WO2020198469A1 - Method for treating epidermal growth factor receptor-driven cancers with protein kinase c inhibitors in combination with an egfr-tyrosine kinase inhibitor - Google Patents

Abstract

Provided are methods for treating epidermal growth factor receptor (EGFR)-driven cancers such as non-small cell lung cancer (NSCLC) by a protein kinase C (PKC) inhibitor in combination with an EGFR tyrosine kinase inhibitor.

Description

METHOD FOR TREATING EPIDERMAL GROWTH FACTOR RECEPTOR- DRIVEN CANCERS WITH PROTEIN KINASE C INHIBITORS IN COMBINATION WITH AN EGFR-TYROSINE KINASE INHIBITOR

RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 62/824,638, filed on March 27, 2019, the content of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

Provided are methods for treating epidermal growth factor receptor (EGFR)-driven cancers such as non-small cell lung cancer (NSCLC) by a protein kinase C (PKC) inhibitor in combination with an EGFR tyrosine kinase inhibitor.

BACKGROUND OF THE INVENTION

Epidermal growth factor receptors (EGFRs) are a large family of receptor tyrosine kinases (TK) expressed in several types of cancer, including breast, lung, esophageal, and head and neck. EGFR and its family members are contributors of a complex signaling cascade that modulates growth, signaling, differentiation, adhesion, migration and survival of cancer cells. Due to their multi-dimensional role in the progression of cancer, EGFR and its family members have emerged as attractive candidates for anti-cancer therapy [Grandis J. R., and Sok J. C., Pharmacol Ther. 2004 Apr; 102(l):37-46] Specifically, the aberrant activity of EGFR has shown to play a key role in the development and growth of tumor cells, where it is involved in numerous cellular responses including proliferation and apoptosis [Wells A. Int J Biochem. Cell Biol. 1999 Jun; 31 (6) : 637 -43 ] .

Lung cancer is responsible for approximately one in five deaths due to cancer world- wide (http://canceratlas.cancer.org/the-burden/lung-cancer). Around 80% of lung cancers are non-small cell lung cancer with most of these presenting at advanced stage (Silvestri GA et al. Chest. 2005; 128:3975-84). Despite advancements in therapies, 5-year survival for NSCLC remains ~15% (Tarver T et al. Cancer Facts & Figures 2012. American Cancer Society (ACS). 2012). EGFR mutations are most prevalent in NSCLC (NCCN. Non- Small Cell Lung Cancer Version 3. 2019). L858R mutation in exon 21 and delE746-A750 in exon 19 represent ~85% of EGFR mutations (Paez JG et al. Science. 2004; 304: 1497-500; Sharma SV et al. Nat Rev Cancer. 2007; 7: 169-81; and Eck MJ et al. Biochim. Biophys. Acta. 2010; 1804:559-66). To target these prevalent mutations, 1^st generation tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib were developed. The median time to disease progression on these agents is ~12mo (Nagano T et al. Cells. 2018; 7, 212; doi: 10.3390/cells7110212) with over 50% of resistance mediated through mutation T790M in exon 20 (Kobayashi S et al. N Engl. J. Med. 2005, 352, 786-792; and Pao et al. PLoS Med. 2005, 2, e73.). T790M inhibits binding of first-generation EGFR-TKIs to the ATP binding site.

To circumvent this issue, second-generation TKIs (afatinib and dacomitinib) were designed to irreversibly bind the cysteine residue of the EGFR (Xu J et al. Oncotarget. 2017, 8, 90557-90578). However, the effect of 2^nd generation TKIs is limited in those progressing with 1^st generation EGFR-TKIs and demonstrating a T790M mutation (Katakami N et al. J Clin Oncol. 2013, 31, 3335-3341). Resultantly, 3^rd generation pyrimidine-based irreversible EGFR-TKIs were then developed against the T790M mutation. Osimertinib, in particular, irreversibly and selectively binds at the cysteine residue at codon 797 [Cross DA et al. Cancer Discov. 2014, 4, 1046-1061] This third -generation agent demonstrates activity against exon 19 deletions as well as L858R mutations and T790M mutations. Osimertinib has since demonstrated improved progression free survival (PFS) versus platinum therapy with pemetrexed in NSCLC patients with EGFR T790M mutation (AURA3) (Akamatsu et al. N Engl J Med. 2017, 376, 629-640) as well as improved PFS (18.9 vs 10.2 months) vs gefitinib or erlotinib (FLAURA trial) (Soria et al. N Engl J Med. 2018, 378, 113-125). Although demonstrating robust clinical response, resistance even to osimertinib is expected (Thress et al. Nat Med. 2015, 21, 560-562; Costa et al. Transl. Fung Cancer Res. 2015,4, 809-815). A well-described mechanism of resistance to osimertinib is the C797S mutation-C797 resides in the ATP binding pocket, and the exon 20 C797S mutation-mediated resistance develops within approximately a year (Xu J et al. Oncotarget. 2017, 8, 90557-90578). If the T790M and C797S mutations are on different alleles, then the EGFR mutation may be susceptible to a combination of 1^st and 3^rd generation TKIs (Wang et al. J Thorac Oncol. 2017, 12, 1723— 1727. Arulananda et al. J Thorac Oncol. 2017, 12, 1728-1732). However, if the mutations are cis, then the cells are typically resistant to all TKIs (Engelman et al. Clin. Cancer Res. 2015, 21, 3924-3933).

Besides the T790M and C797S mutations, additional mechanisms of resistance to osimertinib include amplification of wild type EGFR, loss of T790M, amplification of EGFR, MET, and/or HER2, and SCFC transformation (Nagano T et al. Cells. 2018; 7, 212;

doi: 10.3390/cells7110212). Per National Comprehensive Cancer Network (NCCN. Non-Small Cell Lung Cancer Version 3. 2019), guidance is provided for treatment of non-small cell lung cancer (NSCLC). For advanced of metastatic disease, this includes assessment for activating EGFR mutations (NCCN. Non-Small Cell Lung Cancer Version 3. 2019, NSCL-17). Then, if discovered prior to administration of other systemic therapy, a 1^st, 2^nd, or 3^rd generation EGFR-TKI may be used. Progression on a 1^st or 2^nd generation TKI then prompts T790M testing. If positive, then the patient may be trialed on osimertinib. If negative and/or the patient progresses on osimertinib then the patient may be recommended to receive systemic therapies (NCCN Non- Small Cell Lung Cancer Version 3. 2019, NSCL-17) which may include chemotherapy and/or immune based therapies (NCCN. Non-Small Cell Lung Cancer Version 3. 2019).

While we have described how EGFR-TKIs can be used and are effective, we have also discussed their common and frequent development of resistance. While multiple lines of therapy may be offered thereafter, these are often systemic and hence confer substantial toxicity. Accordingly, there is a need for new therapies targeting resistance mechanisms through novel mechanisms thereby providing treatment options for a large population of patients with EGFR mutated, TKI-resistant cancers. The present disclosure fulfills this need.

SUMMARY

Disclosed herein are methods for treating EGFR-driven cancers by a PKC inhibitor in combination with an EGFR-TKI. The methods are based, at least in part, on findings that PKC inhibitor 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)-pyridin-2-yl)pyrazine -2-carboxamide (hereinafter referred to as Compound A) having the structure:

shows greater anti-proliferative effect on TKI resistant human EGFR mutant NSCLC cell lines H1975 (EGFR L858R/T790, EGFR-TKI resistant), and H1650 (TKI insensitive via PTEN-loss, Akt and NFkB activation) in vitro when administered in combination with gefitinib (see Figs. 1-6B). Radiometric kinase assay, described in Example 1 below, shows Compound A to be generally more active against the PKC g, d, e, z, h, and q isoforms and selective over the classical isoforms a and b.

Compound A is disclosed in PCT application publication No. WO 2016/020864, in Example 9.

Therefore, PKC inhibitors of Formula (I), in particular Compound A, have the potential to be useful for the treatment of EGFR driven NSCLC that is resistant to treatment with EGFR-TKIs as monotherapy.

Accordingly, in a first aspect, provided is a method of treating NSCLC in a patient in need thereof, comprising:

determining if said NSCLC comprises at least one EGFR alteration selected from L858R, exl9del, T790M, and C797S; and

if the NSCLC comprises at least one EGFR alteration selected from L858R, exl9del, T790M, and C797S, then administering to the patient a therapeutically effective amount of a PKC inhibitor of Formula (I):

wherein:

R¹ is 6-10 membered aryl, 5-10 membered heteroaryl or C_5-6 fused heteroaryl, each ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyloxy, C_6-10 aryloxy, C_{5- 10} heteroaryloxy, C_1-6 hydroxyalkyl, C_1-6 alkyl-O-C_1-6 alkyl, C_1-6hydroxyalkyloxy, C_1-6 alkyl-O- C_1-6 alkyloxy, CONH₂, CONH C_1-6 alkyl, CONH C_6-10 aryl, CONH C_{5- 10} heteroaryl, NH₂, NHC_1-6 alkyl, N(C_1-6 alkyl)₂, NHC_1-6 hydroxyalkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, S0₂NH C_6-10 aryl, SO₂NHC_{5- 10} heteroaryl and 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl wherein heterocyclyl or bridged heterocyclyl , said heterocyclyl and bridged heterocyclyl are optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy;

R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy; and

R⁹ is independently H, 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl, each ring substituted with 1 to 4 substituents each independently selected from the group consisting of: H, ²H, amino , halo, CN, C_1-6 alkyl, C_1-6hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl, C_1-6 haloalkyl-0-C_1-6 alkyl, C_1-6 cyanoalkyl, C_1-6 alkoxy, OH, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_2-3 alkynyl, C_2-3 alkenyl, COOC_1-6 alkyl, CONH₂, CONHC_1-6 alkyl, CONHC_6-10 aryl, CONHC_{5- 10} heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_{5- 10} heteroaryl, -0-(CRR’)_n-heterocyclyl (n = 1-3 and each R is H or C_1-6 alkyl), CONH₂, said C_1-6 alkyl or -0-(CRR’)_n-heterocyclyl, said heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, SO, SO₂ each optionally substituted with 1 to 4 substituents selected from H, NH₂, OH, halo, C_1-6 alkyl, C_1-6 alkoxy and C_1-6 haloalkoxy; a pharmaceutically acceptable salt thereof;

in combination with an EGFR tyrosine kinase inhibitor.

