76 (dd, J = 9.6 Hz, 1.6 Hz, 1H), 3.59 (s, 3H)

19

embedded image

K₁
479.3
δ 10.27 (s, 1H), 9.924 (s, 1H), 9.26 (s, 1H), 8.08 (s, 1H), 7.94 (bs, 1H), 7.82 (d, J = 11.6 Hz, 2H), 7.56-7.15 (m, 5H), 6.43-6.36 (m, 1H), 6.24 (d, J = 15.6 Hz, 1H), 5.75 (d, J = 11.2 Hz, 1H), 3.99 (s, 3H), 3.44 (s, 3H)

20

embedded image

K₂
534.2
δ 10.31 (s, 1H), 9.96 (bs, 1H), 9.25 (bs, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.58-7.55 (m, 3H), 7.45- 7.25 (m, 1H), 7.19-6.90 (m, 3H), 6.44-6.37 (m, 1H), 6.24 (dd, J = 19.2 Hz, 2.0 Hz, 1H), 5.75 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 3.55 (s, 3H).

22

embedded image

K₁
528.5
δ 10.21 (s, 1H), 9.15 (bs, 1H), 8.38 (bs, 1H), 7.91 (s, 1H), 7.69-7.76 (m, 2H), 7.64 (s, 1H), 7.57 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.17 (s, 2H), 6.37-6.44 (m, 1H), 6.21 (dd, J = 2.0 & 16.8 Hz, 1H), 5.73 (dd, J = 2.0 & 10.0 Hz, 1H), 3.92 (s, 3H), 3.31 (s, 3H).

Step 1: Synthesis of 5-(5-chloro-2-methoxyphenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (6)

embedded image

To a solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (1) (0.3 g, 0.735 mmol), (5-chloro-2-methoxyphenyl)boronic acid (6) (164 mg, 0.88 mmol) in 1,2-dimethoxyethane (4.00 mL) and water (1.50 mL) was added sodium hydrogen carbonate (0.185 g, 2.20 mmol). Then the reaction mixture was purged with nitrogen for 10 minutes, added bis(triphenylphosphine)palladium(II) dichloride (51.6 mg, 0.073.5 mmol) and the reaction mixture was heated at 80° C. for 16 hours. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under vacuo. The crude product was purified by combiflash purifier with 85% ethyl acetate in hexane as eluent to afford the title compound (6) (0.2 g, 0.426 mmol) as yellow solid. LCMS: [M+H]⁺ 470.0.

Step 2: Preparation of N4-(5-amino-2-fluorophenyl)-5-(5-chloro-2-methoxy-phenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (7)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to afford brown liquid (0.13 g, crude). LCMS: [M+H]⁺ 440.0

Step 3: Synthesis of N-(3-((5-(5-chloro-2-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 23)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K₁to afford off white solid (0.01 g, 9 yield). ¹H NMR (400 MHz, DMSO-d6): δ10.19 (s, 1H), 9.10 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.73 (d, J 6.0 Hz, 1H), 7.57 (s, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.07-7.29 (m, 4H), 6.35-6.39 (m, 1H), 6.22 (d, J=16.4 Hz, 1H), 5.73 (d, J=9.6 Hz, 1H), 3.79 (s, 3H), 3.53 (s, 3H). LCMS: [M+H]⁺ 494.3.

TABLE 2

The following compounds were prepared using the procedures described above:

General

Cmpd.

Pro-
LCMS

No.
Structure
cedure
[M + H]

¹H-NMR (400 MHz, DMSO-d₆)

24

embedded image

K
516.3
δ 10.17 (s, 1H), 9.24 (s, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.70 (d, J = 9.6 Hz, 2H), 7.53 (d, J = 15.2 Hz, 1H), 7.49-7.46 (m, 2H), 7.25-7.17 (m, 3H), 6.41-6.34 (m, 1H), 6.24- 6.24 (s, 1H), 5.73 (d, J = 11.6 Hz, 1H), 5.34 (s, 3H).

25

embedded image

K
516.0
δ 10.19 (bs, 1H), 9.19 (bs, 1H), 8.46 (bs, 1H), 7.94 (s, 1H), 7.78- 7.72 (m, 3H), 7.58-7.53 (m, 2H), 7.26-7.16 (m, 3H), 6.42-6.35 (m, 1H), 6.24-6.20 (m, 1H), 5.73 (d, J = 11.2 Hz, 1H), 3.55 (s, 3H).

26

embedded image

K
466.2
δ 10.25 (s, 1H), 9.73 (s, 1H), 9.07 (s, 1H), 8.35 (s, 1H), 7.98 (s, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.37-7.19 (m, 5H), 7.10-6.93 (m, 1H), 6.43-6.36 (m, 1H), 6.25- 6.21 (m, 1H), 5.76-5.73 (m, 1H), 3.5 (s, 3H).

27

embedded image

K
516.3
δ 10.21 (s, 1H), 9.30 (bs, 1H), 8.62 (bs, 1H), 8.03 (s, 1H), 7.77 (bs, 1H), 7.65-7.60 (m, 4H), 7.30-7.19 (m, 3H), 6.45-6.38 (m, 1H), 6.27- 6.23 (m, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H).

28

embedded image

K₁
491.3
δ 10.31 (s, 1H), 10.19 (s, 1H), 9.50 (s, 1H), 7.88 (s, 2H), 7.20 (s, 1H), 7.37 (s, 1H), 7.30-7.21 (m, 3H), 7.09 (t, J = 8.8 Hz, 2H), 6.46-6.39 (m, 1H), 6.26 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 3.61 (s, 3H), 2.86 (s, 6H).

29

embedded image

K₁
467.3
δ 10.31 (s, 1H), 9.37 (s, 1H), 8.64 (s, 1H), 8.24-8.19 (m, 2H), 8.05 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.63 (s, 1H), 7.37 (s, 1H), 7.20 (d, J = 20.0 Hz, 2H), 6.51-6.44 (m, 1H), 6.33-6.29 (m, 1H), 5.84- 5.80 (m, 1H), 3.60 (s, 3H)

30

embedded image

K₁
482.3
δ 10.11 (s, 1H), 9.06 (s, 1H), 8.30 (s, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 7.73-7.44 (m, 3H), 7.27-7.14 (m, 4H), 7.02 (t, J = 9.2 Hz, 1H), 6.46- 6.39 (m, 1H), 6.24-6.19 (m, 1H), 5.71 (t, J = 10.0 Hz, 1H), 3.58 (s, 3H), 2.80 (s, 6H).

31

embedded image

K₁
495.2
δ 10.33-10.24 (m, 2H), 9.57 (s, 1H), 8.27-8.22 (s, 1H), 8.03- 7.99 (m, 2H), 7.87 (s, 1H), 7.56- 7.15 (m, 5H), 6.43-6.36 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.74 (m, 1H), 4.021-3.99 (s, 3H), 3.57 (s, 3H).

32

embedded image

K
498.2
δ 10.27 (s, 1H), 9.92 (bs, 1H), 9.28 (bs, 1H), 7.98 (s, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.64 (s, 1H), 7.54- 7.57 (m, 3H), 7.33 (bs, 2H), 7.21 (s, 1H), 7.12 (s, 1H), 6.36-6.43 (m, 1H), 6.21-6.26 (m, 1H), 5.73 (d, J = 5.0 Hz, 1H), 3.56 (s, 3H).

33

embedded image

K₁
482.3
δ 10.22 (s, 1H), 9.24 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.68-7.51 (m, 3H), 7.36-7.30 (m, 2H), 7.17-7.10 (m, 2H), 6.45-6.38 (m, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 3.55 (bs, 3H).

34

embedded image

K₁
482.3
δ 10.19 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 7.97 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.57 (s, 1H), 7.37- 7.29 (m, 4H), 7.15 (s, 2H), 6.43- 6.36 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.54 (s, 3H).

35

embedded image

K
516.20
δ 10.25 (bs, 1H), 9.23 (bs, 1H), 8.65 (s, 1H), 8.03 (s, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.76-7.77 (m, 1H), 7.61-7.64 (m, 2H), 7.52-7.54 (m, 1H), 7.31 (s, 1H), 7.08-7.15 (m, 2H), 6.38-6.44 (m, 1H), 6.20- 6.26 (m, 1H), 5.74 (d, J = 10.0 Hz, 1H), 3.53 (s, 3H).

36

embedded image

K
448.88
δ 10.36 (bs, 1H), 9.76 (bs, 1H), 8.46 (s, 1H), 7.78-7.85 (m, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.48- 7.55 (m, 3H), 7.10 (s, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.85 (s, 1H), 6.39- 6.46 (m, 1H), 6.23-6.27 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.50 (s, 3H)

37

embedded image

K₁
498.3
δ 10.27 (s, 1H), 9.77 (s, 1H), 9.16 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.71-7.75 (m, 1H), 7.47-7.56 (m, 3H), 7.39-7.12 (m, 4H), 6.43-6.36 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 3.52 (3H)

38

embedded image

K
461.01
δ 10.37 (bs, 1H), 9.68 (bs, 1H), 8.42 (s, 1H), 7.46-7.68 (m, 5H), 7.25 (t, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.84 (s, 1H), 6.39-6.46 (m, 1H), 6.23- 6.27 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.87 (s, 3H), 3.50 (s, 3H)

39

embedded image

K
464.98
δ 10.37 (bs, 1H), 9.77 (bs, 1H), 8.46 (s, 1H), 7.91-7.92 (m, 1H), 7.49-7.70 (m, 5H), 7.10 (s, 1H), 7.03-7.05 (m, 1H), 6.82 (s, 1H), 6.39-6.46 (m, 1H), 6.23-6.27 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.50 (s, 3H)

40

embedded image

K
465.05
δ 10.37 (bs, 1H), 9.81 (bs, 1H), 8.51 (m, 1H), 7.51-7.79 (m, 6H), 7.04-7.15 (m, 2H), 6.85 (bs, 1H), 6.39-6.51 (m, 1H), 6.23-6.27 (m, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.50 (s, 3H)

41

embedded image

K
445.05
δ 10.35 (bs, 1H), 9.71 (bs, 1H), 8.45 (s, 1H), 7.38-7.91 (m, 6H), 7.10 (bs, 1H), 7.02-7.04 (m, 1H), 6.85 (bs, 1H), 6.39-6.46 (m, 1H), 6.23-6.27 (m, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.50 (s, 3H), 2.27 (s, 3H)

42

embedded image

K₁
491.2
δ 10.20 (s, 1H), 9.13 (s, 1H), 8.25 (s, 2H), 7.94 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 7.12-7.35 (m, 3H), 6.57-6.21 (m, 4H), 5.74 (d, J = 11.6 Hz, 1H), 3.53 (s, 3H), 2.94 (s, 6H).

43

embedded image

K₁
480.2
δ 10.23 (s, 1H), 9.87 (bs, 1H), 9.35 (bs, 1H), 7.82-7.96 (m, 3H), 7.07- 7.58 (m, 7H), 6.95 (s, 1H), 6.39- 6.46 (m, 1H), 6.20-6.25 (m, 1H), 6.72-5.75 (m, 1H), 3.43 (s, 3H).

44

embedded image

K₁
531.0
δ 10.31 (s, 1H), 9.8 (bs, 1H), 9.2 (bs, 1H), 8.79 (s, 1H), 8.42 (s, 1H), 8.09 (bs, 1H), 7.85 (bs, 1H), 7.58-7.36 (s, 3H), 7.22-7.18 (m, 2H), 6.45-6.38 (m, 1H), 6.25 (d, J = 17.2 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H), 3.57 (s, 3H)

45

embedded image

K₁
483.1
δ 10.32 (s, 1H), 9.96 (bs, 1H), 9.28 (bs, 1H), 8.43 (s, 1H), 8.25-8.06 (m, 2H), 7.87-7.16 (m, 6H), 6.45- 6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.68 (s, 3H).

46

embedded image

K₁
479.3
δ 10.22 (bs, 1H), 9.26 (bs, 1H), 8.61 (bs, 1H), 8.47 (s, 1H), 7.94- 7.91 (m, 2H), 7.74-7.26 (m, 1H), 7.56 (bs, 1H), 7.29 (bs, 1H), 7.14- 7.08 (m, 2H), 6.43-6.36 (m, 1H), 6.25-6.21 (m, 1H), 5.75-5.72 (d, J = 11.6 Hz, 1H), 3.52 (s, 3H), 2.65 (s, 3H).