In a second aspect, provided is a method of treating a NSCLC having at least one EGFR alteration selected from L858R, exl9del, T790M, and C797S in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a PKC inhibitor of Formula (I):

wherein:

R¹ is 6-10 membered aryl, 5-10 membered heteroaryl or C_5-6 fused heteroaryl, each ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C _1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyloxy, C_6-10 aryloxy, C_{5- 10} heteroaryloxy, C_1-6hydroxyalkyl, C_1-6 alkyl-O-C_1-6 alkyl, C_1-6hydroxyalkyloxy, C_1-6 alkyl-O- C_1-6 alkyloxy, CONH₂, CONHC_1-6 alkyl, CONHC6-10 aryl, CONHC_{5- 10} heteroaryl, NH₂, NHC_1-6 alkyl, N(C_1-6 alkyl)₂, NHC_1-6 hydroxyalkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_{5- 10} heteroaryl and 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl wherein heterocyclyl or bridged heterocyclyl , said heterocyclyl and bridged heterocyclyl are optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy;

R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy; and

R⁹ is independently H, 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl, each ring substituted with 1 to 4 substituents each independently selected from the group consisting of: H, ²H, amino, halo, CN, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl, C_1-6 haloalkyl-0-C_1-6 alkyl, C_1-6 cyanoalkyl, C_1-6 alkoxy, OH, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_2-3 alkynyl, C_2-3 alkenyl, COOC_1-6 alkyl, CONH₂, CONH C_1-6 alkyl, CONHC_6-10 aryl, CONHC_{5- 10} heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, S0₂NHC_6-10 aryl, SO₂NHC_5-10 heteroaryl, -0-(CRR’)_n-heterocyclyl (n = 1-3 and each R is H or C_1-6 alkyl), CONH₂, said C_1-6 alkyl or -0-(CRR’)_n-heterocyclyl, said heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, SO, SO₂ each optionally substituted with 1 to 4 substituents selected from H, NH₂, OH, halo, C_1-6 alkyl, C_1-6 alkoxy and C_1-6 haloalkoxy; or a pharmaceutically acceptable salt thereof;

in combination with an EGFR tyrosine kinase inhibitor (EGFR-TKI).

In a third aspect, provided is a method of treating NSCLC having at least one EGFR alteration selected from L858R, exl9del, T790M, and C797S and which is resistant to one or more EGFR-TKIs in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a PKC inhibitor of Formula (I) disclosed above or a pharmaceutically acceptable salt thereof;

in combination with an EGFR tyrosine kinase inhibitor.

In a fourth aspect, provided is a method of treating NSCFC having at least one EGFR alteration selected from F858R, exl9del, T790M, and C797S and which is resistant to one or more EGFR-TKIs in a patient in need thereof, comprising: determining if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms, preferably one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon; and

if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms, preferably one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon, then administering to said patient a therapeutically effective amount of a PKC inhibitor of Formula (I) disclosed above pharmaceutically acceptable salt thereof;

in combination with an EGFR tyrosine kinase inhibitor.

Embodiments

1. In embodiment 1, the method of the first aspect further comprises:

if the NSCFC comprises at least one EGFR alteration selected from L858R, exl9del, T790M and C797S, then determining if said NSCLC is resistant to one or more EGF- TKIs.

2. In embodiment 2, the method of embodiment 1 further comprises:

if the NSCLC is resistant to the one or more EGFR-TKIs, then determining if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms.

3. In embodiment 3, the method of embodiment 1 further comprises:

if the NSCLC is resistant to the one or more EGFR-TKIs, then determining if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon.

4. In embodiment 4, the method of embodiment 1 further comprises:

if the NSCLC is resistant to the one or more EGFR-TKI, then determining if the resistance to the one or more EGFR-TKIs is mediated by at least PKC delta.

5. In embodiment 5, the method of any one of embodiments 2 or 3 is wherein the step of determining if the resistance to the one or more TKI is mediated by one of more PKC isoform, comprises determining the presence or absence of nuclear localized PKC (nPKC) of said one or more PKC isoform in said NSCLC wherein the presence of one or more said nPKC isoform in said NSCLC is indicative that the EGFR-TKI resistance may be mediated by said one or more PKC isoforms.

6. In embodiment 6, the method of embodiment 4 is wherein the step of determining if the resistance to the one or more TKI is mediated by at least PKC delta, comprises determining the presence or absence of nuclear localized PKC delta in said NSCLC wherein the presence of nPKC delta in said NSCLC is indicative that the EGFR-TKI resistance may be mediated at least PKC delta.

7. In embodiment 7, the method of the third aspect wherein the resistance to the one or more EGFR-TKIs is mediated by at least PKC delta.

8. In embodiment 8, the method of any one of first, second, third and fourth aspects and embodiments 1 to 7 is wherein the NSCLC comprises L858R and/or exl9del alteration, preferably L858R or exl9del alteration.

9. In embodiment 9, the method of any one of first, second, third and fourth aspects and embodiments 1 to 7 is wherein the NSCLC comprises: (i) L858R and T790M, (ii) exl9del and T790M, or (iii) L858R, exl9del, and T790M alterations, preferably L858R and T790M or exl9del and T790M alterations.

10. In embodiment 10, the method of any one of first, second, third and fourth aspects and embodiments 1 to 7 is wherein the NSCLC comprises (i) L858R T790M and C797S, (ii) exl9del, T790M and C797S or (iii) L858R, exl9del, T790M and C797S alterations, preferably L858R, T790M and C797S or exl9del, T790M and C797S alterations.

11. In embodiment 11 , the method of first to fourth aspects and any one of embodiments 1 to 10 is wherein the one or more EGFR-TKI is selected from gefitinib, erlotinib, icotinib, afatinib, dacomitinib, rociletinib, osimertinib, and olmutinib.

12. In embodiment 12, the method of first to fourth aspects and embodiments 1 to 11 is wherein the PKC inhibitor is a compound of Formula (II):

wherein:

R¹ is substituted 6-10 membered aryl, 5-10 membered heteroaryl having 1 to 4 heteroatoms each independently selected from the group consisting of O, N and S, said heteroaryl, fused heteroaryl, or aryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, CONH₂,

CONHC_I-6 alkyl, CONHC_6-10 aryl, CONHC_5-10 heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_{5- 10} heteroaryl and 4-7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, S and SO₂, said heterocyclyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy;

R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optional substituted with one to two of hydroxyl, halo and C_{1 -3} haloalkoxy;

H, ²H, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl or C_{1 -} 6 alkyl-O- C_1-6 haloalkyl, said C_1-6 alkyl optionally substituted with H, F, OH, C_{1 -3} alkoxy and C i-3 haloalkoxy;

R^5a and R^5b are each independently H, ²H, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with F, OH, or C _1-3 alkoxy, or R^5a and R^5b are joined together forming a methylene or ethylene bridging group; and

R^5c and R^5d are each independently H, ²H, halo, OH, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with F, OH, or C_{1 -3} alkoxy, or R^5c and R^5d are joined together forming a methylene, ethylene or -CH₂-O- bridging group.

13. In embodiment 14, the method of first to fourth aspects and embodiments 1 to 11 is wherein the PKC inhibitor is a compound of formula (III):

wherein:

X is N or CR;

R, R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy; R⁵ is -H, ²H, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl or C_1-6 alkyl-O- C_1-6 haloalkyl, said Ci-63 alkyl optionally substituted with H, F, OH, C_1-6 alkoxy and C_1-6 haloalkoxy;

R^5a and R^5b are each independently H, ²H, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with H, F, OH, C_{1 -3} alkoxy and C_{1 -3} haloalkoxy or R^5a and R^5b are joined together forming a methylene or ethylene bridging group;

R^5c and R^5d are each independently H, ²H, halo C_1-6 alkyl, or C_1-6 alkoxy or R^5c and R^5d are joined together forming a methylene, ethylene or -CH₂-O- bridging group; and

R⁶, R⁷, R ⁸ and R⁹ are each independently selected from H, ²H, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-7 cycloalkyl and 4-7 membered heterocyclyl, each optionally substituted with 1 to 3 substituents selected from H, halo, hydroxyl, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy and C_3-7 cycloalkyl; or

wherein R⁶ and R⁸ together with the carbon to which they are attached from form five or six membered cycloalkyl or heterocyclic ring optionally substituted with 1 to 3 groups selected from: H, ²H, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-7 cycloalkyl and 4- 7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, S and SO₂, preferably

R¹ is pyridinyl, pyrimidinyl, thiazolyl, indolyl, azaindolyl, imidazolyl, pyrazinyl, quinolinyl, azaquinolinyl, isoquinolinyl purinyl, benzothiazolyl, benzopyridyl,

benzimidazolyl, phenyl or naphthyl, each unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN, C_{1 -3} alkyl, C_{1 -3} alkoxy, C_{1 -3} haloalkyl, C_{1 -3} haloalkoxy, C_3-7 cycloalkyl, morpholino, piperidinyl and piperazinyl;

R², R³ and R⁴ are each H;

R⁵ is H, ²H, CH₃, CH₂F, CHF₂, CF₃, CH₂OH, C_1-3 alkyl, CH₂-O- C_1-3 alkyl, CH₂-O- C_{1 -3} alkyl or CH₂-O- C_{1 -3} haloalkyl;

R^5a and R^5b are each H, F, C_{1 -3} alkyl, C_{1 -3} alkoxy or R^5a and R^5b are joined together forming a methylene or ethylene bridging group; and

R^5c and R^5d are each independently H, F, C_{1 -3} alkyl, or C_{1 -3} alkoxy or R^5c and R^5d are joined together forming a methylene, ethylene or -CH₂-O- bridging group; more preferably R¹ is independently pyridinyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, pyrazinyl, quinolinyl, isoquinolinyl or phenyl, each unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN, acetylene, C_1-3 alkyl, C_1-3 alkoxy, Ci-₃ haloalkyl, C_1-3 haloalkoxy, C_3-7 cycloalkyl, morpholino, piperidinyl and piperazinyl;

R², R³ and R⁴ are each H;

R⁵ is independently H, ²H, CH₃, CH₂F, CHF₂, CF₃, C_1-3 alkyl, CH₂OH, CH₂-0- C_1-3 alkyl CH₂-0- C_1-3 haloalkyl;

R^5a and R^5b are each H; and

R^5c and R^5d are each H.

14. In embodiment 14, the method of first to fourth aspects and embodiments 1 to 11 is wherein the PKC inhibitor is the PKC inhibitor is selected from: 3-amino-N-(3-(4-amino- piperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3- amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy) pyridin-2- yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-l- yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3- (4-amino-4-methyl-piperidin- 1 -yl)pyridin-2-yl)-6-(3 morpholinoisoquinolin- 1 -yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)-pyridin-2-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4- (hydroxymethyl)piperidin- 1 -yl)pyridin-2-yl)-6-(3 -(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(2-morpholino-4- (trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin- 1 - yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3- amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(2-morpholinothiazol-4-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(2-morpholino- 5-(trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-fluoro-2-methylquinazolin-4-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4-methoxy-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(3,3-difluoroazetidin-l-yl)-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-cyclopropyl-3-(trifluoromethyl)pyridin-2- yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6- (6-methoxy-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4- amino-4-ethylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3- chloropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin- 1 - yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-((lR,5S,8s)- 8-amino-3 -azabicyclo[3.2.1 ] octan-3 -yl)pyridin-2-yl)-6-(6-morpholino-3 - (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-fluoro-4-methoxypyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-(methoxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3- fluoropyridin-2-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l- yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4- amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyanopyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-ethylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-

2 - y I ) pyrazine 2 - carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)- 6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- (methoxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-((lS,5R,8S)-8-amino- 6-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(5,6,7,8-tetrahydroquinazolin-4-yl)pyrazine-2-carboxamide, 3-amino-N- (3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2- carboxamide,

3-amino-N-(3-(4-amino-4-(2-hydroxyethyl)piperidin-l-yl)pyridin-2-yl)-6-(3-fluoropyridin-2- yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6- (6-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3- ((lR,5S,8s)-8-amino-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-6-(6-morpholino-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(4-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-(2-methoxyethyl) piperidin- 1 -yl)pyridin-2-yl)-6-(3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2- yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6- (6-fluoroquinazolin-4-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazine-2-carboxamide, 3- amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3-morpholinoplienyl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3,6- bis(trifluoromethyl)pyridin-2-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(5-morpholino-2-(trifluoromethyl)phenyl)pyrazine-2- carboxamide, (+) 3-amino-N-(3-((cis)-4-amino-3-fluoropiperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(2-morpholinopyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4- amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(2-(3,6-dihydro-2H-pyran-4-yl)-5- (trifluoromethyl) pyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(2-morpholinoquinazolin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l -yl)pyri din-2 -yl)-6-(l -methyl- lH-indazol-4-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(7- fluoroisoquinolin-l-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4- aminopiperidin-l-yl)pyridin-2-yl)-6-(6-morpholinopyridin-2-yl)pyrazine-2-carboxamide, 3- amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3-morpholinophenyl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(7- chloroisoquinolin-l-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(6-(azetidin-l-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-((3S,4R)-4-amino-3-fluoropiperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(2-(trifluoromethyl)- 1 H-indol-4-yl)pyrazine -2-carboxamide, 3-amino-N- (3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(5-morpholino-2-

(trifluoromethyl)phenyl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin- 1 - yl)pyridin-2-yl)-6-(6-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(2-(4,4- difluoropiperidin-l-yl)-5-fluoropyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4- amino-4-ethylpiperidin-l-yl)pyridin-2-yl)-6-(3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(5-fluoro-2- morpholinopyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(l -methyl- lH-indol-4-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4- aminopiperi din- l-yl)pyri din-2 -yl)-6-(lH-indazol-4-yl)pyrazine-2-carboxamide, 3-amino-N- (3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4-cyano-3-(trifluoromethyl)pyridin-2- yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(6-fluoro- 2-morpholinoquinazolin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(2-methyl-lH-indol-4-yl)pyrazine -2-carboxamide, 3-amino-N-(3-(4- aminopiperidin-l-yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine- 2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4-ethoxy-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 4-(5-amino-6-((3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)carbamoyl)pyrazin-2-yl)-5-fluoropyrimidine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(2-cyano-5- (trifluoromethyl)pyrimidin-4-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(2-amino-5-chloropyrimidin-4-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(lH-indol-4-yl)pyrazine- 2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3- morpholinoisoquinolin-l-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)pyridin-2-yl)-6-(3-morpholino-5-(trifluoromethyl)phenyl)pyrazine -2-carboxamide, 3- amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4-chloro-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(5-morpholino-2- (trifluoromethyl)phenyl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin- 1 - yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3- amino-N-(3-(4-aminopiperidin-l-yl)pyridin-2-yl)-6-(3-morpholinoisoquinolin-l-yl)pyrazine- 2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l-yl)-6-methylpyridin-2-yl)-6-(3- (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-aminopiperidin-l- yl)-6-methylpyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3- amino-N-(3-(4-amino-3-methoxypiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin- 2 - y I )pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)- 6-(3-fluoro-4-methylpyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(4-ethoxy-3-fluoropyridin-2-yl)pyrazine-2- carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4- (hydroxymethyl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide and 3-amino-N-(3- (4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(4-(methoxymethyl)-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-cyano-3-fluoropyridin-2-yl)pyrazine-2-carboxamide, 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(2-methylmorpholino)-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- (ethoxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-(ethoxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3- (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- ((difluoromethoxy)methyl)piperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2- yl)pyrazine -2-carboxamide; 3-amino-N-(3-(4-amino-4-((difluoromethoxy)methyl)piperidin-

1-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine -2-carboxamide; 3-amino-N- (3-(4-amino-4-(hydroxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(l-morpholinoisoquinolin-3- yl)pyrazine -2-carboxamide; 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-l- yl)pyridin-2-yl)-6-(6-morpholino-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3- amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4-isopropoxypyridin-

2 - y I )pyrazine-2-carboxamide 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)- 6-(3-cyano-4-cyclopropoxypyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(4-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-(hydroxymethyl)piperidin-l-yl)pyridin-2-yl)-6-(3- cyano-4-methoxypyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- (hydroxymethyl)piperidin- 1 -yl)pyridin-2-yl)-6-(3 -cyanopyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4- (trifluoromethoxy)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4-phenoxypyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(5-methoxy-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-3-fluoro-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(3- hydroxyazetidin-l-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N- (3-(4-amino-4-(cyanomethyl)piperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2- yl)pyrazine -2-carboxamide; 3-amino-N-(3-(4-amino-4-(cyanomethyl)piperidin-l-yl)pyridin- 2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-3- fluoro-4-methylpiperidin- 1 -yl)pyridin-2-yl)-6-(3 -(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide; (R)-3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(3- methylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; (S)-3-amino-N- (3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(3-methylmorpholino)-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 6-(6-(3-oxa-8-azabicyclo[3.2.1]octan- 8-yl)-3-(trifluoromethyl)pyridin-2-yl)-3-amino-N-(3-(4-amino-4-methylpiperidin-l- yl)pyridin-2-yl)pyrazine -2-carboxamide; 3-amino-N-(3-((3S,4R)-4-amino-3-fluoro-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethoxy)pyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4- ethoxypyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4-methylpiperidin-l- yl)pyridin-2-yl)-6-(6-(3-isopropylmorpholino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2- carboxamide; 3-amino-N-(3-(4-amino-3-fluoro-4-(2-hydroxyethyl)piperidin-l-yl)pyridin-2- yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- (cyanomethyl)piperidin-l-yl)pyridin-2-yl)-6-(3-cyano-4-methoxypyridin-2-yl)pyrazine-2- carboxamide; (R)-3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-((l- hydroxypropan-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; (S)-3- amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-((l-hydroxypropan-2- yl)amino)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino- 4-methylpiperidin-l-yl)pyridin-2-yl)-6-(6-((2-hydroxyethyl)amino)-3- (trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide; 3-amino-N-(3-(4-amino-4- methylpiperidin-l-yl)pyridin-2-yl)-6-(6-(2-hydroxyethoxy)-3-(trifluoromethyl)pyridin-2- yl)pyrazine -2-carboxamide; and 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2- yl)-6-(6-(3-methoxyazetidin-l-yl)-3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide.

15. In embodiment 16, the method of first to fourth aspects and embodiments 1 to 11 is wherein the PKC inhibitor is:

or a pharmaceutically acceptable salt thereof.

16. In embodiment 16, the method of first to fourth aspects and embodiments 1 to 11 is wherein the PKC inhibitor is:

17. In embodiment 17, the method of any one of first to fourth aspects and embodiments 1 to 14 is wherein the PKC inhibitor inhibits at least one, preferably at least two, of PKC isoforms, selected from gamma, delta, epsilon, eta, and theta. Preferably, the PKC inhibitor inhibits at least PKC delta.

18. In embodiment 18, the method of claim 17 is wherein the PKC inhibitor inhibits PKC isoforms gamma and/or delta at IC50 of less than 15 or 20 nm, preferably 10 nm.

19. In embodiment 19, the method of any one of first to third aspects and embodiments 1 to 18 is wherein the PKC inhibitor is administered one or more EGFR-TKI is selected from gefitinib or erlotinib.

20. In embodiment 20, the method of any one of first to fourth aspects and embodiments 1 to 18 is wherein the PKC inhibitor is administered one or more EGFR-TKI is selected from icotinib, afatinib, dacomitinib, rociletinib, osimertinib, and olmutinib.

21. In embodiment 21 , the method of any one of first to fourth aspects and embodiments 1 to 18 is wherein the PKC inhibitor is administered one or more EGFR-TKI is selected from rociletinib or osimertinib.