47

embedded image

K₁
517.3
δ 10.30 (s, 1H), 9.88 (s, 1H), 9.21 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.04-7.85 (s, 3H), 7.55 (s, 1H), 7.19 (d, J = 19.6 Hz, 3H), 6.43-6.21 (m, 2H), 5.75 (d, J = 11.6 Hz, 1H), 3.47 (s, 3H)

48

embedded image

K₁
479.3
δ 10.33 (s, 1H), 10.21 (s, 1H), 9.45 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.20-6.97 (m, 2H), 6.44-6.37 (m, 1H), 6.25 (d, J = 17.2 Hz, 1H), 5.75 (d, J = 1.6 Hz, 1H), 3.57 (s, 3 H), 2.48 (d, J = 2.8 Hz, 3H).

49

embedded image

K₁
464.2
δ 10.24 (s, 1H), 10.09 (s, 1H), 9.40 (s, 1H), 7.93-7.74 (m, 3H), 7.57- 7.52 (m, 4H), 7.39-7.34 (m, 3H), 7.23-7.17 (m, 1H), 6.48- 6.42 (m, 1H), 6.25 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.76 (dd, J = 10.4 Hz, 1.6 Hz, 1H), 3.62 (s, 3H).

50

embedded image

K₁
498.1
δ 10.29 (s, 1H), 9.90 (s, 1H), 9.24 (s, 1H), 7.96 (s, 1H), 7.82-7.73 (m, 3H), 7.55-7.11 (m, 6H), 6.42- 6.36 (m, 1H), 6.25-6.20 (m, 1H), 5.76-5.73 (m, 1H), 3.62 (m, 3H).

51

embedded image

K₂
528.4
δ 10.26 (s, 1H), 9.91 (bs, 1H), 9.27 (bs, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.52 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.32-7.31 (m, 2H), 7.22 (bs, 2H), 6.42-6.36 (m, 1H), 6.23 (dd, J = 18.8 Hz, 2.0 Hz, 1H), 5.74 (dd, J = 11.6 Hz, 1.6 Hz, 1H), 3.84 (bs, 2H), 3.55 (bs, 2H). OH peak is merged along with solvent peak.

52

embedded image

K₁
516.0
10.26 (s, 1H), 9.21 (bs, 1H), 7.97 (bs, 1H), 7.83-7.85 (m, 1H), 7.73- 7.75 (m, 1H), 7.49-7.59 (m, 4H), 7.32-7.35 (m, 2H), 6.96- 6.26 (dd, J = 16.0 Hz, 1.9 Hz, 1H), 5.78 (dd, J = 8.0 Hz, 1.9 Hz, 1H), 3.63 (s, 3H).

53

embedded image

K₂
524.9
δ 10.33 (bs, 2H), 9.41 (bs, 1H), 8.00 (bs, 1H), 7.88 (bs, 1H), 7.75- 7.74 (m, 1H), 7.57-7.29 (m, 7H), 6.46-6.39 (m, 1H), 6.28- 6.24 (m, 1H), 5.79-5.77 (m, 1H), 5.18 (s, 1H), 4.83-4.73 (m, 4H)

54

embedded image

K₂
532.9
δ 10.33-10.29 (m, 2H), 9.46 (s, 1H), 8.09 (bs, 1H), 8.01-7.98 (m, 1H), 7.88 (bs, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.38 (bs, 2H), 7.26-7.24 (m, 1H), 7.16 (bs, 1H), 6.46-6.39 (m, 1H), 6.28- 6.23 (m, 1H), 5.78-5.75 (m, 1H), 3.59 (s, 3H merged with DMSO peak).

55

embedded image

K₂
541.2 [M − H]⁺
δ 10.29 (s, 1H), 9.94 (bs, 1H), 9.70 (bs, 1H), 8.90 (bs, 1H), 7.99 (s, 1H), 7.85 (d, J = 4.8 Hz, 1H), 7.58 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.42-7.37 (m, 3H), 7.42 (m, 2H), 6.46-6.39 (m, 1H), 6.27-6.32 (m, 1H), 6.09 (s, 1H), 5.78-5.75 (m, 1H), 4.05-4.01 (m, 2H), 3.82- 3.78 (m, 2H), 3.50 (s, 3H), 2.91- 2.87 (m, 3H), 2.72-2.67 (m, 2H).

56

embedded image

K₂
540.1
δ 10.32 (s, 1H), 10.20 (bs, 2H), 9.38 (bs, 1H), 8.01 (bs, 1H), 7.85 (bs, 2H), 7.57-7.24 (m, 6H), 6.43- 6.37 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.74 (m, 1H), 5.20- 5.10 (m, 1H), 4.80-4.69 (m, 4H).

57

embedded image

K₁
539.1
δ 9.95 (s, 1H), 9.0 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.74-7.71 (m, 1H), 7.62-7.44 (m, 6H), 7.24 (dd, J = 18.8 Hz, 9.6 Hz, 1H), 6.46- 6.39 (m, 1H), 6.26 (dd, J = 18.8 Hz, 1.6 Hz, 1H), 5.75 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 4.32-4.29 (m, 2H), 3.49-3.32 (m, 3H), 2.797 (s, 6H).

58

embedded image

K
555.1
δ 10.28 (s, 1H), 10.00 (bs, 1H), 9.39 (bs, 1H), 9.10 (bs, 1H), 7.99- 7.22 (m, 9H), 6.43-6.36 (m, 1H), 6.23 (dd, J = 18.4 Hz, 2.0 Hz, 1H), 5.75 (dd, J = 11.6 Hz, 1.6 Hz, 1H), 4.22 (s, 2H), 3.41 (s, 2H), 2.75-2.30 (m, 6H).

59

embedded image

K₂
485.2
δ 10.33 (s, 1H), 9.95 (bs, 1H), 9.62 (bs, 1H), 7.93-7.81 (m, 2H), 7.67- 7.59 (m, 1H), 7.37-6.96 (m, 6H), 6.64 (d, J = 8.0 Hz, 1H), 6.43-6.39 (m, 1H), 6.26-6.21 (m, 1H), 5.76 (dd, J = 11.6 Hz, 1.2 Hz, 1H), 3.58-3.56 (m, 3H), 3.32 (t, J = 8.5 Hz, 2H), 2.94 (t, J = 8.5 Hz, 2H), 2.81 (s, 3H).

60

embedded image

K₁
503.2 [M − H]−
CD₃OD, δ 7.98-7.91 (m, 2H), 7.75-7.71 (m, 2H), 7.59-7.30 (m, 8H), 6.45-6.33 (m, 3H), 5.80- 5.77 (m, 1H), 4.49 (s, 2H), 3.65 (s, 3H), 2.94 (s, 6H).

61

embedded image

K₁
516.9
δ 10.26 (s, 1H), 9.43 (s, 1H), 9.04 (s, 1H), 8.80-8.55 (m, 2H), 8.19 (d, J = 11.6 Hz, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.13 (d, J = 22.0 Hz, 1H), 6.43-6.36 (m, 1H), 6.23 (d, J = 16.4 Hz, 1H), 5.75 (d, J = 11.2 Hz, 1H), 3.52 (s, 3H).

62

embedded image

K₂
511.9
δ 10.26 (s, 1H), 9.92 (bs, 1H), 9.19 (bs, 1H), 7.96 (bs, 1H), 7.86-7.85 (m, 1H), 7.73-7.71 (m, 1H), 7.57- 7.51 (m, 3H), 7.32-7.27 (m, 4H), 6.45-6.38 (m, 1H), 6.25 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.76 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 3.88 (bs, 2H), 3.59 (bs, 2H). Note: OH peak is merged along with solvent peak.

embedded image

Step 1: Synthesis of N4-(2-fluoro-5-nitrophenyl)-5-(2-fluoro-6-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (9)

To a stirred solution of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (2) (350 mg, 0.85 mmol) in 1,4-dioxane (2.7 mL) and water (0.30 mL) was added tripotassium phosphate (546 mg, 2.57 mmol) and (2-fluoro-6-methoxyphenyl)boronic acid (8) (175 mg, 103 mmol). Then the reaction mixture was purged with nitrogen for 5 minutes, added XPhos Pd G2 (67.5 mg, 0.085 mmol) and the reaction mixture was heated to 100° C. for 16 hours. The progress of the reaction was monitored by TLC. Once the reaction was completed, the reaction mixture was quenched with water (50.0 mL) and extracted with dichloromethane (3×35 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum. The crude compound was purified by silica gel column chromatography using 18 to 22% ethyl acetate in hexane as eluent to afford the title compound (9) (0.33 g, Yield: 84.88%) as yellow solid. LCMS: [M+H]⁺ 454.2.

Step 2: Synthesis of N4-(5-amino-2-fluorophenyl)-5-(2-fluoro-6-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (10)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to afford yellow solid (0.25 g, crude). LCMS: [M+H]⁺ 424.2.

Step 3: Synthesis of N-(4-fluoro-3-((5-(2-fluoro-6-methoxyphenyl)-2-((1-methyl-11H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (Compound 63)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K to afford off white solid (0.06 g, 21%). ¹H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.10 (bs, 1H), 7.94 (s, 1H), 7.71-7.76 (m, 2H), 7.57 (s, 2H), 7.35-7.41 (m, 1H), 7.16-7.23 (m, 2H), 6.87-6.95 (m, 2H), 6.35-6.42 (m, 1H), 6.20-6.24 (m, 1H), 5.72-5.75 (m, 1H), 3.79 (s, 3H), 3.53 (s, 3H). LCMS: [M+H]⁺ 478.3.

embedded image

Step 1: Preparation of 2-(3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12)

To a solution of 1-bromo-3-fluoro-5-methoxybenzene (1) (1.0 g, 4.88 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.40 g, 1.60 mmol) in N,N-dimethylformamide (5 mL) was added potassium acetate (0.57 g, 5.85 mmol) and the reaction mixture was degassed with nitrogen for 10 minutes. Then added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.356 g, 0.488 mmol) and the reaction mixture was heated at 85° C. for 12 hours in a sealed tube. The reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by combiflash purifier, the desire product was eluted with 20% ethyl acetate in hexane to afford the title compound (12) (1.0 g) as pale yellow liquid. LCMS [M+H]⁺ 253.1

Step 2: Preparation of 5-(3-fluoro-5-methoxyphenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (13)

Title compound was prepared in a manner substantially similar General Procedure M3 to afford the title compound (13) as white solid (0.15 g; Yield: 39%). LCMS: [M+H]⁺ 454.2

Step 3: Preparation of N4-(5-amino-2-fluorophenyl)-5-(3-fluoro-5-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (14)

Title compound was prepared in a manner substantially similar General Procedure L to afford the title compound (14) as white solid (0.12 g; Yield: 51%). LCMS: [M+H]⁺ 424.2

Step 4: Preparation of N-(4-fluoro-3-{[5-(3-fluoro-5-methoxyphenyl)-2-[(1-methyl-1H-pyrazol-4-yl) amino]pyrimidin-4-yl]amino}phenyl)prop-2-enamide (Compound 65)

Title compound was prepared in a manner substantially similar General Procedure K to afford the title compound (Compound 65) as off white solid (0.01 g; Yield: 6%). ¹H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 9.83 (bs, 1H), 9.19 (bs, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.60 (s, 1H), 7.35 (bs, 1H), 7.23-7.13 (m, 2H), 6.93-6.89 (m, 3H), 6.45-6.38 (m, 1H), 6.25 (d, J=17.2 Hz, 1H), 5.77 (d, J=10.0 Hz, 1H), 3.84 (s, 3H), 3.55 (3H merged with DMSO water peak). LCMS: [M+H]⁺ 478.3

embedded image

Step 1: Synthesis of 5-bromo-2-chloro-N-(3-nitrophenyl)pyrimidin-4-amine (15)

To a stirred a solution of 3-nitroaniline (4.00 g, 29.0 mmol) and 5-bromo-2,4-dichloropyrimidine (7.92 g, 34.8 mmol) in N,N-dimethylformamide (40.0 mL) was added potassium carbonate (12.0 g, 86.9 mmol) at room temperature. The reaction mixture was heated at 100° C. for 36 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled to 0° C., diluted with ice-cold water (50 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography by using combiflash purifier and was eluted with 10% ethyl acetate in hexane to afford 5-bromo-2-chloro-N-(3-nitrophenyl)pyrimidin-4-amine (15) (3.00 g) as yellow solid.

Step 2: Synthesis of 5-bromo-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine (16)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure H, to afford the desired compound (16) as yellow solid. LCMS [M+H]⁺ 390.2.