22. In embodiment 20, the method of any one of first to fourth aspects and embodiments 1 to 21 is wherein the PKC inhibitor and the TKI inhibitor are administered simultaneously.

23. In embodiment 20, the method of any one of first to fourth aspects and embodiments 1 to 21 is wherein the PKC inhibitor and the TKI inhibitor are administered sequentially.

24. In embodiment 24, the method of embodiment 23 is wherein the TKI is administered prior to administration of the PKC inhibitor.

25. In embodiment 25, the method of embodiment 23 is wherein the TKI is administered after administration of the PKC inhibitor.

25. In embodiment 25, the method of any one of embodiments 16 to 25 is wherein Compound A, is administered from about 100 mg/day to about 1600 mg/day. In a first sub- embodiment of embodiment 25, the PKC inhibitor, preferably Compound A, is administered from about 100, about 200, about 300, about 400, about 500 mg/day, about 600 mg/day, about 700 m/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day. In a second embodiment of embodiment 25, the PKC inhibitor, preferably Compound A, is administered about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 m/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, or about 1200 mg/day. In a third sub-embodiment, the PKC inhibitor, preferably Compound A, is administered in a dose of about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700 mg once/day. In a fourth sub-embodiment, the PKC inhibitor, preferably Compound A, is administered in a dose of from about 200 mg, about 250, about 300 mg, about 350, about 400, about 450, about 500, about 550, about 600 mg 2 times/day, preferably 300, 400, or 500 mg BID, more preferably 300 mg BID. About as used herein means +/- 5 to 10% of a stated value.

26. In embodiment 26, the method of any one of previous embodiment wherein the compounds are administered in combination with radiation therapy.

27. In embodiment 27, the method of any one of previous embodiments wherein the compounds are in combination an additional chemotherapeutic agent.

Compounds of Formula (I), (II), (III) and specific compounds disclosed herein are disclosed in PCT application publication No. WO 2016/020864, the disclosure of which is incorporated herein in its entirety.

EGFR mutation status may be determined by tests available in the art, e.g. QIAGEN therascreen® EGFR test or other CAP/CLIA approved tests. The therascreen EGFR RGQ PCR Kit is an FDA-approved, qualitative real-time PCR assay for the detection of specific mutations in the EGFR oncogene. Evidence of EGFR mutation can be obtained from existing local data and testing of tumor samples and cell free DNA. EGFR mutation status may be determined from any available tumor tissue.

Patients may be tested for presence of nuclear PKC delta (nPKCd) utilizing a variety of techniques and time points. These may include immunohistochemistry (IHC) on pre- treated (before receiving an EGFR tyrosine kinase inhibitor) patient biopsies and post- treatment (including at progression) biopsies. A possible quantification method would ascribe numerical values to degree of staining with 0 indicating no staining of neoplastic cells, 1 indicating <10% staining, 2 indicating 10-50% staining, or 3 indicating >50% staining

[DeRycke et al, Am J Clin. Pathol. 2009 132(6):846-856]. A positive assessment would include whether there is presence of nuclear PKCd signal above that of background signal (i.e., scoring >1 on IHC) at any time point. Further, to clarify, an increase in nPKCb staining on subsequent biopsies shall also be interpreted as a positive result. Alternatively, other techniques may be used to assess nPKCd signal in the same populations including immunofluorescence which may be quantified using an h-score or other appropriate method.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 shows antiproliferative effect of gefitinib and sotrastaurin and Compound A either alone or in combination with gefitinib in HCC827 (gefitinib-sensitive) model treated for 10 days.

Fig 2 shows antiproliferative effect of gefitinib and sotrastaurin, Compound A, and Go6983 either alone or in combination with gefitinib in H1975 (gefitinib-resistant) model treated for 10 days.

Fig 3 shows antiproliferative effect of gefitinib and sotrastaurin, and Compound A either alone or in combination with gefitinib in HI 650 (gefitinib resistant via PTEN loss, Atk and NFkB activation) model treated for 10 days.

Fig 4 shows antiproliferative effect of gefitinib and sotrastaurin, and Compound A either alone or in combination with gefitinib in HCC827 (gefitinib-sensitive) model treated for 3 days.

Fig 5 shows antiproliferative effect of gefitinib and sotrastaurin, and Compound A either alone or in combination with gefitinib in H1975 (gefitinib-resistant) model treated for 3 days.

Fig 6 shows antiproliferative effect of gefitinib and sotrastaurin, and Compound A either alone or in combination with gefitinib in HI 650 (gefitinib resistant via PTEN loss, Atk and NFkB activation) model treated for 3 days.

DETAILED DESCRIPTION

Definitions:

Unless otherwise indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.

Terms used in compounds of Formula (I), (II), and (III) have the following definitions.

As used herein,“C_1-6 alkyl” is a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms that is optionally substituted with one to three substituents independently selected from with halo, hydroxy, amino, nitro and cyano groups, unless stated otherwise. Representative C_1-6 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, trifluoromethyl, chloromethyl, trichloromethyl, trifluoromethyl, fluoromethyl, fluoroethyl, chloroethyl, hydroxymethyl, hydroxyethyl, and the like.

As used herein,“C_2-3 alkenyl” is a straight hydrocarbon radical containing a double bond e.g., vinyl.

As used herein,“C_2-3 alkynyl” is a straight hydrocarbon radical containing a triple bond e.g., ethynyl.

As used herein,“C_1-6 alkoxy” as used herein refers to - -OR radical, wherein R is C_1-6 alkyl, as defined above. Representative examples of C_1-6 alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.

As used herein, the term“halogen” or“halo” refers to chloro, bromo, fluoro and iodo groups.

As used herein,“C_1-6 haloalkyl” refers to is a straight or branched hydrocarbon radical of one to six carbon atoms substituted with one or more halogen atoms. Representative examples include difluoromethyl, trifluoromethyl, and the like.

As used herein,“C_1-6 cyanoalkyl” refers to is a straight or branched hydrocarbon radical of one to six carbon atoms substituted with a cyano group e.g., cyanomethyl, cyanoethyl, and the like.

The term“C_1-6 haloalkoxy” refers to -OR radical where R is a straight or branched hydrocarbon chain of one to six carbon atoms substituted with one or more halogen atoms. Representative examples include difluoromethoxy, trifluoromethoxy, and the like.

As used herein,“hydroxy” refers to the group -OH.

As used herein,“C_1-6 hydroxyalkyl” means a linear or branched hydrocarbon radical of one to six carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4- hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2 -hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and 1 -(hydroxymethyl)-2-hydroxyethyl.

As used herein“C_1-6 hydroxyalkyl-O-C_1-6 alkyl” means -R-OR’ radical where R is unsubstituted C_1-6 alkyl and R’ is C_1-6 hydroxyalkyl, each as defined above. As used herein“C_1-6 hydroxyalkyloxy” means -OR’ radical where R’ is C_1-6 hydroxyalkyl as defined above.

As used herein“C_1-6 alkyl-O-C_1-6 alkyl” means -R-OR radical where each R is unsubstituted C_1-6 alkyl as defined above.

As used herein“C_1-6 alkyl-O-C_1-6 alkyloxy” means -O-R-OR radical where each R is unsubstituted C_1-6 alkyl as defined above. As used herein“C_1-6 haloalkyl-O-C_1-6 alkyl” means -R-OR’ radical where R is unsubstituted C_1-6 alkyl and R’ is C_1-6 haloalkyl, each as defined above.

As used herein, "amino" refers herein to the group -NEE.

As used herein“6 to 10 membered aryl” is monocyclic or bicyclic aromatic hydrocarbon ring of 6 to 10 carbon atoms e.g., phenyl or naphthyl.

As used herein, "carbonyl" refers to the divalent group -C(O)-.

As used herein, "Carboxy" refers to-C(=0)-OH.

The term“C_3-7 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of three to seven ring atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

The term“C_3-7 cycloalkyloxy" refers to -OR radical where R is C_3-7 cycloalkyl as defined above. Representative examples include cyclopropoxy, cyclobutoxy,

cyclopentyloxy, and the like.

As used herein“4 to 7 membered heterocyclyl” means a saturated or unsaturated monovalent monocyclic ring of 4 to 7 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(0)_n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. Examples include, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is may be referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

As used herein“5 to 10 membered bridged heterocyclyl” means a saturated ring having 5 to 10 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R is independently H or methyl (also may be referred to herein as“bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(0)_n, where n is an integer from 0 to 2. Examples include, but are not limited to, 2- azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like.

Representative examples of heterocyclyl and bridged heterocyclyl rings are provided below.

The term“C_6-10 aryl” refers to optionally substituted monocyclic and bicyclic aromatic ring having from 6 to 10 carbons. Exemplary C_6-10 aryl include phenyl and naphthyl. The C6-io aryl is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, CONH₂, CONHC_1-6 alkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, and 4-7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, said heterocyclyl optionally substituted one or two substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, and C_1-6 haloalkoxy.

The term "C_6-10 aryloxy" refers to -OR radical where R is C_6-10 aryl as defined above.

The term“5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one

embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples when R¹ is heteroaryl used in accordance with the invention are listed below:

The term“5 or 6 fused membered fused heteroaryl” refers to a monocyclic aromatic radical of 5 or 6 ring atoms where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon that is fused to C_3-7 cycloalkyl or 4 to 7 membered heterocyclyl, each as defined herein.

The term“C_5-10 heteroaryl” refers to a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative heteroaryls include, for example, imidazolyl, pyridinyl (also referred to as pyridyl), pyrazinyl, thiazolyl, triazolyl, benzimidazolyl, benzothiazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, pyrazolyl, imidazoyl, and benzoxazolyl. C_5-10 heteroaryl is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, CONH₂, CONHC_1-6 alkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, and 4-7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, said heterocyclyl optionally substituted one or two substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy.

The term“C_5-10 heteroaryloxy” refers to -OR radical where R is C_5-10 heteroaryl as defined above.

The term“²H” refers to a heavy isotope of hydrogen that is also referred to as deuterium (D). The compounds of the invention, including the compounds of formulas (I), (II) or (III) or their tautomers, as well as the pharmaceutically acceptable salts, esters, metabolites and prodrugs of any of them, may comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention existing in enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, such as in (R)- or (S)- forms. As a result, all such possible isomers, individual stereoisomers in their optically pure forms, mixtures thereof, racemic mixtures (or "racemates"), mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms“S” and “R” configuration, as used herein, are as defined by the IUPAC 1974 RECOMMENDATIONS FOR SECTION E, FUNDAMENTAL STEREOCHEMISTRY, Pure Appl. Chem. 45: 13-30 (1976). The terms a and b are employed for ring positions of cyclic compounds. The a-side of the reference plane is that side on which the preferred substituent lies at the lower numbered position. Those substituents lying on the opposite side of the reference plane are assigned b descriptor. It should be noted that this usage differs from that for cyclic stereoisomers, in which "a" means "below the plane" and denotes absolute configuration. The terms a and b configuration, as used herein, are as defined by the CHEMICAL ABSTRACTS INDEX GUIDE- APPENDIX IV (1987) paragraph 203.

As used herein, the term“pharmaceutically acceptable salts” refers to the nontoxic acid or alkaline earth metal salts of the compounds of Formulas (I), (II) or (III). These salts can be prepared in situ during the final isolation and purification of the compounds of Formulas (I), (II) or (III), or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively. Representative salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate,

benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate,

2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium,

tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

As used herein, the term“pharmaceutically acceptable ester” refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term“prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

It will be apparent to those skilled in the art that the compounds of the invention, including the compounds of formulas (I), (II) or (III) or their tautomers, prodrugs and stereoisomers, as well as the pharmaceutically acceptable salts, esters and prodrugs of any of them, may be processed in vivo through metabolism in a human or animal body or cell to produce metabolites. The term“metabolite” as used herein refers to the formula of any derivative produced in a subject after administration of a parent compound. The derivatives may be produced from the parent compound by various biochemical transformations in the subject such as, for example, oxidation, reduction, hydrolysis, or conjugation and include, for example, oxides and demethylated derivatives. The metabolites of a compound of the invention may be identified using routine techniques known in the art. See, e.g., Bertolini, G. et al„ J. Med. Chem. 40: 2011-2016 (1997); Shan, D. et al, J. Pharm. Sci. 86( 7):765-767; Bagshawe K., Drug Dev. Res. 34: 220-230 (1995); Bodor, N., Advances in Drug Res. 73:224- 331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, I. K., Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991). It should be understood that individual chemical compounds that are metabolites of the compounds of formulas (I), (II) or (III) or their tautomers, prodrugs and stereoisomers, as well as the pharmaceutically acceptable salts, esters and prodrugs of any of them.

By“EGFR-driven cancer” refers to a cancer characterized by an alteration in an EGFR gene or polypeptide, including the specific alteration noted herein. Preferably, the alteration(s) in an EGFR gene increases the biological activity of an EGFR nucleic acid molecule or polypeptide compared to wild type EGFR. EGFR alterations include one or more deletions, substitutions, or additions in the amino acid or nucleotide sequences of EGFR. EGFR-driven cancers include non-small cell lung cancer (NSCLC), including one or more of squamous cell carcinoma, adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), BAC with focal invasion, adenocarcinoma with BAC features, and large cell carcinoma; neural tumors, such as glioblastomas; head and neck cancers (e.g., squamous cell carcinoma); breast cancer; skin cancer (non-melanoma), esophageal, bladder, endometrial, melanoma and small cell lung cancer.

EGFR alterations across cancer indications based on cBioportal are disclosed in Table below:

Alterations in EGFR can occur in any part of the EGFR sequence. Generally, EGFR mutants arise from alterations in the kinase domain (i.e., exons 18-24 in the EGFR sequence) or in the extracellular domain (i.e., exons 2-16 in the EGFR sequence). For example, alterations typically occur in the kinase domain, including one or more of a point mutation in exon 18 (e.g., L688P, V689M, P694L/S, N700D, L703V, E709K/Q/A/GN, I715S, L718P, G719C/A/S/R, or S720P/F), a deletion in exon 19 that may or may not include an insertion (e.g., delG719, delE746_E749, delE746_A750, delE746_A750insRP, delE746_A750insQP, delE746_ T751, delE746_ T751 insA/IN, delE746_ T751 ins VA, delE746_S752, delE746_S752insAN/D, delE746_P53insLS, dell747 _E749, dell747 _A750, dell747 _A750insP, dell747 _ T751, delL747_T751insP/S/Q, delL747_T751insPI, dell747_S752, delL747_S752insQ, dell747 _P753, dell747 _P753insS/Q, dell747 _L754insSR, delE749_A750, delE7 49_A 7 50insRP, delE7 49_ T751, deIT751_I759, delT751

_I759insS/N, or deIS752_I759), a duplication in exon 19 (e.g., K739_I44dupKIPVAI), a point mutation in exon 19 (e.g., L730F, W731Stop, P733L, G735S, V742A, E746V/K, A750P, T751I, S752Y, P753S, A754P, or D761Y), an in-frame insertion in exon 20 (e.g., D761_E762insEAFQ, A767 _S768insTLA, V769_D770insY, V769_D770insCV,

V769_D770insASV, D770_N771 insD/G, D770_N771 insNPG, D770_N771 insSVQ, P772_H773insN , P772_H773insYNP, or V774_C775insHV), a deletion in exon 20 that may or may not include an insertion (e.g., delM766_A767, delM766_A767insAI, delA767 _ V769, deID770, or delP772_H773insNP), a duplication in exon 20 (e.g.,

S768_D770dupSVD, A767 _ V769dupASV, or H773dupH), a point mutation in exon 20 (e.g., D761N, A763V, V765A/M, S768I, V769L/M, S768I, P772R, N771T, H773R/Y/L, V774M, R776G/H/C, G779S/F, T783A, T784F, L792P, L798H/F, T790M, R803W, K806E, or L814P), or a point mutation in exon 21 (e.g., G810S, N826S, L833V, H835L, L838V, A839T, K846R, T847I, H850N, V851 I/A, I853T, L858M/R, A859T, L861Q/R, G863D, A864T, E866K, or G873E).

In NSCLC cancer, activation alterations are typical, and 90% deletion of 746-750 (ELREA) and L858R result in sustained phosphorylation of EGFR without ligand stimulation. Drug resistance in 50% of lung cancers is said to arise from the T790M point mutation (e.g., T263P or A289D/TN in domain II), exon 8 (e.g., R324L or E330K), exon 15 (e.g., P596L or G598V in domain IV), or exon 21 (L861Q in the kinase domain). EGFR mutants also include those with a combination of two or more alterations, as described herein. Exemplary combinations include S7681 and G719A; S7681 and V769L; H773R and

W731Stop; R776G and L858R; R776H and L861Q; T790M and L858R; T790M and delE746_A750; R803W and delE746_T751insVA; dell747 _E749 and A750P; dell747 _S752 and E746V; dell747 _S752 and P753S; P772_H773insYNP and H773Y;

P772_H773insNP and H773Y; and D770_N771insG and N771T. Combinations of particular current interest include combinations of T790M together with another mutation (e.g., T790M and L858R or T790M and delE746_A750).

Certain mutations encode mutant EGFR proteins that actively signal in the absence of an EGF ligand but which are characterized by sensitivity to EGFR inhibitors such as for example, in glioblastoma, mutations typically, but not exclusively, occur in the extracellular domain, including EGFR variant I (EGFRvI) lacking the extracellular domain and resembling the v-erbB oncoprotein; EGFRvII lacking 83 amino acids from domain IV; and EGFRvIII lacking amino acids 30-297 from domains I and II, which is the most common amplification and is reported in 30-50% of glioblastomas and 5% of squamous cell carcinoma. Other mutations for glioblastoma include one or more of point mutations in exon 2 (e.g., D46N or G63R), exon 3 (e.g., R108K in domain I), exon 7 (e.g., T263P or A289D/TN in domain II), exon 8 (e.g., R324L or E330K), exon 15 (e.g., P596L or G598V in domain IV), or exon 21 (L861Q in the kinase domain).

EGFR mutants also include those with a combination of two or more mutations, as described herein. Exemplary combinations include S7681 and G719A; S7681 and V769L; H773R and W731Stop; R776G and L858R; R776H and L861Q; T790M and L858R; T790M and delE746_A750; R803W and delE746_T751insVA; dell747 _E749 and A750P; dell747 _S752 and E746V; dell747 _S752 and P753S; P772_H773insYNP and H773Y;

P772_H773insNP and H773Y; and D770_N771insG and N771T. Combinations of particular current interest include combinations of T790M together with another mutation (e.g., T790M and L858R or T790M and delE746_A750). Certain mutations encode mutant EGFR proteins that actively signal in the absence of an EGF ligand but which are characterized by sensitivity to EGFR inhibitors such as gefitinib and erlotinib. G719C/S/A, delE746_A750, and L858R are examples of such mutations. Other EGFR mutations confer resistance to such drugs, even when present in combination with one of the previously mentioned activating mutations. T790M is an example of a mutation that confers resistance to those drugs.

The invention described herein will be of interest for patients who have, or have a higher risk of, a TKI-resistant EGFR alteration. In particular, the inventions relate to treatment of EGFR-driven NSCLC having the delE746_A750 and/or L858R and T790M point mutations.

Outside mutations targeting EGFR itself, other reported mechanisms of resistance in EGFR driven lung cancer include (but not limited to), MET amplification, HER2 amplification, PIK3CA mutations, BRAF mutations, Activation of IGFR1, Transformation to SCLC, EMT transformation, AXL upregulation, EGFR exon 20 insertions (intrinsic resistance mechanisms), PTEN mutations (intrinsic resistance mechanisms) and BIM mutations (intrinsic resistance mechanisms (see Vyse S et al. J Mol. Biol, 429, 1767-1786, 2017).