Step 3: Synthesis of 5-(3-chloro-5-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine (17)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2, to afford the desired compound (17) as yellow solid. LCMS [M+H]⁺ 440.2

Step 4: Synthesis of N4-(3-aminophenyl)-5-(3-chloro-5-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (18)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (18) as yellow solid. LCMS [M+H]⁺ 410.1

Step 5: Synthesis of N-(3-((5-(3-chloro-5-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide. TFA (Compound 66)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K, to afford the desired compound (Compound 66) as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.89 (s, 1H), 9.32 (s, 1H), 7.97 (bs, 1H), 7.83 (bs, 1H), 7.33-7.16 (s, 9H), 6.41-6.48 (m, 1H), 6.25 (dd, J=17.2 Hz, 2.0 Hz, 1H), 5.76 (dd, J=10.0 Hz, 1.6 Hz, 1H), 3.60 (s, 3H); LCMS [M+H]⁺ 464.3

TABLE 3

The following compounds were prepared using the procedures described above:

LCMS

Cmpd. No.
Structure
General Procedure
[M + H]

¹H-NMR (400 MHz, DMSO-d₆)

64

embedded image

K
462.3
δ 10.29 (s, 1H), 9.89 (s, 1H), 9.19 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 5.2 Hz, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 7.21-7.08 (m, 5H), 6.44- 6.37 (m, 1H), 6.24 (d, J = 16.4 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 3.56 (s, 3H), 2.38 (s, 3H).

67

embedded image

K₁
448.3
δ 10.19 (m, 2H), 9.44 (s, 1H), 8.19 (s, 1H), 7.92-7.13 (m, 9H), 6.46- 6.39 (m, 1H), 6.23 (d, J = 16.0 Hz, 1H), 5.75 (d, J = 11.2 Hz, 1H), 3.60 (d, J = 23.6 Hz, 3H).

68

embedded image

K₁
464.3
δ 10.25 (s, 2H), 9.45 (s, 1H), 7.95- 7.12 (m, 10H), 6.46-6.39 (m, 1H), 6.25-6.21 (m, 1H), 5.75 (d, J = 11.2 Hz, 1H), 3.58 (s, 3H).

69

embedded image

K₁
460.0
δ 10.28 (m, 2H), 9.58 (s, 1H), 7.90- 7.84 (m, 2H), 7.62-7.13 (m, 9H), 6.46-6.40 (m, 1H), 6.26-6.20 (m, 1H), 5.76-5.73 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H).

70

embedded image

K₁
466.2
At 90° C., δ 10.07 (s, 1H), 9.55 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.57 (s, 1H), 8.23-8.20 (m, 1H), 7.68- 7.67 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.49-7.45 (m, 1H), 7.25 (s, 2H), 7.05-7.02 (m, 1H), 6.47- 6.40 (m, 1H), 6.29-6.24 (m, 1H), 5.79-5.73 (m, 1H), 3.60 (s, 3H)

71

embedded image

K₁
462.5
δ 10.06 (s, 1H), 9.37 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.97-7.94 (m, 1H), 7.65-7.60 (m, 2H), 7.48- 7.44 (m, 1H), 7.25-7.00 (m, 4H), 6.47-6.40 (m, 1H), 6.29- 6.24 (m, 1H), 5.76-5.75 (m, 1H), 4.03 (s, 3H), 3.61 (s, 3H).

72

embedded image

K₁
462.2
δ 10.38 (s, 1H), 9.83 (s, 1H), 8.53 (d, J = 24.0 Hz, 2H), 8.12 (s, 1H), 7.61 (t, J = 36.0 Hz, 3H), 7.09- 7.02 (m, 2H), 6.85 (s, 1H), 6.45- 6.38 (m, 1H), 6.23 (d, J = 12.0 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 3.49 (s, 3H), 2.38 (s, 3H).

73

embedded image

K1
516.2
At 90° C., δ 10.07 (s, 1H), 9.87 (s, 1H), 9.01-9.00 (m, 1H), 8.62 (s, 1H), 8.57-8.56 (m, 1H), 7.68- 7.66 (m, 2H), 7.48-7.46 (m, 1H), 7.31-7.21 (m, 2H), 7.12-7.02 (m, 1H), 6.47-6.40 (m, 1H), 6.28- 6.24 (m, 1H), 5.75 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H).

74

embedded image

K₁
474.2
At 90° C., δ 10.06 (s, 1H), 9.28 (s, 1H), 8.41 (s, 1H), 7.63-7.61 (m, 2H), 7.48-7.38 (m, 3H), 7.24- 7.16 (m, 2H), 7.06-6.97 (m, 2H), 6.47-6.36 (m, 2H), 6.29-6.24 (m, 1H), 5.76-5.73 (m, 1H), 3.60 (s, 3H), 2.88 (s, 6H).

75

embedded image

K₁
450.3
δ 10.07 (s, 1H), 9.49 (s, 1H), 8.53 (s, 1H), 8.36-8.28 (m, 2H), 7.67- 7.60 (m, 2H), 7.49-7.44 (m, 2H), 7.25-7.20 (m, 2H), 7.04- 7.02 (m, 1H,), 6.47-6.40 (m, 1H), 6.28-6.24 (m, 1H), 5.77-5.76 (d, J = 2.0 Hz, 1H), 3.60 (s, 3H).

embedded image

Step 1: Synthesis of 4-(4-bromo-2-fluorophenyl) morpholine (19)

To a stirred solution of 4-bromo-2-fluoro-1-iodobenzene (5.00 g, 16.6 mmol) in toluene (50.0 mL) was added morpholine (1.45 g, 16.6 mmol), cesium carbonate (13.5 g, 41.5 mmol), xantphos (0.962 g, 1.66 mmol) and the reaction mixture was purged with argon for 10 minutes. Then added tris(dibenzylideneacetone)dipalladium(0) (0.457 g, 0.499 mmol) and the reaction mixture was heated at 100° C. for 12 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography and was eluted with 10 to 20% ethyl acetate in hexane as eluent to afford 4-(4-bromo-2-fluorophenyl) morpholine (19) (1.80 g, 41%).

Step 2: Synthesis of 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]morpholine (20)

To a stirred solution of 4-(4-bromo-2-fluorophenyl) morpholine (19) (1.20 g, 4.61 mmol) in 1,4-dioxane (10.0 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.17 g, 4.61 mmol), potassium acetate (1.36 g, 13.8 mmol) and the reaction mixture was purged with argon for 10 minutes. Then added (1,1′-bis(diphenylphosphino)ferrocene) palladium(II) dichloride (0.376 g, 0.461 mmol) and the reaction mixture was heated at 100° C. for 12 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography and was eluted with 10 to 20% ethyl acetate in hexane as eluent to afford 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] morpholine (20) (1.2 g, 52%). LCMS [M+H]⁺ 308.0

Step 3: Synthesis of 5-[3-fluoro-4-(morpholin-4-yl) phenyl]-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (21)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M3 to get desired product (21) as white solid. LCMS [M+H]⁺ 509.2

Step 4: synthesis of Synthesis of N4-(5-amino-2-fluorophenyl)-5-[3-fluoro-4-(morpholin-4-yl)phenyl]-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (22)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to get desired product (22) as yellow solid. LCMS [M+H]⁺ 479.5

Step 5: Synthesis of N-[4-fluoro-3-({5-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)phenyl]prop-2-enamide (Compound 76)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K₁to get desired product (Compound 76) as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.32 (bs, 1H), 10.19 (bs, 1H), 9.39 (bs, 1H), 7.85 (s, 1H), 8.06-7.83 (m, 2H), 7.58 (bs, 1H), 7.48-6.97 (m, 6H), 6.44-6.38 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.74 (m, 1H), 3.76-3.74 (m, 4H), 3.56 (bs, 3H), 3.03 (m, 4H); LCMS [M+H]⁺ 533.3

TABLE 4

The following compounds were prepared using the procedures described above:

General

Cmpd. No.
Structure
Procedure
LCMS [M + H]

¹H-NMR (400 MHz, DMSO-d₆)

77

embedded image

K
517.3
δ 10.26 (s, 1H), 9.96 (s, 1H), 9.26 (s, 1H), 7.84 (d, J = 4.8 Hz, 2H), 7.57-7.52 (m, 2H), 7.40-7.16 (m, 5H), 6.83 (t, J = 9.2 Hz, 1H), 6.43-6.37 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.74 (m, 1H), 3.58 (s, 3H). 3.36 (d, J = 1.6 Hz, 4H), 1.91 (t, J = 6.0 Hz, 4H).

78

embedded image

K₁
531.0
δ 10.33 (s, 2H), 9.59 (s, 1H), 7.92- 7.85 (m, 2H), 7.58 (s, 1H), 7.36- 7.12 (m, 7H), 6.43-6.36 (m, 1H), 6.22 (d, J = 16.4 Hz, 1H), 5.73 (d, J = 11.6 Hz, 1H), 3.66 (s, 3H), 3.02 (t, J = 4.8 Hz, 4H). 1.66 (s, 4H), 1.54 (d, J = 4.8 Hz, 2H).

79

embedded image

K₁
533.2
δ 10.31 (s, 1H), 10.14 (bs, 1H), 9.41 (bs, 1H), 7.85-7.84 (m, 2H), 7.57 (s, 1H), 7.35-7.08 (m, 5H), 7.08-6.95 (m, 1H), 6.68 (t, J = 9.0 Hz, 1H), 6.43-6.36 (m, 1H), 6.23 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.75 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 4.33-4.28 (m, 1H), 4.17 (t, J = 6.4 Hz, 2H), 3.74-3.56 (m, 2H), 3.56 (s, 3H), 3.23 (s, 3H).

80

embedded image

K₁
503.3
δ 10.16 (s, 1H), 9.00 (bs, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.57 (bs, 1H), 7.10- 7.27 (m, 5H), 6.60 (t, J = 8.8 Hz, 1H), 6.36-6.43 (m, 1H), 6.21- 6.25 (m, 1H), 5.72-5.75 (m, 1H), 3.90-3.93 (m, 4H), 3.55 (bs, 3H), 2.26-2.33 (m, 2H).

81

embedded image

K₁
546.3
δ 10.29 (s, 1H), 9.80 (bs, 2H), 9.05 (bs, 1H), 7.92-7.86 (m, 2H), 7.57 (s, 1H), 7.38-6.97 (m, 6H), 6.46- 6.39 (m, 1H), 6.26 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.77 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.58-3.55 (m, 7H), 3.27 (bs, 2H), 3.17-3.04 (m, 2H), 2.90 (s, 3H)

82

embedded image

K₂
588.3
δ 10.27 (s, 1H), 9.17 (bs, 1H), 8.35 (bs, 1H), 7.99 (s, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.17- 7.37 (m, 5H), 6.46-6.53 (m, 1H), 6.33 (dd, J = 18.8 Hz, 2.0 Hz, 1H), 5.84 (dd, J = 12.0 Hz, 2.0 Hz, 2H), 3.95 (s, 2H), 3.09-3.14 (m, 6H), 2.19 (s, 6H), 1.76 (bs, 4H), 1.65 (d, J = 4.8 Hz, 2H).

83

embedded image

K₁
546.2
δ 10.70 (bs, 1H), 10.33 (s, 1H), 10.16 (bs, 1H), 9.21 (bs, 1H), 7.90 (d, J = 4.4 Hz, 2H), 7.59 (bs, 1H), 7.35-7.21 (m, 5H), 6.77-6.72 (m, 1H), 6.47-6.40 (m, 1H), 6.25 (dd, J = 17.2 Hz, 2.0 Hz, 1H), 5.77 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 4.24 (bs, 4H), 4.15-4.13 (m, 1H), 3.60 (bs, 3H), 2.83 (s, 6H).

84

embedded image

K₂
547.2
δ 10.28 (s, 1H), 9.96 (bs, 1H), 9.32 (bs, 1H), 7.85-7.84 (m, 2H), 7.57 (s, 2H), 7.35-7.34 (m, 1H), 7.25- 7.19 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.07 (m, 2H), 6.43-6.36 (m, 1H), 6.23 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.75 (dd, J = 10.0 Hz, 1.6 Hz, 1H), 3.75 (t, J = 4.6 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.57 (bs, 3H), 3.48-3.46 (m, 4H), 1.97-1.91 (m, 2H).