As used herein, the term "PKC inhibitor" refers to a small molecule protein kinase C inhibitor that may be pan (multi-subtype) or selective to one or more PKC isozymes. The term PKC generally refers to the entire family of isoforms: conventional isoforms; alpha, beta, and gamma, novel isoforms; delta, epsilon, eta, and theta, and atypical isoforms; zeta, and iota.

The term "selective PKC inhibitor" refers to a PKC inhibitor that inhibits at least two PKC isoforms selected from gamma, delta, epsilon, eta, and theta. In one embodiment, the PKC inhibitor inhibits PKC isoforms gamma and/or delta at IC50 of less than 15 or 20 nm, preferably 10 nm.

Additional PKC for use in the methods disclosed herein include maleimide derivatives such as compounds described in U.S. Pat. Nos. 5,380,746, 5,489,608, 5,545,636; 5,668,152; 5,698,578; 5,710,145; 6,645,970; 7,220,774; 7,235,555; US Publication No. 2008/0318975; European Patent Nos. 0776895 B1; 0817627 B1; 1449529 B1; 1337527 Bl; and PCT Publication Nos. WO03/082859; and W007/006,533, the disclosure of which is incorporated herein by reference in their entirety.

The terms“treat,”“treating” or“treatment,” as used herein, refers to methods of alleviating, abating or ameliorating a disease e.g. NSCLC, or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting or reducing the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

As used herein, the expression“first generation EGFR-TKIs” includes erlotinib, gefitinib, icotinib and any combinations thereof.

As used herein, the expression“second generation EGFR-TKIs” includes afatinib, dacomitinib and any combinations thereof.

As used herein, the expression“third generation EGFR-TKIs” includes osimertinib or rociletinib. Other examples of third generation EGFR-TKIs include ASP8273, HM61713 and PF06747775. A more preferred third generation EGFR-TKI is osimertinib (AZD9291).

“Resistant to a TKI therapy” refers to a cancer that has progressed on or is no longer responding to EGFR-TKI treatment with one or more EGFR-TKI such as those disclosed herein. The progression of cancer may be monitored by methods well known to those in the art. For example, the progression may be monitored by way of visual inspection of the cancer, such as, by means of X-ray, CT scan or MRI or by tumor biomarker detection. For example, an increased growth of the cancer indicates progression of the cancer. Progression of cancer such as NSCFC or tumors may be indicated by detection of new tumors or detection of metastasis or cessation of tumor shrinkage. Tumor evaluations can be made based on RECIST criteria (Therasse et al 2000), New Guidelines to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European Journal of Cancer;

45:228-247. Tumor progression may be determined by comparison of tumor status between time points after treatment has commenced or by comparison of tumor status between a time point after treatment has commenced to a time point prior to initiation of the relevant treatment.

The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. An appropriate“effective” amount in any individual case may be determined using techniques, such as a dose escalation study. In connection with the administration of the drug, an“effective amount” indicates an amount that results in a beneficial effect for patients, such as an improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.

A“pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.“A pharmaceutically acceptable carrier/ excipient” as used in the specification and claims includes both one and more than one such excipient.

The term“about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term“about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.

Pharmaceutical Composition

The compounds of the invention are useful in vitro or in vivo in inhibiting the growth of cancer cells. The compounds may be used alone or in compositions together with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers or excipients include, for example, processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc,

monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl -b-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

For purposes of the present invention, a therapeutically effective dose will generally be a total daily dose administered to a host in single or divided doses may be in amounts, for example, of from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The compounds of the present invention may be administered orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq. (1976).

While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of cancer. The compounds of the present invention are also useful in combination with known therapeutic agents and anti-cancer agents, and combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V. T. Devita and S. Heilman (editors), 6^th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.

The references cited throughout the application are incorporated herein by reference in their entirety.

Combination Therapy

Besides EGFR-TKI, the PKC inhibitors can be administered in combination with one or more additional therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may allow for a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.

Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

As used herein,“combination” is meant to include therapies that can be

administered separately, for example, formulated separately for separate administration and therapies that can be administered together in a single formulation (i.e., a“co-formulation”).

In certain embodiments, the PKC inhibitor is administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other

embodiments, the PKC inhibitor is administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co- formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present invention.

The PKC inhibitor of the present invention may be used in combination with at least one other (active) agent in any manner appropriate under the circumstances. In one embodiment, treatment with the at least one active agent and at least a PKC inhibitor of the present invention is maintained over a period of time. In another embodiment, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a PKC inhibitor of the present invention is maintained at a constant dosing regimen. In a further embodiment, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a PKC inhibitor of the present invention is reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen). In yet another embodiment, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with a PKC inhibitor of the present invention is increased (e.g., higher dose, more frequent dosing or longer treatment regimen). In yet another embodiment, treatment with the at least one active agent is maintained and treatment with a PKC inhibitor of the present invention is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen). In yet another embodiment, treatment with the at least one active agent and treatment with a PKC inhibitor of the present invention is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).

The PKC inhibitor described herein can be administered in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic suppression of tumor growth. As used herein, the term“signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Examples of signal transduction inhibitors (STIs) useful in methods described herein include, but are not limited to: (i) bcr/abl kinase inhibitors (e.g., GLEEVEC); (ii) her-2/neu receptor inhibitors (e.g., HERCEPTIN); (iii) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin);

(iv) cell cycle kinase inhibitors (e.g., flavopiridol); and (v) phosphatidyl inositol kinase inhibitors. Agents involved in immunomodulation can also be used in combination with PKC inhibitor described herein for the suppression of tumor growth in cancer patients.

Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime;

nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid;

aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil;

bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;

mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid;

triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; abraxane; chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT 11 ; topoisomerase inhibitors; difluoromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; VEGF inhibitors such as bevacizumab; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti-estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and

pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent.

Additional treatment modalities that may be used in combination with PKC inhibitor include radiotherapy, a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy). Immune Checkpoint Inhibitors. The present invention contemplates the use of the modulators of PKC inhibitor described herein in combination with immune checkpoint inhibitors.

The tremendous number of genetic and epigenetic alterations that are characteristic of all cancers provides a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate amplitude (e.g., levels of cytokine production or proliferation) and quality (e.g., the type of immune response generated, such as the pattern of cytokine production) of the response, which is initiated through antigen recognition by the T-cell receptor (TCR), is regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are crucial for the prevention of autoimmunity (i.e., the maintenance of self-tolerance) and also for the protection of tissues from damage when the immune system is responding to pathogenic infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism.

Examples of immune checkpoint inhibitors include but are not limited to CTLA-4, PD- 1/Ll, BTLA, TIM3, LAG3, 0X40, 41BB, VISTA, CD96, TGFb, CD73, CD39, A2AR, A2BR, IDOl, TD02, Arginase, B7-H3, B7-H4. Cell-based modulators of anti-cancer immunity are also contemplated. Examples of such modulators include but are not limited to chimeric antigen receptor T-cells, tumor infdtrating T-cells and dendritic-cells.

The present invention contemplates the use of the PKC inhibitor described herein in combination with inhibitors of the aforementioned immune-checkpoint receptors and ligands, as well as yet-to-be-described immune-checkpoint receptors and ligands. Certain modulators of immune checkpoints are currently available, whereas others are in late-stage development. To illustrate, when it was approved for the treatment of melanoma in 2011, the fully humanized CTLA4 monoclonal antibody ipilimumab (YERVOY; Bristol-Myers Squibb) became the first immune checkpoint inhibitor to receive regulatory approval in the US.

Fusion proteins comprising CTLA4 and an antibody (CTLA4-Ig; abatcept (ORENCIA; Bristol-Myers Squibb)) have been used for the treatment of rheumatoid arthritis, and other fusion proteins have been shown to be effective in renal transplantation patients that are sensitized to Epstein Barr Virus. PD1/PDL1 inhibitors include lambrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab. PD 1 inhibitors in development include pidilizumab (Cure Tech), AMP-224 and AMP-514 (GSK), PDR001 (Novartis) and cemiplimab (Regeneron and Sanofi) and anti-PDLl antibodies in development include BMS- 936559 (BMS) and CK-301 (Checkpoint Therapeutics). Nivolumab has shown promise in patients with melanoma, lung and kidney cancer.

EXAMPLES

Example 1

PKC kinase assay performed by ProQinase (Freiburg, Germany)

A radiometric protein kinase assay (³³PanQinase^® Activity Assay) was used for measuring the kinase activity of the 9 PKC protein kinases. All kinase assays were performed in 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA) in a 50 ml reaction volume. The reaction cocktail was pipetted in four steps in the following order:

• 20 ml of assay buffer (standard buffer)

• 5 ml of ATP solution (in H₂O)

• 5 ml of test compound (in 10 % DMSO)

• 10 ml of substrate / 10 ml of enzyme solution (premixed)

The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl₂, 3 mM nCl₂, 3 mM Na-orthovanadate, 50 mg/ml PEG₂₀₀₀₀, 1.2 mM DTT, ATP (variable concentrations, corresponding to the apparent ATP-Km of the respective kinase, see Table 1), [g-33R]-ATR (approx. 1 x 10⁰⁶ cpm per well), protein kinase (variable amounts; see Table 1), and substrate (variable amounts; see Table 1).

All PKC assays additionally contained 1 mM CaCl₂, 4 mM EDTA, 5 mg/ml

Phosphatidylserine and 1 mg/ml 1,2-Dioleyl-glycerol.

Table 1 Assay parameters for the tested protein kinases

The reaction cocktails were incubated at 30 °C for 60 minutes. The reaction was stopped with 50 ml of 2 % (v/v) H₃PO₄, plates were aspirated and washed two times with 200 ml 0.9 % (w/v) NaCl. Incorporation of ³³Pi was determined with a microplate scintillation counter (Microbeta, Wallac). All assays were performed with a BeckmanCoulter/SAGIAN™ Core System. As shown in Table 1-1 below, Compound A inhibited all PKC isoforms with the exception of the atypical family member, PKC zeta. The data indicated Compound A was generally more active against the PKC g, d, e, z, h, and q isoforms and selective over the classical isoforms a and b.

Table 1-1 Biochemical activity of Compound A against PKC isoforms

Example 2

Evaluation of EGFR-driven tumor cell dependence on the PKC pathway To evaluate EGFR-driven tumor cell dependence on the PKC pathway, we assessed response to three different PKC inhibitors: sotrastaurin and Compound A, each with different PKC isoform selectivity. We used three different EGFR mutant lung cancer models: HCC827 which harbors EGFR exon 19 deletion and is sensitive to first and second generation EGFR tyrosine kinase inhibitors (TKIs), and HI 975 which harbors both an L858R EGFR driver mutation rendering cells dependent on EGFR signaling and also carry a T790M mutation which renders H1975 resistant to first and second generation TKIs; and lastly H1650 cells which have L858R EGFR driver mutation and are referred to in the literature as TKI-resistant through various mechanisms including PTEN-loss, Akt and NFKB activation. Using above models, we evaluated response to a first generation TKI, gefitinib, in parallel to response to each of the two PKC inhibitors (sotrastaurin and Compound A) alone or in combination with gefitinib. Cell viability was measured after a 3- day and 10-day course following treatment with increasing doses of each of the PKC inhibitors and gefitinib or a combination of the two. 3-Day Treatment Assay

Method

NSCLC cell lines (HCC827, H1975 and H1650) were screened for sensitivity to the EGFR inhibitor gefitinib alone or in combination with three PKC inhibitors: sotrastaurin, and Compound A; at increasing doses according to Table 2 below, in a 3-day assays.

Table 2

Cells were seeded at 5000 cells/well in 96-well tissue culture plates 24 h before treatment. Briefly, all cells were maintained in 10%FBS/RPMI media and incubated in a humidified incubator at 37°C with 5% CO₂. Three days after treatment, 50 ul Cell-Titer-Glo reagent (Promega) was added per well and fluorescence intensity was measured using a standard plate reader. Data was normalized to the growth rate of cells treated with DMSO between the day of treatment and day 3 (end of experiment). % Growth values around 0 represent cell stasis (complete growth inhibition) and negative values represent cytotoxicity (cell death). Results

HCC827 (TKI-sensitive) model:

In the HCC827 TKI-sensitive model (Fig. 4), we observed dose-dependent growth inhibition in response to gefitinib starting as low as 0.005 mM with cytotoxicity occurring at doses above 1 mM (Fig. 4A-B). The PKC inhibitor sotrastaurin (Fig. 4A) showed no effects on cell growth at low doses and growth inhibition only began at around 10 mM for sotrastaurin Fig. 4A). Surprisingly, Compound A (Fig. 4B) inhibited cell growth at doses as low as 1 mM (approximately 20%) with cytotoxicity at doses of 5 mM and above (Fig. 4B). Combination treatments of gefitinib with sotrastaurin show similar profiles to single agent gefitinib treatment (Fig. 4A). Combination effects of Compound A and gefitinib, however, showed similar profiles to single agent gefitinib treatment at low doses, but at doses above 0.1 mM gefitinib and 1 mM Compound A, there is cytotoxicity comparable to the effects of Compound A alone with no synergistic effect observed.

H1975 resistant) model:

In the H1975 TKI-resistant model (Fig. 5), no growth inhibition was observed with single agent gefitinib treatment (Fig. 5A-B). Single agent treatment with sotrastaurin had no observable effect on cell growth at any dose. Surprisingly, single agent treatment with the PKC inhibitor Compound A inhibited cell growth dose-dependently between 5-20 mM (Fig. 5B). The combination of any of the two PKC inhibitors at higher doses with gefitinib led to a deeper response than any of the single agents alone, however the strongest synergy was seen with Compound A where strong cytotoxic effects were observed between 10-20 mM (Fig. 5B).

HI 650 (TKI-resistant) model:

In the H1650 TKI-resistant model (Fig. 6), gefitinib single agent treatment inhibited cell growth starting at 5 mM (Fig. 6A-B), suggesting again that this model is not as resistant to TKI as H1975 (Fig. 5) but also not as sensitive to TKI as HCC827 (Fig. 4). Treatment of H1650 cells with single agent sotrastaurin shows no effect on cell growth up to 20 mM (Fig. 6A) while single agent treatment with Compound A started to inhibit cell growth at 5 mM (Fig. 6B). The combination of gefitinib with sotrastaurin did not show any synergistic effect (Fig. 6A) whereas the combination of gefitinib with either Compound A showed synergistic inhibition of cell growth only at doses above 5 mM (Fig. 6B). 10-Day Treatment Assay

Method

NSCLC cell lines HCC827, H1975 and H1650 were screened for sensitivity to the EGFR inhibitor gefitinib alone or in combination with and PKC inhibitors: sotrastaurin, and Compound A; at increasing doses according to Table 2 above, for 10 days. All cells were maintained in 10% FBS/RPMI media and incubated in a humidified incubator at 37°C with 5% CO2. In contrast to 3- day treatment assay, 500 cells/well were seeded 24 h before treatment in 48-well tissue culture plates. On day 10, media was removed from each well and cells were washed with lx PBS. Cells were fixed in 3.7% formaldehyde (1 h/RT) and then stained in 0.1% crystal violet/20% methanol (lh/RT). Stained cells were then washed using tap water to remove excess stain from each well and plates were dried overnight at RT. Crystal violet was then solubilized using lOOul of 10% acetic acid per well and the optical density of each well was measured at 590 nm using an EFISA plate reader. Average optical density of cells treated with DMSO was set to 100% and the % viable cells were calculated accordingly.

Results

HCC827 (TKI-sensitive) model:

In the HCC827 TKI-sensitive model (Fig. 1) we observed a dose-dependent response to gefitinib starting as low as 0.005 uM and with complete loss of cell viability at 1 uM (Fig. 1A-B). PKC inhibitors sotrastaurin (Fig. 1A) showed no cell viability effects at low doses and growth inhibition only began at 5 uM for sotrastaurin. Surprisingly, PKC inhibitor Compound A showed cell viability effects as low as 1 uM (70% reduction in cell viability) and complete loss of cell viability at 5 uM (Fig. IB). Combination treatments of gefitinib with each of the PKC inhibitors showed similar profiles to gefitinib treatment alone, suggesting the absence of a synergistic effect following inhibition of both EGFR and PKC signaling (Figs. 1A-B).

H1975 (TKI-resistant) model:

In the H1975 TKI-resistant model (Fig. 2), no viability effects were observed with single agent gefitinib treatment at low doses and only began at higher doses starting at 5 uM (Fig. 2A-B). Single agent treatment with the PKC inhibitor Compound A showed dose- dependent viability effects that are well-differentiated from gefitinib single agent treatment and started as low as 1 uM (Fig. 2B). These findings are unique to Compound A as sotrastaurin single agent treatment only showed viability effects at higher doses of 10 uM or above with a response profile similar to gefitinib single agent treatment (Fig. 2A). In the combination treatment arm, Compound A, showed similar response profile when used as single agents compared to when combined with gefitinib (Fig. 2B). Sotrastaurin combination with gefitinib also showed minimal synergistic effects at high doses of 10 uM sotrastaurin or higher (Fig 2A).

HI 650 (TKI-resistanf) model:

In the H1650 TKI-resistant model (Fig. 3), interestingly, gefitinib single agent treatment showed viability effects starting at 0.01 uM (Fig. 3A-B), suggesting that this model is not fully resistant to TKI as H1975 (Fig. 2) but also not as sensitive to TKI as HCC827 (Fig. 1). Treatment of HI 650 cells with single agent sotrastaurin shows no viability effects up to 20 uM (Fig. 3 A) while single agent treatment with Compound A started to show viability effects at 5 uM (Fig. 3B). The combination of gefitinib with the PKC inhibitor did not show any synergistic effects for sotrastaurin (Fig. 3A) while Compound A showed synergistic effects at high doses (Fig. 3B).

Claims

CLAIMS WHAT IS CLAIMED:

1. A method of treating NSCLC in a patient in need thereof, comprising:

determining if said NSCLC comprises at least one EGFR alteration selected from L858R, exl9del, T790M, and C797S; and

if the NSCLC comprises at least one EGFR alteration selected from L858R, exl9del, T790M and C797S, then determining if said NSCLC is resistant to one or more EGFR-TKIs; and

if the NSCLC is resistant to the one or more EGFR-TKIs, then administering to the patient a therapeutically effective amount of a PKC inhibitor of Formula (I):

wherein:

R¹ is 6-10 membered aryl, 5-10 membered heteroaryl or C_5-6 fused heteroaryl, each ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyloxy, C_6-10 aryloxy, C_{5- 10} heteroaryloxy, C_1-6hydroxyalkyl, C_1-6 alkyl-O-C_1-6 alkyl, C_1-6hydroxyalkyloxy, C_1-6 alkyl-O- C_1-6 alkyloxy, CONH₂, CONHC_1-6 alkyl, CONHC_6-10 aryl, CONHC_5-10 heteroaryl, NFL, NHC_1-6 alkyl, N(C_1-6 alkyl)₂, NHC_1-6 hydroxyalkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, S0₂NHC_6-10 aryl, SO₂NHC_{5- 10} heteroaryl and 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl wherein heterocyclyl or bridged heterocyclyl , said heterocyclyl and bridged heterocyclyl are optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN, C_1-6 alkyl, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy; R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy; and

R⁹ is independently H, 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl, each ring substituted with 1 to 4 substituents each independently selected from the group consisting of: H, ²H, amino, halo, CN, C_1-6 alkyl, C_1-6hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl, C_1-6 haloalkyl-0-C_1-6 alkyl, C_1-6 cyanoalkyl, C_1-6 alkoxy, OH, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_2-3 alkynyl, C_2-3 alkenyl, COOC_1-6 alkyl, CONH₂, CONHC_1-6 alkyl, CONHC_6-10 aryl, CONHC_{5- 10} heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_{5- 10} heteroaryl, -0-(CRR’)_n-heterocyclyl (n = 1-3 and each R is H or C_1-6 alkyl), CONH₂, said C_1-6 alkyl or -0-(CRR’)_n-heterocyclyl, said heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, SO, SO₂ each optionally substituted with 1 to 4 substituents selected from H, NH₂, OH, halo, C_1-6 alkyl, C_1-6 alkoxy and C_1-6 haloalkoxy in combination with an EGFR tyrosine kinase inhibitor (EGFR-TKI).