85

embedded image

K₂
545.2
δ 10.22 (bs, 1H), 10.01 (bs, 1H), 9.31 (s, 1H), 7.80-7.78 (m, 2H), 7.52 (bs, 1H), 7.31-7.26 (m, 1H), 7.16-7.06 (m, 5H), 6.96-6.92 (s, 1H), 6.38-6.31 (m, 1H), 6.20- 6.10 (m, 1H), 5.71-5.68 (m, 1H), 3.52 (s, 3H merged with DMSO peak), 3.35-3.32 (m, 4H), 1.72 (bs, 4H), 1.50 (bs, 4H)

embedded image

Step 1: Synthesis of N1-(4-bromo-2-fluorophenyl)-N1,N2,N2-trimethylethane-1,2-diamine (23)

To a stirred solution of 4-bromo-2-fluoro-1-iodobenzene (5.00 g, 16.6 mmol), [2-(dimethylamino)ethyl](methyl)amine (1.70 g, 16.6 mmol), cesium carbonate (13.5 g, 41.5 mmol) in 1,4-dioxane (50.0 mL) was purged with nitrogen for 5 minutes. Then added tris(dibenzylideneacetone)dipalladium(O) (0.76 g, 0.831 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.96 g, 1.66 mmol) and the reaction mixture was heated at 100° C. for 12 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by combiflash purifier and was eluted with 5-10% methanol in dichloromethane to afford 4-bromo-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylaniline (23) (1.00 g, 3.63 mmol) as brown oil. LCMS [M+H]⁺ 275.0

Step 2: Synthesis of N1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N1,N2,N2-trimethylethane-1,2-diamine (24)

To a stirred solution of 4-bromo-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylaniline (23) (1.50 g, 5.45 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.52 g, 6.00 mmol), potassium acetate (1.60 g, 16.4 mmol) in 1,4-dioxane (20.0 mL) was purged with nitrogen for 5 minutes. Then added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.445 g, 0.545 mmol) and the reaction mixture was heated at 90° C. for 16 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled and concentrated under reduced pressure. The crude product was purified by using combiflash purifier and was eluted with 10-18% methanol in dichloromethane to afford N-[2-(dimethylamino)ethyl]-2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (24) (1.20 g, 2.20 mmol). LCMS [M+H]⁺ 323.3

Step 3: Synthesis of 5-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (25)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2 to get desired product (25) as white solid. LCMS [M+H]⁺ 524.2

Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-5-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (26)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (26) as yellow solid.

LCMS [M+H]⁺ 494.3

Step 5: Synthesis of N-(3-((5-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 86)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K, to afford the desired compound as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.80 (bs, 1H), 9.36 (bs, 1H), 7.88-8.16 (m, 2H), 7.58 (s, 1H), 7.02-7.34 (m, 7H), 6.25-6.44 (m, 1H), 6.23 (dd, J=17.2 Hz, 1.6 Hz 1H), 5.75 (dd, J=10.0 Hz, 1.6 Hz, 1H), 3.76 (s, 3H), 3.43 (t, J=13.6 Hz, 2H), 3.31 (s, 2H), 2.83 (s, 9H); LCMS [M+H]⁺ 548.5

embedded image

Step 1: Preparation of 5-(4-amino-3-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (28)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M3 to get desired product (28) as white solid. LCMS [M+H]⁺ 439.2

Step 2: Synthesis of 5-(4-bromo-3-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (29)

To a solution of 5-(4-amino-3-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (28) (2.00 g, 4.56 mmol), bromotrichloromethane (4.50 mL, 45.6 mmol), sodium nitrite (1.57 g, 22.8 mmol) in dichloromethane (20.0 mL), water (20.0 mL) was added acetic acid (5.22 mL, 91.2 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified with silica gel column chromatography and was eluted in 60-65% ethyl acetate in hexane to give 5-(4-bromo-3-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (29) (1.20 g, 2.39 mmol) as yellow solid (1.2 g, 52%). LCMS [M+H]⁺ 502.0

Step 3: Synthesis of N4-(5-amino-2-fluorophenyl)-5-(4-bromo-3-fluorophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (30)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to get desired product (30) as white solid. LCMS [M+H]⁺ 471.8

Step 4: Synthesis of N-(3-{[5-(4-bromo-3-fluorophenyl)-2-[(1-methyl-1H-pyrazol-4-yl) amino] pyrimidin-4-yl] amino}-4-fluorophenyl) prop-2-enamide (Compound 87)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K₁to get desired product (Compound 87) as white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.24 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.75 (t, J=8.0 Hz, 2H), 7.57 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.13-7.06 (m, 2H), 6.43-6.36 (m, 1H), 6.23 (d, J=17.2 Hz, 1H), 5.74 (d, J=11.6 Hz, 1H), 3.52 (s, 3H); LCMS [M+H]⁺ 526.2.

TABLE 5

The following compounds were prepared using the procedures described above:

General

Cmpd.

Pro-
LCMS

No.
Structure
cedure
[M + H]

¹H-NMR (400 MHz, DMSO-d₆)

88

embedded image

K₁
542.0
10.30 (s, 1H), 9.92 (s, 1H), 9.30 (s, 1H), 7.97-7.11 (m, 10H), 6.43- 6.21 (m, 2H), 5.75 (d, J = 12.0 Hz, 1H), 3.17 (s, 3H).

89

embedded image

K₂
601.1
δ 10.20 (s, 1H), 9.24 (bs, 1H), 8.51 (bs, 1H), 7.94 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.68-7.73 (m, 2H), 7.58 (s, 1H), 7.36 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 7.10-7.27 (m, 4H), 6.35-6.42 (m, 1H), 6.22 (dd, J = 18.8 Hz, 1.6 Hz, 1H), 5.74 (dd, J = 11.6 Hz, 1.6 Hz, 1H), 3.81 (s, 4H), 2.05 (s, 6H).

90

embedded image

K₁
542.0
δ 10.24 (s, 1H), 9.43 (bs, 1H), 8.76 (bs, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.79-7.78 (m, 1H), 7.72- 7.70 (m, 1H), 7.58-7.50 (m, 2H), 7.31-7.08 (m, 4H), 6.45-6.38 (m, 1H), 6.27-6.23 (m, 1H), 5.77- 5.75 (m, 1H), 3.57 (s, 3H).

91

embedded image

K₂
544.0
δ 10.28 (s, 1H), 9.85 (bs, 1H), 9.04 (bs, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.57 (bs, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.18 (s, 1H), 7.10-6.90 (m, 2H), 6.43-6.39 (m, 1H), 6.25-6.21 (m, 1H), 5.76- 5.73 (m, 1H), 3.54 (s, 3H).

92

embedded image

K
660.1
δ 10.25 (s, 1H), 9.17 (bs, 2H), 7.97 (bs, 2H), 7.84-7.80 (m, 2H), 7.55- 7.52 (m, 2H), 7.32-7.28 (m, 2H), 6.93-7.19 (m, 1H), 6.42- 6.36 (m, 1H), 6.25-6.21 (m, 1H), 5.73-5.76 (m, 1H), 3.59 (s, 3H).

93

embedded image

K₂
584.0
δ 10.29 (s, 1H), 9.98 (bs, 1H), 9.25 (bs, 1H), 8.00 (bs, 1H), 7.86-7.82 (m, 2H), 7.57-7.54 (m, 2H), 7.35- 6.90 (m, 5H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.79-5.60 (m, 1H), 4.63-4.60 (m, 1H), 3.89- 3.85 (m, 2H), 3.79-3.74 (m, 2H), 2.33-2.07 (m, 2H).

94

embedded image

K₂
568.0
δ 10.30 (s, 1H), 9.87 (bs, 1H), 9.13 (bs, 1H), 7.99 (s, 1H), 7.85-7.81 (m, 2H), 7.51-7.53 (m, 2H), 7.42- 6.90 (m, 5H), 6.45-6.39 (m, 1H), 6.26 (dd, J = 18.8 Hz, 1.6 Hz, 1H), 5.77 (dd, J = 11.6 Hz, 1.6 Hz, 1H), 5.14 (bs, 1H), 4.90-4.72 (m, 4H).

95

embedded image

K₂
570.0
δ 10.23 (s, 1H), 9.44 (s, 1H), 8.71 (s, 1H), 7.95 (s, 1H), 7.79-7.75 (m, 2H), 756-7.48 (m, 3H), 7.28- 7.06 (m, 4H), 6.42-6.38 (m, 1H), 6.35-6.20 (m, 1H), 5.73 (d, J = 10.0 Hz, 1H), 3.90 (s, 2H), 3.35-3.45 (m, 2H), 3.11 (s, 3H).

96

embedded image

K₂
556.0
δ 10.23 (s, 1H), 9.63 (bs, 1H), 8.97 (bs, 1H), 7.97 (s, 1H), 7.83-7.79 (m, 3H), 7.52 (d, J = 10.8 Hz, 3H), 7.31-7.20 (m, 3H), 6.45-6.38 (m, 1H), 6.24 (dd, J = 12 Hz, J = 2 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 3.86 (bs, 1H), 3.58 (s, 4H)

97

embedded image

K₂
526.1
δ 10.32 (s, 1H), 9.62 (bs, 1H), 9.05 (bs, 1H), 7.97 (s, 1H), 7.80-7.76 (m, 1H), 7.52-7.50 (m, 2H), 7.38- 7.36 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.18-6.93 (m, 3H), 6.43- 6.36 (m, 1H), 6.26-6.22 (m, 1H), 5.78-5.75 (m, 1H), 3.61 (bs, 3H).

embedded image

Step 1: Synthesis of 5-bromo-2-chloro-4-(2-fluoro-5-nitrophenoxy) pyrimidine (31)

To a stirred solution of 5-bromo-2,4-dichloropyrimidine (3 g, 13.2 mmol) and 2-fluoro-5-nitrophenol (2.07 g, 13.2 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.73 g, 19.7 mmol) and the reaction mixture was stirred at 60° C. for 3 hours. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with cold water (15 mL), the precipitated solid was filtered, washed with cold water and dried to obtain 5-bromo-2-chloro-4-(2-fluoro-5-nitrophenoxy)pyrimidine (31) (4.20 g, 12.1 mmol) as off-white solid. LCMS [M+H]⁺ 347.9

Step 2: Synthesis of 5-bromo-4-(2-fluoro-5-nitrophenoxy)-N-(1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (32)

To a stirred solution of 5-bromo-2-chloro-4-(2-fluoro-5-nitrophenoxy)pyrimidine (296) (1 g, 2.87 mmol) in N,N-diisopropylethylamine (2.50 mL, 14.3 mmol) was added 1-methyl-1H-pyrazol-4-amine (0.33 g, 3.44 mmol) and trifluoroacetic acid (0.44 mL, 3.44 mmol). The reaction mixture was heated to 100° C. for 16 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (25 mL), dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography using combiflash purifier and was eluted in 40% ethyl acetate in hexane to obtain 5-bromo-4-(2-fluoro-5-nitrophenoxy)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (32) (0.7 g, 1.71 mmol) as an yellow solid. LCMS [M+H]⁺ 409.0

Step 3: Synthesis of 5-(4-chloro-3-fluorophenyl)-4-(2-fluoro-5-nitrophenoxy)-N-(1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (33)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2 to get desired product (33) as yellow solid. LCMS [M+H]⁺ 459.1

Step 4: Synthesis of 4-(5-amino-2-fluorophenoxy)-5-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (34)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L to get desired product (34) as brown solid. LCMS [M+H]⁺ 429.8

Step 5: Synthesis of N-(3-{[5-(4-chloro-3-fluorophenyl)-2-[(1-methyl-1H-pyrazol-4-yl) amino] pyrimidin-4-yl] oxy}-4-fluorophenyl) prop-2-enamide (Compound 98)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K₁to get desired product (Compound 98) as pale yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 9.50 (s, 1H), 8.53 (s, 1H), 7.94-7.47 (m, 7H), 7.23-7.15 (m, 2H), 6.45-6.38 (m, 1H), 6.27 (d, J=16.8 Hz, 1H), 5.77 (d, J=1.6 Hz, 1H), 3.61 (s, 3H); LCMS [M+H]⁺ 483.1.

embedded image

Step 1: Synthesis of 5-bromo-N-(2-fluoro-5-nitrophenyl)-2-(methylthio)pyrimidin-4-amine (35)

To a stirred solution of 2-fluoro-5-nitroaniline (0.71 g, 4.59 mmol) in tetrahydrofuran (12 mL) at 0° C. was added sodium hydride (0.33 g, 8.35 mmol, 60% w/w) and the reaction mixture was stirred at room temperature for 30 min. Then the reaction mixture was cooled to 0° C. and was added a solution of 5-bromo-4-chloro-2-(methylsulfanyl)pyrimidine (1.00 g, 4.18 mmol) in tetrahydrofuran (3 mL) and the reaction mixture was stirred at room temperature for 2 hours. Then the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic extract was washed with brine (50 mL), dried over anhydrous sulfate and evaporated. The crude product was purified by column chromatography using combiflash purifier and was eluted with 15% ethyl acetate in hexane to get the title compound (35) as brown solid (1.0 g, 66%). LCMS [M+H]⁺ 360.7

Step 2: Synthesis of 5-bromo-N-(2-fluoro-5-nitrophenyl)-2-(methylsulfonyl)pyrimidin-4-amine (36)

To a stirred solution of 5-bromo-N-(2-fluoro-5-nitrophenyl)-2-(methylsulfanyl)pyrimidin-4-amine (35) (0.87 g, 2.42 mmol) in dichloromethane (10.0 mL) at 0° C. was added 3-chlorobenzene-1-carboperoxoic acid (1.67 g, 9.69 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using combiflash purifier and was eluted with 50% ethyl acetate in hexane to get the title compound (36) as yellow solid (0.69 g, 72%). LCMS [M+H]⁺ 391.0

Step 3: Synthesis of 5-bromo-N4-(2-fluoro-5-nitrophenyl)-N2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (37)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure H, to afford the desired compound (37) as yellow solid. LCMS [M+H]⁺ 452.0.

Step 4: Synthesis of 5-(3-chloro-4-fluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (38)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2, to afford the desired compound (38) as off white solid. LCMS [M+H]⁺ 502.1

Step 5: Synthesis of N4-(5-amino-2-fluorophenyl)-5-(3-chloro-4-fluorophenyl)-N2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (39)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (39) as brown solid. LCMS [M+H]⁺ 472.2.

Step 6: Synthesis of N-(3-((5-(3-chloro-4-fluorophenyl)-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-4-fluorophenyl)acrylamide (Compound 100)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K2, to afford the desired compound (Compound 100) as white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.93 (bs, 1H), 9.19 (bs, 1H), 7.96 (s, 1H), 7.85 (d, J=5.2 Hz, 1H), 7.73 (d, J=6.4 Hz, 1H), 7.51-7.57 (m, 3H), 7.22-7.35 (m, 4H), 6.38-6.45 (m, 1H), 6.24 (dd, J=18.4 Hz, 1.6 Hz, 1H), 5.76 (dd, J=11.6 Hz, 1.6 Hz, 1H), 3.97 (s, 4H), 3.51 (s, 3H). LCMS [M+H]⁺ 526.1

TABLE 6

The following compounds were prepared using the procedures described above:

Cmpd.

General
LCMS

No.
Structure
Procedure
[M + H]

¹H-NMR (400 MHz, DMSO-d₆)

99

embedded image

K
481.1
At 90° C. δ 10.06 (s, 1H), 9.42 (bs, 1H), 8.48 (bs, 1H), 7.92 (s, 1H), 7.68-7.61 (m, 4H), 7.48-7.44 (m, 2H), 7.24-7.14 (m, 2H), 7.01 (d, J = 12.0 Hz, 1H), 6.46-6.44 (m, 1H), 6.29-6.24 (m, 1H), 5.75 (d, J = 12.0 Hz, 1H), 3.60 (s, 3H).

101

embedded image

K₂
470.2
δ 10.29 (s, 1H), 9.93 (bs, 1H), 9.24 (bs, 1H), 8.25-8.18 (m, 3H), 8.03 (bs, 1H), 7.87 (bs, 1H), 7.57 (s, 1H), 7.36-7.08 (m, 3H), 6.45- 6.39 (m, 1H), 6.28-6.23 (m, 1H), 5.79-5.76 (m, 1H).

102

embedded image

528.0
δ 10.21 (s, 1H), 9.21 (bs, 1H), 8.47 (bs, 1H), 7.97 (s, 1H), 7.70- 7.79 (m, 2H), 7.88-7.72 (m, 2H), 7.58 (s, 1H), 7.35-7.30 (m, 1H), 7.20-7.19 (m, 1H), 7.10-7.08 (m, 1H), 6.40 (s, 1H), 3.56 (s, 3H).

103

embedded image

469.2
δ 10.28 (s, 1H), 9.36 (s, 1H), 9.63 (s, 1H), 8.16-8.11 (m, 3H), 7.76 (s, 1H), 7.76 (bs, 1H), 7.55 (bs, 1H), 7.30 (bs, 1H), 7.13 (d, J = 19.2 Hz, 1H), 6.38 (s, 1H), 3.52 (s, 3H).

104

embedded image

K₂
500.1
δ 10.26 (s, 1H), 9.30 (bs, 2H), 8.00 (bs, 1H), 7.83-7.81 (m, 1H), 7.55-7.08 (m, 7H), 6.43-6.36 (m, 1H), 6.26-6.21 (m, 1H), 5.76-5.73 (m, 1H), 3.60 (bs, 2H).

105

embedded image

J
583.1
δ 10.44 (s, 1H), 9.79 (bs, 1H), 8.91 (bs, 1H), 7.97 (s, 1H), 7.81- 7.77 (m, 3H), 7.58 (bs, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.33-7.27 (m, 1H), 7.16-7.08 (m, 3H), 6.74-6.67 (m, 1H), 6.43-6.39 (m, 1H), 3.92 (d, J = 6.4 Hz, 2H), 3.54 (bs, 3H), 2.77 (s, 6H).

106

embedded image

K₂
512.2
δ 10.25 (s, 1H), 9.17 (bs, 2H), 7.98 (bs, 1H), 7.85-7.84 (m, 1H), 7.58-7.56 (m, 1H), 7.34-7.30 (m, 1H), 7.21 (s, 1H), 6.95-6.90 (m, 4H), 6.45-6.38 (m, 1H), 6.28- 6.24 (m, 1H), 5.79-5.76 (m, 1H), 4.01 (s, 3H), 3.62 (s, 3H).

107

embedded image

K₂
516.2
10.26 (s, 1H), 9.69 (bs, 1H), 8.70 (bs, 2H), 7.79 (d, J = 9.2 Hz, 2H), 7.68-7.59 (m, 4H), 7.31 (s, 1H), 7.19-7.12 (m, 2H), 6.41-6.34 (m, 1H), 6.22 (d, J = 15.2 Hz, 1H), 5.74 (d, J = 9.2 Hz, 1H), 3.56 (s, 3H).

108

embedded image

K₂
532.1
δ 10.27 (s, 1H), 9.29 (s, 1H), 8.03 (bs, 1H), 7.84 (dd, J = 2.4 Hz, J = 2.4 Hz, 1H), 7.59-7.50 (m, 4H), 7.35-7.30 (m, 1H), 7.24 (s, J = 12.0 Hz, 1H), 7.10-6.97 (m, 3H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.82 (s, 3H).

109

embedded image

K₂
526.1
δ 10.29 (s, 1H), 9.80 (bs, 1H), 9.18 (s, 1H), 8.02 (bs, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.61-7.65 (m, 3H), 7.42-7.36 (m, 2H), 7.21 (s, 1H), 7.13 (bs, 1H), 7.08 (bs, 1H), 6.46-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.57 (s, 3H).

110

embedded image

K₂
525.2
δ 10.25 (s, 1H), 9.18 (bs, 2H), 7.89 (bs, 2H), 7.58-7.56 (m, 1H), 7.34-7.30 (m, 2H), 7.12-7.10 (m, 3H), 7.04-7.02 (m, 1H), 6.46- 6.39 (m, 1H), 6.28-6.24 (m, 1H), 5.79-5.76 (m, 1H), 3.82 (s, 9H).

111

embedded image

K₂
488.2
δ 10.19 (s, 1H), 9.06 (bs, 2H), 8.17 (bs, 2H), 7.84 (s, 1H), 7.76 (bs, 1H), 7.57 (bs, 1H), 7.25- 6.89 (m, 4H), 6.43-6.36 (m, 1H), 6.25-6.20 (m, 1H), 5.75- 5.72 (m, 1H), 4.25 (s, 4H), 3.53 (bs, 3H).

112

embedded image

K₂
526.1
δ 10.30 (s, 1H), 10.06 (bs, 1H), 9.36 (bs, 1H), 7.99 (bs, 1H), 7.82-7.77 (m, 2H), 7.59 (bs, 1H), 7.50-7.47 (m, 1H), 7.38-6.95 (m, 5H), 6.42-6.35 (m, 1H), 6.26- 6.21 (m, 1H), 5.76-5.73 (m, 1H), 3.56 (bs, 3H).

113

embedded image

K₂
526.1
δ 10.33 (s, 1H), 10.24 (bs, 1H), 9.44 (bs, 1H), 8.01 (s, 1H), 7.83 (bs, 1H), 7.73-7.70 (m, 1H), 7.59- 7.57 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.37 (bs, 1H), 7.37-7.12 (m, 3H), 6.45-6.38 (m, 1H), 6.28- 6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.59 (s, 3H).

114

embedded image

K₂
502.2
δ 10.31 (s, 1H), 9.93 (bs, 1H), 9.28 (bs, 1H), 7.87-7.85 (m, 2H), 7.58 (bs, 1H), 7.36-6.95 (m, 4H), 6.98-6.91 (m, 3H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.79- 5.76 (m, 1H), 3.58 (bs, 3H), 1.73 (s, 6H).

115

embedded image

K₂
509.1
δ 10.74-10.69 (m, 2H), 9.97 (bs, 1H), 8.39 (s, 1H), 8.33-8.24 (m, 2H), 8.02-8.00 (m, 2H), 7.92- 7.82 (m, 4H), 7.75-7.40 (m, 1H), 6.90-6.83 (m, 2H), 6.69-6.64 (m, 1H), 6.20-6.17 (m, 1H), 4.04 (bs, 3H).

116

embedded image

K₂
490.2
δ 10.31 (bs, 1H), 9.91 (bs, 1H), 9.23 (bs, 1H), 7.96 (bs, 1H), 7.87- 7.85 (m, 1H), 7.62 (bs, 1H), 7.40- 7.00 (m, 4H), 6.67 (bs, 2H), 6.58 (s, 1H), 6.46-6.39 (m, 1H), 6.28- 6.24 (m, 1H), 5.78 (dd, J = 9.6 Hz, J = 1.6 Hz, 1H), 3.86 (s, 6H), 3.46 (s, 3H, merged with DMSO- H₂O peak)

117

embedded image

J
523.2
δ 10.15 (bs, 1H), 9.27 (bs, 1H), 8.53 (bs, 1H), 7.99 (s, 1H), 7.76- 7.65 (m, 1H), 7.65-7.59 (m, 1H), 7.30-7.09 (m, 5H), 6.76-6.59 (m, 2H), 6.25 (d, J = 15.2 Hz, 1H), 3.54 (bs, 3H), 3.06-3.04 (m, 2H), 2.12 (s, 6H).

118

embedded image

K₂
558.1
δ 10.28 (s, 1H), 9.89 (bs, 1H), 9.26 (bs, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.82- 7.74 (m, 2H), 7.61-7.58 (m, 2H), 7.34-7.01 (m, 5H), 6.42- 6.36 (m, 1H), 6.25-6.20 (m, 1H), 5.76-5.73 (m, 1H), 3.55 (bs, 3H).

119

embedded image

K₂
551.2
δ 10.29 (s, 1H), 10.01 (bs, 1H), 9.40 (bs, 1H), 7.94 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.51 (bs, 2H), 7.34- 6.93 (m, 5H), 6.43-6.36 (m, 1H), 6.25-6.21 (m, 1H), 5.77-5.74 (m, 1H), 3.56 (bs, 3H), 2.77-2.60 (m, 6H).

120

embedded image

K₂
503.2
δ 10.29 (bs, 1H), 9.93 (bs, 1H), 9.28 (bs, 1H), 7.93-7.85 (m, 2H), 7.61 (bs, 1H), 7.35-6.95 (m, 5H), 6.59-6.23 (m, 4H), 5.79-5.76 (m, 1H), 3.88-3.84 (m, 6H), 3.57 (s, 3H).

121

embedded image

K₂
517.3
δ 10.27 (bs, 1H), 9.77 (bs, 1H), 9.11 (s, 1H), 7.94-7.84 (m, 2H), 7.61 (bs, 1H), 7.34-6.97 (m, 4H), 6.51-6.36 (m, 4H), 6.28-6.23 (m, 1H), 5.79-5.76 (m, 1H), 3.59 (bs, 3H), 3.29-3.17 (m, 4H), 1.99- 1.96 (m, 4H).

embedded image

Step 1: Synthesis of 4-bromo-2-chloro-1-[(3-fluorophenyl)methoxy]benzene (40)

To a stirred solution of 4-bromo-2-chlorophenol (1.20 g, 5.78 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.40 g, 17.3 mmol) and allowed to stir at room temperature for 10 minutes. To this reaction mixture was added 1-(bromomethyl)-3-fluorobenzene (1.31 g, 6.94 mmol) and stirred the reaction at room temperature for 12 hours.