2. The method of claim 2, further comprising:

if the NSCLC is resistant to the one or more EGFR-TKIs, then determining if the resistance to the one or more EGFR-TKIs is mediated by at one or more PKC isoforms.

3. The method of claim 1, further comprising:

if the NSCLC is resistant to the one or more EGFR-TKIs, then determining if the resistance to the one or more EGFR-TKIs is mediated by at one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon.

4. The method of claim 1, further comprising:

if the NSCLC is resistant to the one or more EGFR-TKIs, then determining if the resistance to the one or more EGFR-TKIs is mediated by PKC delta.

5. The method of claim 4, wherein the step of determining if the resistance to the one or more TKI is mediated by PKC delta, comprises determining the presence or absence of nuclear localized PKC delta in said NSCLC wherein presence of nuclear localized PKC delta in said NSCLC is indicative that the EGFR-TKI resistance in said NSCLC is mediated by PKC delta.

6. A method of treating a NSCLC having at least one EGFR alteration selected from L858R, exl9del, T790M and C797S and which is resistant to one or more EGF-TKIs in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a PKC inhibitor of Formula (I):

wherein:

R¹ is 6-10 membered aryl, 5-10 membered heteroaryl or C_5-6 fused heteroaryl, each ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyloxy, C_6-10 aryloxy, C_{5- 10} heteroaryloxy, C_1-6 hydroxyalkyl, C_1-6 alkyl-O-C_1-6 alkyl, C_1-6hydroxyalkyloxy, C_1-6 alkyl-O- C_1-6 alkyloxy, CONH₂, CONHC_1-6 alkyl, CONHC_6-10 aryl, CONHC_{5- 10} heteroaryl, NH₂, NHC_1-6 alkyl, N(C_1-6 alkyl)₂, NHC_1-6 hydroxyalkyl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_5-10 heteroaryl and 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl wherein heterocyclyl or bridged heterocyclyl , said heterocyclyl and bridged heterocyclyl are optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl, and C_1-6 haloalkoxy;

R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy; and

R⁹ is independently H, 4-7 membered heterocyclyl or 5 to 10 membered bridged heterocyclyl, each ring substituted with 1 to 4 substituents each independently selected from the group consisting of: H, ²H, amino , halo, CN, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl, C_1-6 haloalkyl-0-C_1-6 alkyl, C_1-6 cyanoalkyl, C_1-6 alkoxy, OH, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, C_2-3 alkynyl, C_2-3 alkenyl, COOC_1-6 alkyl, CONH₂, CONHC_1-6 alkyl, CONHC_6-10 aryl, CONH C_{5- 10} heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, S0₂NHC_6-10 aryl, SO₂NHC_5-10 heteroaryl, -0-(CRR’)_n-heterocyclyl (n = 1-3 and each R is H or C_1-6 alkyl), CONH₂, said C_1-6 alkyl or -0-(CRR’)n-heterocyclyl, said heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, SO, SO₂ each optionally substituted with 1 to 4 substituents selected from H, NH₂, OH, halo, C_1-6 alkyl, C_1-6 alkoxy and C_1-6 haloalkoxy in combination with an EGFR-TKI.

7. A method of treating NSCLC having at least one EGFR alteration selected from L858R, exl9del, T790M and C797S and which is resistant to one or more EGFR-TKIs in a patient in need thereof, comprising:

determining if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms, preferably one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon;

if the resistance to the one or more EGFR-TKIs is mediated by one or more PKC isoforms, preferably one or more PKC isoforms selected from gamma, delta, eta, theta, and epsilon, then administering to said patient a PKC inhibitor of claim 1 in combination with an EGFR-TKI.

8. The method of claim 7, wherein the resistance to the one or more EGFR-TKIs is mediated by at least PKC delta.

9. The method of any one of claims 1 to 8 wherein the NSCLC comprises L858R and/or exl9del alteration, preferably L858R or exl9del alteration.

10. The method of any one of claims 1 to 8 wherein the NSCLC comprises (i) L858R and T790M, (ii) exl9del and T790M, or (iii) L858R, exl9del, and T790M alterations, preferably L858R and T790M or exl9del and T790M alterations.

11. The method of any one of claims 1 to 8 wherein the NSCLC comprises (i) L858R T790M and C797S, (ii) exl9del, T790M and C797S or (iii) L858R, exl9del, T790M and C797S alterations, preferably L858R, T790M and C797S or exl9del, T790M and C797S alterations.

12. The method of any one of claims 1 to 11 wherein the one or more EGFR-TKI is selected from gefitinib, erlotinib, icotinib, afatinib, dacomitinib, rociletinib, osimertinib, and olmutinib.

13. The methods of any one of claims 1 to 12 wherein the PKC inhibitor is a compound of Formula (II):

wherein:

R¹ is substituted 6-10 membered aryl, 5-10 membered heteroaryl having 1 to 4 heteroatoms each independently selected from the group consisting of O, N and S, said heteroaryl, fused heteroaryl, or aryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: H, ²H, halo, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, C_1-6 haloalkoxy, C_3-7 cycloalkyl, CONH₂,

CONHC_I-6 alkyl, CONHC_6-10 aryl, CONHC_5-10 heteroaryl, SO₂NH₂, SO₂NHC_1-6 alkyl, SO₂NHC6-10 aryl, SO₂NHC_{5- 10} heteroaryl and 4-7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, S and SO₂, said heterocyclyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: H, ²H, halo, CN , C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, and C_1-6 haloalkoxy;

R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optional substituted with one to two of hydroxyl, halo and C_{1 -3} haloalkoxy;

is H, ²H, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl or C_{1- 6} alkyl-O- C_1-6 haloalkyl, said C_1-6 alkyl optionally substituted with H, F, OH, C_{1 -3} alkoxy and Ci-3 haloalkoxy; R^5a and R^5b are each independently H, ²H, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with F, OH, or C 1-3 alkoxy, or R^5a and R^5b are joined together forming a methylene or ethylene bridging group; and

R^5c and R^5d are each independently H, ²H, halo, OH, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with F, OH, or C_{1 -3} alkoxy, or R^5c and R^5d are joined together forming a methylene, ethylene or -CH₂-O- bridging group.

14. The methods of any one of claims 1 to 12 wherein the PKC inhibitor is a compound of formula (III):

wherein:

X is N or CR;

R, R², R³ and R⁴ are each independently H, ²H, halo, hydroxy, C_1-6 alkoxy, C_1-6 haloalkyl or C_1-6 alkyl optionally substituted with one to two of hydroxy, halo and C_1-6 haloalkoxy;

R⁵ is -H, ²H, C_1-6 alkyl, C haloalkyl, C_1-6 hydroxyalkyl, C_1-6 alkyl-O- C_1-6 alkyl or C_1-6 alkyl-O- C_1-6 haloalkyl, said C_1-63 alkyl optionally substituted with H, F, OH, C_1-6 alkoxy and C_1-6 haloalkoxy;

R^5a and R^5b are each independently H, ²H, C_1-6 alkyl, said C_1-6 alkyl optionally substituted with H, F, OH, C_{1 -3} alkoxy and C_{1 -3} haloalkoxy or R^5a and R^5b are joined together forming a methylene or ethylene bridging group;

R^5c and R^5d are each independently H, ²H, halo C_1-6 alkyl, or C_1-6 alkoxy or R^5c and R^5d are joined together forming a methylene, ethylene or -CH₂-O- bridging group; and

R⁶, R⁷, R⁸ and R⁹ are each independently selected from H, ²H, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-7 cycloalkyl and 4-7 membered heterocyclyl, each optionally substituted with 1 to 3 substituents selected from H, halo, hydroxyl, C_2-3 alkynyl, C_2-3 alkenyl, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6haloalkyl, C_1-6 haloalkoxy and C_3-7 cycloalkyl; or

wherein R⁶ and R⁸ together with the carbon to which they are attached from form five or six membered cycloalkyl or heterocyclic ring optionally substituted with 1 to 3 groups selected from: H, ²H, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-7 cycloalkyl and 4- 7 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, S and SO₂.

15. The methods of any one of claims 1 to 12 wherein the PKC inhibitor is:

or a pharmaceutically acceptable salt thereof.

16. The methods of any one of claims 1 to 12 wherein the PKC inhibitor is:

17. The method of any one of claims 1 to 16 wherein the PKC inhibitor inhibits PKC isoforms gamma and/or delta at IC50 of less than 15 or 20 nm, preferably 10 nm.

18. The method of any one of claims 1 to 17 wherein the PKC inhibitor is administered in combination one or more of EGFR-TKIs selected from gefitinib or erlotinib.

19. The method of any one of claims 1 to 17 wherein the PKC inhibitor is administered in combination afatinib or dacomitinib.

20. The method of any one of claims 1 to 17 wherein the PKC inhibitor is administered in combination osimertinib.

21. The method of any one of claims 1 to 20 wherein the EGFR-TKI and PKC inhibitors are administered simultaneously.

22. The method of any one of claims 1 to 20 wherein the EGFR-TKI and PKC inhibitors are administered sequentially.

23. The method of claim 22 wherein EGFR-TKI is administered prior to administration of the PKC inhibitor.

24. The method of claim 22 wherein EGFR-TKI is administered after administration of the PKC inhibitor.

25. The method of any one of claims 1 to 24 wherein the chemotherapeutic agent and PKCi are administered in an amount that is synergistic.

26. The method of any one of claims 1 to 25 wherein the PKC inhibitor is compound A and is administered from about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 m/day, about 800 mg/day.

27. The method of any one of claims 1 to 25 wherein the PKC inhibitor is compound A and is administered from about 300 mg BID, about 400 mg BID, or about 500 BID.