The progress of the reaction was monitored by TLC. After the reaction completion, reaction mixture was quenched with ice water and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate and concentrated under vacuum to the desired product (40) as off white solid (1.4 g, 76%). LCMS [M−H]⁺ 313.0.

Step 2: Synthesis of 2-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41)

To a stirred solution of 4-bromo-2-chloro-1-[(3-fluorophenyl)methoxy]benzene (40) (1.00 g, 3.17 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.21 g, 4.75 mmol) in 1,4-dioxane (10.0 mL) was added potassium acetate (0.933 g, 9.51 mmol) and the mixture was purged with nitrogen for 5 minutes, followed by addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), complex with dichloromethane (0.129 g, 0.158 mmol) and the reaction mixture was heated at 90° C. for 2 hours. After completion (TLC monitoring), reaction mixture was cooled and filtered through celite. The filtrate was concentrated to get black colored gum, which was diluted with water (10 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to get titled compound (41) as black solid. (0.7 g, 60%). LCMS [M−H]⁺ 361.1.

Step 3: Synthesis of 5-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (42)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2, to afford the desired compound (42) as off white solid. LCMS [M+H]⁺ 564.2.

Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-5-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (43)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (43) as brown solid. LCMS [M+H]⁺ 534.2.

Step 5: Synthesis of N-{3-[(5-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl)amino]-4-fluorophenyl}prop-2-enamide TFA salt (Compound 122)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K2, to afford the desired compound (Compound 122) as off white solid.

¹H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.74 (bs, 1H), 9.15 (bs, 1H), 7.89 (bs, 1H), 7.82 (d, J=4.8 Hz, 1H), 7.59 (bs, 2H), 7.51-7.43 (m, 1H), 7.43-7.41 (m, 1H), 7.36-7.24 (m, 5H), 7.22-7.17 (m, 3H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.78-5.75 (m, 1H), 5.31 (s, 2H), 3.59 (bs, 3H). LCMS [M+H]⁺ 588.2.

Table 7: The following compounds were prepared using the procedures described above:

TABLE 7

The following compounds were prepared using the procedures described above:

Gen-

eral

Pro-
LCMS

Cmpd.

ce-
[M +

¹H-NMR (400

No.
Structure
dure
H]
MHz, DMSO-d₆)

123

embedded image

K₂
560.1
δ 10.29 (s, 1H), 9.83 (bs, 1H), 9.16 (bs, 1H), 8.02 (bs, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.69- 7.47 (m, 3H), 7.35 (bs, 1H), 7.22- 6.94 (m, 3H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.78- 5.75 (m, 1H), 3.57 (s, 3H).

124

embedded image

K₂
496.2
δ 10.24 (s, 1H), 9.93 (bs, 1H), 9.40 (s, 1H), 7.93- 7.85 (m, 2H), 7.61 (d, J = 11.2 Hz, 1H), 7.52- 7.49 (m, 3H), 7.39- 7.31 (m, 5H), 7.16-7.13 (m, 1H), 6.48-6.41 (m, 1H), 6.27-6.22 (m, 1H), 5.78- 5.75 (m, 1H), 3.52 (bs, 3H merged with DMSO peak).

126

embedded image

K₂
496.2
δ 10.27 (s, 1H), 9.80 (bs, 1H), 9.14 (bs, 1H), 7.93 (bs, 1H), 7.79 (d, J = 4.4 Hz, 1H), 7.59 (bs, 1H), 7.34 (bs, 2H), 7.26-7.14 (m, 4H), 6.44-6.37 (m, 1H), 6.25 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 5.77 (dd, J = 10.0 Hz, J = 2.0 Hz, 1H),

3.99 (s, 3H),

3.58 (bs, 3H).

127

embedded image

K₂
460.2
δ 10.26 (s, 1H), 10.10 (bs, 1H), 9.25 (bs, 1H), 7.93-7.82 (s, 2H), 7.50-7.37 (m, 4H), 7.22-6.88 (m, 5H), 6.46- 6.39 (m, 1H), 6.25- 6.21 (m, 1H), 6.25-6.21 (m, 1H) 3.81 (s, 3H), 3.57 (bs, 3H)

129

embedded image

K₂
506.3
δ 10.28 (s, 1H), 9.91 (bs, 1H), 9.24 (bs, 1H), 7.96-7.85 (m, 2H), 7.60 (s, 1H), 7.35-7.09 (m, 4H), 6.96-6.85 (m, 3H), 6.45-6.39 (m, 1H), 6.28- 6.23 (m, 1H), 5.79- 5.76 ( m, 1H), 4.74-4.68 (m, 1H), 3.45 (s, 3H), 1.37-1.25 (m, 6H).

130

embedded image

K₂
518.2
δ 10.21 (s, 1H), 9.16 (bs, 1H), 8.35 (bs, 1H), 7.96 (s, 1H), 7.78- 7.77 (m, 1H), 7.70-7.50 (m, 1H), 7.70-7.18 (m, 3H), 6.87-6.76 (m, 4H), 6.45- 6.38 (m, 1H), 6.27- 6.23 (m, 1H), 5.77-5.74 (m, 1H), 3.93-3.84 (m, 2H), 3.56 (bs,

3H), 1.27-1.19

(m, 1H), 0.61-

0.56 (m, 2H),

0.35-0.31

(m, 2H).

132

embedded image

K₂
574.1
δ 10.33 (s, 1H), 9.87 (bs, 1H), 9.29 (bs, 1H), 7.96 (bs, 1H), 7.77 (d, J = 14.4 Hz, 2H), 7.59 (d, J = 11.6 Hz, 1H), 7.51-7.47 (m, 3H), 7.38-7.36 (m, 2H), 7.30 (s, 1H), 7.26-6.95 (m, 1H), 6.45- 6.38 (m, 1H), 6.29- 6.25 (m, 1H), 5.81-5.78 (m, 1H), 3.68 (bs, 3H).

133

embedded image

K₂
546.2
δ 10.28 (s, 1H), 9.77 (bs, 1H), 9.09 (bs, 1H), 8.09 (s, 1H), 7.85- 7.84 (m, 1H), 7.60 (bs, 1H), 7.35 (bs, 1H), 7.45 (bs, 1H), 7.23-7.08 (m, 4H), 6.95 (s, 1H), 6.28-6.23 (m, 1H), 5.76 (d, J = 12.0 Hz, 1H), 4.03 (s, 3H), 3.57 (bs, 3H).

134

embedded image

K₂
538.1
δ 10.30 (s, 1H), 9.98 (bs, 1H), 9.30 (s, 1H), 8.57 (bs, 1H), 7.98 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.35 (bs, 1H), 7.25 (s, 2H), 7.16 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.42 (dd, J = 16.8 Hz, J = 8.8 Hz,

1H), 6.25 (dd, J =

16.8 Hz, J = 2.0

Hz, 1H), 5.77 (dd,

J = 12.0 Hz, J =

4.0 Hz, 1H), 3.92

(s, 3H), 3.50

(s, 3H, merged

with DMSO

peak).

141

embedded image

K₂
516.2
δ 10.32 (s, 1H), 10.04 (s, 1H), 9.30 (s, 1H), 8.02 (s, 1H), 7.86 (s, 2H), 7.58 (s, 2H), 7.45-7.32 (m, 2H), 7.23-7.18 (m, 3H), 6.45- 6.39 (m, 1H), 6.26 (d, J = 16.0 Hz, 1H), 5.79-5.76 (m, 1H), 3.59 (s, 3H).

142

embedded image

J
623.1
δ 10.43 (s, 1H), 9.65 (bs, 1H), 9.40 (bs, 1H), 8.91 (bs, 1H), 8.07 (s, 1H), 7.83-7.79 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.35-7.29 (m, 2H), 7.2 (d, J = 7.6 Hz, 1H), 7.09 (bs, 1H), 6.80-6.72 (m, 1H), 6.43 (d, J = 16.0 Hz, 1H), 3.94 (bs, 2H), 3.71 (bs, 3H), 2.94-2.87 (m,

2H), 1.84 (d, J =

12.0 Hz,

2H), 1.76-

1.58 (m, 6H).

144

embedded image

K₂
535.3
δ 10.47 (s, 1H), 9.84 (bs, 1H), 9.07 (bs, 1H), 8.05 (bs, 1H), 7.84- 7.81 (s, 1H), 7.62 (bs, 1H), 7.38- 7.36 (m, 1H), 7.24-7.12 (m, 2H), 6.98-6.87 (m, 4H), 6.78- 6.70 (m, 1H), 6.48- 6.43 (m, 1H), 4.04-3.99 (m, 2H), 3.84 (s, 3H), 3.69 (bs, 3H), 2.85 (s, 6H).

embedded image

Step 1: Synthesis of 1-bromo-3-nitrobenzene-6-d (44)

To a stirred solution of 2-bromo-4-nitroaniline (0.1 g, 0.461 mmol) in N,N-dimethylformamide D₇(0.3 mL) was added tert-butyl nitrite (0.111 mL, 0.922 mmol) drop wise and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was quenched with water and was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (20 mL×3), brine (20 mL), dried over anhydrous sulfate and evaporated. The crude product was purified by column chromatography using combiflash purifier and was eluted with 5% ethyl acetate in hexane to get the title compound (44) as colourless liquid (0.05 g, 53%). ¹H NMR (400 MHz, CDCl₃): δ 8.41 (d, J=2.0 Hz, 1H), 8.20 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.48-7.45 (m, 1H).

Step 2: Synthesis of 5-(3-fluoro-5-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-nitrophenyl-6-d)pyrimidine-2,4-diamine (46)

To a stirred solution of 5-(3-fluoro-5-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (45) (0.150 g, 0.477 mmol) in 1,4-dioxane (5 mL) were added 1-bromo-3-nitro(6-²H)benzene (44) (0.145 g, 0.716 mmol), caesium carbonate (0.466 g, 1.43 mmol). The reaction mixture was degasified and purged with argon for 5 minutes then was added Tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol) and [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.013 g, 0.023 mmol) and the reaction mixture was heated at 100° C. for 15 hours in a sealed tube. The reaction mixture was cooled, diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography using combiflash purifier and was eluted with 50% ethyl acetate in hexane to get the title compound (46) as yellow solid (0.15 g, 72%). LCMS [M+H]⁺ 437.0.

Step 3: Synthesis of N4-(3-aminophenyl-6-d)-5-(3-fluoro-5-methoxyphenyl)-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (47)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (47) as brown solid. LCMS [M+H]⁺ 407.2.

Step 4: Synthesis of N-(3-((5-(3-fluoro-5-methoxyphenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl-4-d)acrylamide. TFA (Compound 145)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K2, to afford the desired compound (Compound 145) as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (bs, 1H), 9.40 (bs, 1H), 7.93 (bs, 1H), 7.82 (s, 1H), 7.49-7.07 (m, 5H), 6.94-6.87 (m, 3H), 6.46-6.39 (m, 1H), 6.25-6.24 (m, 1H), 5.75-5.72 (m, 1H), 3.92 (s, 3H), 3.58 (bs, 3H merged with DMSO peak). LCMS [M+H]⁺ 461.2.

Table 8: The following compounds were prepared using the procedures described above:

TABLE 8

The following compounds were prepared using the procedures described above:

Gen

eral

Pro-
LCMS

¹H-NMR

Cmpd.

ce-
[M +
(400 MHz,

No.
Structure
dure
H]
DMSO-d₆)

148

embedded image

K₂
466.2
δ 10.27 (s, 2H), 9.42 (bs, 1H), 8.99 (bs, 1H), 7.97-7.84 (m, 2H), 7.52-7.13 (m, 7H), 6.46-6.40 (m, 1H), 6.25-6.21 (m, 1H), 5.76- 5.73 (m, 1H), 3.75 (s, 3H)

149

embedded image

K₂
484.2
δ 10.31 (s, 1H), 10.06 (s, 1H), 9.24 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.57-7.49 (m, 3H), 7.36 (s, 1H), 7.20-7.12 (m, 3H), 6.44- 6.37 (m, 1H), 6.24 (d, J = 8.0 Hz, 1H), 5.75 (m, J = 12.0 Hz, 1H), 3.56 (s, 3H).

150

embedded image

J
503.3
δ 10.41 (s, 1H), 10.07 (bs, 1H), 9.85 (s, 1H), 9.34 (bs, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.53 (bs, 1H), 7.40 (bs, 2H), 7.31-7.23 (m, 5H), 6.77-6.69 (m, 1H), 6.49- 6.45 (m, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.61 (bs, 3H), 2.80 (bs, 6H).

152

embedded image

K₂
526.1
δ 10.24 (bs, 1H), 10.07 (bs, 1H), 9.43 (bs, 1H), 7.98-7.77 (m, 2H), 7.47-6.99 (m, 7H), 6.46-6.42 (m, 2H), 6.25- 6.20 (m, 1H), 5.76- 5.73 (m, 1H), 3.50 (s, 3H)

153

embedded image

K₂
516.2
δ 10.21 (s, 1H), 9.80 (bs, 1H), 9.24 (bs, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.57 (d, J = 11.2 Hz, 3H), 7.49-7.32 (m, 4H), 7.21-7.08 (m, 1H), 6.48- 6.41 (m, 1H), 6.25 (dd, J = 16.8 Hz, J = 2.0 Hz, 1H),

5.76 (dd,

J = 10.0

Hz, J = 1.6 Hz,

1H), 3.49

(bs, 3H).

154

embedded image

K₂
544.0
δ 10.25 (s, 1H), 10.01 (bs, 1H), 9.40 (bs, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.47-6.46 (m, 6H), 6.43-6.39 (m, 1H), 6.25- 6.20 (m, 1H), 5.76- 5.73 (m, 1H), 3.48 (bs, 3H).

155

embedded image

K₂
529.5
δ 10.44 (bs, 1H), 10.34 (s, 1H), 9.69 (bs, 1H), 8.07 (bs, 1H), 7.89- 7.81 (m, 4H), 7.59 (bs, 1H), 7.39- 7.24 (m, 2H), 7.19-7.12 (m, 1H), 7.05 (s, 2H), 6.99 (s, 1H), 6.45-6.39 (m, 1H), 6.28-6.23 (m, 1H), 5.79- 5.76 (m,

1H), 3.61

(s, 3H).

156

embedded image

K₂
509.2
δ 10.31 (s, 1H), 10.12 (bs, 1H), 9.46 (bs, 1H), 7.94-7.85 (m, 3H), 7.58-7.52 (m, 1H), 7.36 (bs, 1H), 7.19-7.07 (m, 3H), 6.94 (bs, 1H), 6.43-6.36 (m, 1H), 6.26-6.21 (m, 1H), 5.76 (d, J = 12.0 Hz, 1H),

3.58 (bs, 3H

merged

with DMSO

peak), 2.85

(s, 6H).

embedded image

Step 1: Synthesis of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (48)

To a stirred solution of 4-bromo-2,6-difluoroaniline (2 g, 9.62 mmol) in 1,4-dioxane (30 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.69 g, 10.6 mmol), potassium acetate (2.83 g, 28.8 mmol), the reaction mixture was purged in nitrogen for 5 min and added [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride in dichloromethane (0.704 g, 0.962 mmol) and the reaction mixture was heated at 100° C. for 12 hours. The progress of the reaction was monitored by TLC/LCMS. After the reaction completion, the reaction mixture was filtered through the celite and the filtrate was evaporated under reduced pressure to afford 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (48) (2 g, 82%) as dark brown liquid. ¹H NMR (400 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.28 (s, 1H), 3.95 (s, 2H), 1.30 (s, 12H).

Step 2: Synthesis of 5-(4-amino-3,5-difluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (49)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure M2, to afford the desired compound (49) as pale yellow solid. LCMS [M+H]⁺ 457.1.

Step 3: Synthesis of 5-[3,5-difluoro(4-²H) phenyl]-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (50)

To a stirred solution of 5-(4-amino-3,5-difluorophenyl)-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (49) (0.2 g, 0.438 mmol) in dimethyl formamide-d7 (0.8 mL) was added tert-butyl nitrite (0.226 g, 2.19 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LCMS. After reaction completion, reaction mass was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was washed with water (10 mL×3), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography by using combiflash purifier and was eluted with 30-50% ethyl acetate in hexane to afford 5-[3,5-difluoro(4-²H) phenyl]-N4-(2-fluoro-5-nitrophenyl)-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (50) (0.05 g, 26%) as a pale brown solid. LCMS [M+H]⁺ 443.1.

Step 4: Synthesis of N4-(5-amino-2-fluorophenyl)-5-[3,5-difluoro(4-²H) phenyl]-N2-(1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine (51)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure L, to afford the desired compound (51) as brown solid. LCMS [M+H]⁺ 413.2.

Step 5: Synthesis of N-[3-({5-[3,5-difluoro(4-²H) phenyl]-2-[(1-methyl-1H-pyrazol-4-yl) amino] pyrimidin-4-yl} amino)-4-fluorophenyl] prop-2-enamide (Compound 157)

The title compound was prepared in a manner substantially similar to procedure mentioned in General Procedure K2, to afford the desired compound (Compound 157) as off white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.63 (s, 1H), 8.98 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.59 (s, 1H), 7.34 (s, 1H), 7.26-7.20 (m, 5H), 6.45-6.38 (m, 1H), 6.28-6.23 (m, 1H), 5.78-5.75 (m, 1H), 3.47 (s, 3H). LCMS [M+H]⁺ 467.2.

TABLE 9

The following compounds were prepared using the procedures described above:

Cmpd.

General
LCMS

No.
Structure
Procedure
[M + H]

¹H-NMR (400 MHz, DMSO-d₆)

158

embedded image

K₂
500.2
δ 10.28 (s, 1H), 9.77 (bs, 1H), 9.07 (bs, 1H), 7.99 (s, 1H), 7.82 (bs, 1H), 7.56 − 7.47 (m, 2H), 7.33 (bs, 1H), 7.19 − 7.06 (m, 3H), 6.43 − 6.36 (m, 1H), 6.25 − 6.21 (m, 1H), 5.76 − 5.73 (m, 2H), 3.54 (s, 3H).

159

embedded image

K₂
542.1
δ 10.27 (s, 1H), 9.83 (bs, 1H), 9.21 (bs, 1H), 7.91 (bs, 1H), 7.76 − 7.72 (m, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 9.2 Hz, 2H), 7.30 − 7.21 (m, 4H), 6.38 − 6.31 (m, 1H), 6.19 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 5.72 (dd, J = 10.0 Hz, J = 1.6 Hz, 1H), 3.60 (s, 3H).

160

embedded image

K₂
532.2
δ 10.22 (s, 1H), 9.79 (bs, 1H), 9.03 (bs, 1H), 7.92 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.50 − 7.46 (m, 2H), 7.32 − 7.29 (m, 3H), 7.15 − 6.90 (m, 3H), 6.38 − 6.31 (m, 1H), 6.20 − 6.16 (m, 1H), 5.71 − 5.68 (m, 1H), 3.51 (bs, 3H).

162

embedded image

K₂
472.3
δ 10.29 (s, 1H), 10.04 (bs, 1H), 9.37 (bs, 1H), 7.87 − 7.85 (m, 2H), 7.60 (s, 1H), 7.39 − 7.09 (m, 5H), 6.98 − 6.93 (m, 2H), 6.45 − 6.38 (m, 1H), 6.28 − 6.23 (m, 1H), 5.79 − 5.76 (m, 1H), 4.60 ( t, J = 8.0 Hz, 2H), 3.60 (bs, 3H), 3.24 (t, J = 8.8 Hz, 2H).

163

embedded image

K₂
560.1
δ 10.33 (s, 1H), 9.64 (bs, 1H), 9.10 (bs, 1H), 8.01 (s, 1H), 7.62 − 7.0 (m, 8H), 6.46 − 6.24 (m, 2H), 5.80 − 5.77 (m, 1H), 3.67 (bs, 3H).

164

embedded image

K₂
534.2
δ 10.35 (s, 1H), 9.82 (bs, 1H), 9.21 (bs, 1H), 8.07 (s, 1H), 7.56 − 7.34 (m, 7H), 7.12 − 7.07 (m, 1H), 6.44 − 6.37 (m, 1H), 6.27 − 6.23 (m, 1H), 5.78 − 5.75(m, 1H), 3.62 (s, 3H).

165

embedded image

K₂
481.3
δ 10.29 (s, 1H), 9.22 (bs, 1H), 7.98 (bs, 1H), 7.86 − 7.84 (m, 1H), 7.61 (bs, 1H), 7.35 (bs, 1H), 7.23 (bs, 1H), 7.10 (bs, 1H), 6.97 − 6.88 (m, 4H), 6.45 − 6.39 (m, 1H), 6.28 − 6.23 (m, 1H), 5.79 − 5.76 (m, 2H), 3.59 (bs, 3H).

166

embedded image

J
596.2
δ 10.39 (s, 1H), 9.93 (bs, 1H), 9.45 (bs, 1H), 8.74 (bs, 1H), 7.96 (s, 1H), 7.80 − 7.76 (m, 2H), 7.56 − 7.27 (m, 4H), 7.15 − 7.08 (m, 2H), 6.60 − 6.57 (m, 1H), 6.37 − 6.33 (m, 1H), 4.13 − 3.99 (m, 4H), 3.53 (bs, 3H), 2.48 (s, 2H), 2.38 (s, 2H).

167

embedded image

J
524.3
δ 10.56 (s, 2H), 10.13 (bs, 1H), 9.50 (s, 1H), 8.09 (s, 1H), 7.88 − 7.86 (m, 1H), 7.65 (s, 1H), 7.40 − 7.14 (m, 6H), 6.82 − 6.71 (m, 1H), 6.48 − 6.45 (m, 1H), 3.96 − 3.94 (s, 2H), 2.85 − 2.75 (m, 6H).

168

embedded image

K₂
514.3
δ 10.37 (s, 1H), 9.95 (bs, 1H), 9.27 (bs, 1H), 8.09 (bs, 1H), 7.87 − 7.86 (m, 1H), 7.60 (bs, 1H), 7.37 (bs, 2H), 7.30 − 7.14 (m, 6H), 6.45 − 6.39 (m, 1H), 6.28 − 6.23 (m, 1H), 5.79 − 5.76 (d, J = 12.0 Hz, 1H), 3.59 (bs, 3H).

169

embedded image

K₂
529.2
δ 10.29 (s, 1H), 9.92 (bs, 1H), 9.27 (bs, 1H), 7.97 (s, 1H), 7.84 − 7.80 (m, 2H), 7.54 (d, J = 9.6 Hz, 2H), 7.34 − 7.28 (m, 2H), 7.19 − 7.06 (m, 3H), 6.43 − 6.36 (m, 1H), 6.25 − 6.21 (dd, J = 16.8 Hz, J = 3.2 Hz, 1H), 5.76 − 5.73 (m, 1H).

170

embedded image

K₂
496.3
δ 9.82 (s, 1H), 9.76 (bs, 1H), 9.21 (s, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 7.52 − 7.45 (m, 3H), 6.94 − 6.89 (m, 4H), 6.51 − 6.44 (m, 1H), 6.29 − 6.25 (m, 1H), 5.82 − 5.79 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H).

171

embedded image

J
601.2
δ 10.55 (s, 1H), 10.23 (bs, 1H), 10.10 (bs, 1H), 9.31 (bs, 1H), 8.07 (s, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.63 (bs, 1H), 7.47 − 7.38 (m, 2H), 7.26 (s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 6.79 − 6.72 (m, 1H), 6.46 (d, J = 16.0 Hz, 1H), 3.94 (d, J = 8.0 Hz, 2H), 3.58 (s, 3H), 2.79 (s, 6H).

172

embedded image

K₂
532.3
δ 10.22 (s, 1H), 9.28 (bs, 1H), 8.59 (s, 1H), 8.01 (s, 1H), 7.78 − 7.77 (m, 1H), 7.59 (bs, 1H), 7.43 − 7.40 (m, 1H), 7.33 (bs, 3H), 7.25 − 7.0 (m, 2H), 6.45 − 6.38 (m, 1H), 6.28 − 6.23 (m, 1H), 5.77 − 5.74 (m, 1H), 3.56 (bs, 3H).

173

embedded image

K₂
542.2
δ 10.30 (s, 1H), 9.55 (bs, 1H), 8.95 (bs, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.46 − 7.34 (m, 6H), 7.22 − 6.96 (m, 1H), 6.45 − 6.39 (m, 1H), 6.29 − 6.24 (m, 1H), 5.80 − 5.77 (m, 1H), 3.67 (s, 3H).

174

embedded image

K₂
558.1
δ 10.35 (bs, 1H), 10.04 (bs, 1H), 9.40 (s, 1H), 8.01 (s, 1H), 7.92 − 7.78 (m, 2H), 7.73 − 7.46 (m, 6H), 7.08 (s, 2H), 6.43 − 6.36 (m, 1H), 6.25 (d, J = 16, 1H), 5.77 (d, J = 12.0 Hz, 1H), 3.65 (s, 3H).

175

embedded image

J
558.0
10.31 (s, 1H), 10.14 (s, 1H), 9.80 (s, 1H), 9.00 (s, 1H), 7.98 (s, 1H), 7.84 − 7.80 (m, 2H), 7.53 (d, J = 10.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 (bs, 2H), 6.92 − 6.82 (m, 1H), 6.35 (d, J = 15.2 Hz, 1H), 5.24 (s, 1H), 5.12 (s, 1H), 3.50 (s, 3H, merged in solvent peak).

176

embedded image

K₂
546.3
δ 10.28 (s, 1H), 9.79 (bs, 1H), 9.06 (bs, 1H), 8.00 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.61 (bs, 1H), 7.34 (bs, 1H), 7.22 (bs, 1H), 7.11 − 6.96 (m, 5H), 6.46 − 6.39 (m, 1H), 6.26 (dd, J = 16.8 Hz, J = 1.6 Hz, 1H), 5.77 (dd, J = 10.4 Hz, J = 2.0 Hz, 1H), 4.90 − 4.84 (m, 2H), 3.65 (bs, 3H).

177

embedded image

J
544.1
δ 10.45 (s, 1H), 9.92 (bs, 1H), 9.26 (bs, 1H), 7.97 (bs, 1H), 7.86 − 7.80 (m, 2H), 7.66 (bs, 1H), 7.54 − 7.52 (m, 1H), 7.37 (bs, 1H), 7.30 (bs, 1H), 7.28 − 7.20 (m, 2H), 7.07 (bs, 1H), 5.75 − 5.62 (m, 1H), 5.45 − 5.40 (m, 1H), 3.50 (bs, 3H).

178

embedded image

J
529.0
10.53 (s, 1H), 10.00 (bs, 1H), 7.93 (bs, 1H), 7.83 − 7.81 (s, 1H), 7.62 (bs, 1H), 7.37 − 7.35 (s, 2H), 7.20 − 7.10 (m, 2H), 6.96 − 6.90 (m, 2H), 6.75 − 6.68 (m, 1H), 6.45 − 6.41 (m, 1H), 4.59 − 4.55 (m, 2H), 3.93 − 3.91 (m, 2H), 3.57 (s, 3H), 3.24 − 3.20 (m, 2H), 2.77 (s, 6H).

Example 2: Cellular Proliferation (Alamar Blue) Assays

Cell line details:

- 1. EGFR(D770_N771insSVD) expressing Ba/F3 stable cell line
- 2. EGFR (A767_dupASV) expressing Ba/F3 stable cell line
- 3. A431 cells
- 4. EGFR (H773insNPH) expressing Ba/F3 stable cell line
- 5. HER2 (A775_G776insYVMA) expressing Ba/F3 stable cell line

Assay Procedure:

- 1. Seed cells at 5000 for A431 and 15,000 cells for Ba/F3 in 100 μL/well in complete media (for A431: DMEM with 10% FBS and for Ba/F3 cells: RPMI with 10% FBS) in 96-well tissue culture plate. Leave outer wells without cells for background measurements. Incubate at 37 degree Celsius in 5% CO₂humidified incubator for 16-18 hours.
- 2. Add 0.025 ml of 5X concentration compound dilution or DMSO control. Final compound concentration range is 10-0.0005 μM prepared in 3-fold serial dilutions. Incubate for 72 hr at 37 degree Celsius in 5% CO₂humidified incubator.
- 3. Add 0.0125 ml Alamar Blue™ reagent to each well with multi-channel pipette and tap gently on each side of the plate to mix. Incubate for 3 hours at 37 degree Celsius in 5% CO₂humidified incubator.
- 4. Read plates on fluorescence reader (Tecan Spark Control, Device: Spark, Serial #: 1801006040) at 540 nm excitation, 590 nm emission wavelength.
- 5. Data analysis was performed using XLfit 5.5.0.5.

Table 10 shows the activity of compounds of the present disclosure in the EGFR and HER2 cellular proliferation assays.

TABLE 10

Cellular proliferation data.

A431
A767
D770
NPH
YVMA

Cmpd

IC₅₀
IC₅₀
IC₅₀
IC₅₀
IC₅₀

No.
Structure
(nM)
(nM)
(nM)
(nM)
(nM)

1

embedded image

269
36
36
36
91

2

embedded image

>10000
896
1050
ND
ND

3

embedded image

2317
91
90
103
432

4

embedded image

>10000
293
295
ND
262

5

embedded image

200
39
30
79
208

6

embedded image

810
80
51
83
187

7

embedded image

229
97
94
97
377

8

embedded image

>10000
749
1591
ND
644

9

embedded image

>10000
721
930
ND
838

10

embedded image

>10000
3232
3936
ND
ND

11

embedded image

1951
262
194
124
1067

12

embedded image

ND
919
363
ND
ND

13

embedded image

147
42
28
79
114

14

embedded image

140
26
33
59
107

15

embedded image

84
45
36
102
124

16

embedded image

460
9
10
24
43

17

embedded image

75
32
35
96
42

18

embedded image

251
166
113
56
220

19

embedded image

108
12
12
33
35

20

embedded image

13
61
33
ND
164

21

embedded image

>10000
181
107
261
1029

22

embedded image

>10000
428
329
ND
890

23

embedded image

2892
2764
2731
ND
ND

24

embedded image

9421
321
300
ND
588

25

embedded image

49
87
102
91
341

26

embedded image

443
35
27
31
112

27

embedded image

73
31
35
55
150

28

embedded image

193
27
29
47
271

29

embedded image

20
7
8
33
21

30

embedded image

299
33
35
40
91

31

embedded image

582
34
50
92
94

32

embedded image

>10000
159
294
160
1156

33

embedded image

35
21
20
52
73

34

embedded image

303
39
33
50
84

35

embedded image

45
99
35
84
99

36

embedded image

767
91
71
140
212

37

embedded image

51
34
30
51
93

38

embedded image

195
17
24
52
62

39

embedded image

1319
136
271
310
483

40

embedded image

482
42
35
82
146

41

embedded image

196
83
37
105
129

42

embedded image

4510
737
942
ND
ND

43

embedded image

707
41
35
24
84

44

embedded image

52
15
24
33
36

45

embedded image

35
10
7
25
16

46

embedded image

102
29
17
30
34

47

embedded image

46
34
21
20
25

48

embedded image

68
12
12
31
36

49

embedded image

246
44
38
27
65

50

embedded image

70
26
32
61
86

51

embedded image

110
56
38
79
ND

52

embedded image

194
307
104
ND
ND

53

embedded image

1219
119
104
153
211

54

embedded image

ND
184
85
186
260

55

embedded image

2229
800
2237
3643
ND

56

embedded image

587
95
104
84
118

57

embedded image

699
207
111
62
112

58

embedded image

85
257
130
214
100

59

embedded image

575
957
300
ND
ND

60

embedded image

1185
150
170
462
952

61

embedded image

ND
11
12
33
37

62

embedded image

1002
80
75
91
103

63

embedded image

>10000
3089
3270
ND
884

64

embedded image

554
104
61
95
159

65

embedded image

1073
226
114
304
112

66

embedded image

55
26
15
14
47

67

embedded image

213
41
36
100
60

68

embedded image

60
23
14
21
35

69

embedded image

73
14
12
21
27

70

embedded image

608
34
37
101
57

71

embedded image

150
30
25
38
62

72

embedded image

1675
96
84
61
227

73

embedded image

985
95
106
153
104

74

embedded image

108
91
50
44
197

75

embedded image

586
25
34
23
65

76

embedded image

1265
72
220
236
240

77

embedded image

297
113
340
353
584

78

embedded image

102
59
111
144
286

79

embedded image

105
248
312
ND
ND

80

embedded image

54
43
95
ND
171

81

embedded image

3014
343
906
ND
ND

82

embedded image

397
239
313
ND
149

83

embedded image

1064
376
1007
ND
ND

84

embedded image

522
101
122
92
ND

85

embedded image

2822
268
314
ND
884

86

embedded image

3575
2244
2938
ND
ND

87

embedded image

18
33
12
116
83

88

embedded image

280
87
66
57
118

89

embedded image

343
108
102
56
123

90

embedded image

185
122
100
156
164

91

embedded image

11
31
15
ND
59

92

embedded image

45
102
74
54
113

93

embedded image

33
46
35
ND
173

94

embedded image

31
40
33
35
144

95

embedded image

4770
43
29
ND
197

96

embedded image

37
28
25
96
56

97

embedded image

12
24
13
ND
62

98

embedded image

990
104
36
153
252

99

embedded image

821
294
168
ND
ND

100

embedded image

1198
301
274
ND
860

101

embedded image

ND
12
15
ND
ND

102

embedded image

69
30
35
ND
117

103

embedded image

20
14
25
ND
ND

104

embedded image

17
44
34
ND
64

105

embedded image

85
663
129
ND
125

106

embedded image

125
35
285
ND
568

107

embedded image

3129
ND
ND
ND
7345

108

embedded image

23
96
39
ND
243

109

embedded image

534
97
53
ND
192

110

embedded image

819
ND
ND
ND
5779

111

embedded image

164
ND
ND
ND
1077

112

embedded image

497
ND
ND
ND
923

113

embedded image

73
92
70
ND
463

114

embedded image

77
ND
ND
ND
4568

115

embedded image

11
36
32
ND
86

116

embedded image

3522
ND
ND
ND
>10000

117

embedded image

668
328
135
ND
141

118

embedded image

215
ND
ND
ND
352

119

embedded image

1159
ND
ND
ND
5198

120

embedded image

9276
ND
ND
ND
>10000

121

embedded image

>10000
ND
ND
ND
>10000

122

embedded image

290
ND
ND
ND
669

123

embedded image

71
50
40
ND
66

124

embedded image

6
21
11
ND
49

126

embedded image

43
100
40
ND
153

127

embedded image

123
312
89
ND
167

128

embedded image

ND
ND
ND
ND
ND

129

embedded image

>10000
ND
ND
ND
>10000

130

embedded image

>10000
ND
ND
ND
>10000

131

embedded image

ND
ND
ND
ND
ND

132

embedded image

51
40
34
ND
345

133

embedded image

394
322
251
ND
1272

134

embedded image

238
ND
ND
ND
453

135

embedded image

ND
ND
ND
ND
ND

136

embedded image

ND
ND
ND
ND
ND

137

embedded image

ND
ND
ND
ND
ND

138

embedded image

ND
ND
ND
ND
ND

139

embedded image

ND
ND
ND
ND
ND

140

embedded image

ND
ND
ND
ND
ND

141

embedded image

13
25
16
ND
167

142

embedded image

301
ND
ND
ND
738

143

embedded image

ND
ND
ND
ND
ND

144

embedded image

4881
ND
ND
ND
970

145

embedded image

388
ND
ND
ND
264

146

embedded image

ND
ND
ND
ND
ND

147

embedded image

ND
ND
ND
ND
ND

148

embedded image

29
33
10
ND
45

149

embedded image

11
34
11
ND
92

150

embedded image

214
110
126
ND
237

151

embedded image

ND
ND
ND
ND
ND

152

embedded image

8
34
11
ND
40

153

embedded image

1084
34
13
ND
98

154

embedded image

1761
81
34
ND
154

155

embedded image

338
133
107
ND
1670

156

embedded image

19
ND
ND
ND
309

157

embedded image

23
35
16
ND
151

158

embedded image

10
15
11
ND
40

159

embedded image

23
29
24
ND
125

160

embedded image

261
63
68
ND
163

161

embedded image

759
140
217
ND
62

162

embedded image

84
116
38
ND
428

163

embedded image

128
22
26
ND
104

164

embedded image

103
18
22
ND
157

165

embedded image

387
110
70
ND
208

166

embedded image

613
299
75
ND
555

167

embedded image

512
234
84
ND
142

168

embedded image

67
132
262
ND
574

169

embedded image

11
33
36
ND
147

170

embedded image

5248
>10000
>10000
ND
>9036

171

embedded image

57
99
79
ND
113

172

embedded image

585
967
843
ND
5982

173

embedded image

776
311
101
ND
1521

174

embedded image

358
120
42
ND
759

175

embedded image

347
224
136
ND
1616

176

embedded image

ND
859
1132
ND
>10000

177

embedded image

326
1725
939
ND
ND

178

embedded image

350
722
927
ND
ND

ND: Not determined

Number	Date	Country
63271993	Oct 2021	US
63236194	Aug 2021	US
63108185	Oct 2020	US

PYRIMIDINE COMPOUNDS, COMPOSITIONS, AND MEDICINAL APPLICATIONS THEREOF

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

CROSS-REFERENCE

PCT Information

Provisional Applications (3)