AU2016201820B2 - Sulfonyl amide derivatives for the treatment of abnormal cell growth - Google Patents

Abstract

Abstract The present invention relates to a compound of the formula I R4 -N HN-(CR2 R3), B 5 (R)m wherein R' to R6, A, B, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the 0 treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

Description

The present invention relates to a compound of the formula I

2016201820 23 Mar 2016

Abstract

R⁵

I wherein R¹ to R⁶, A, Β, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

2016201820 04 Jul2016

SULFONYL AMIDE DERIVATIVES FOR THE TREATMENT OF ABNORMAL

CELL GROWTH

The present application is a divisional application of Australian Application No: 2014201847, which is incorporated in its entirety herein by reference.

Background of the Invention

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

This invention relates to novel sulfonyl amide derivatives that are useful in the 10 treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of the transformation of a 15 portion of its DNA into an oncogene (i.e., a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr,

FGFr, and VEGFR. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.

2016201820 04 Jul2016

- 1a Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma that expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma that does not express the EGF receptor. Thus, selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in -22016201820 23 Mar 2016 particular cancer, in mammais. in addition to receptor tyrosine kinases, selective inhibitors of certain non-receptor tyrosine kinases, such as FAK (focal adhesion kinase), lek, src, abl or serine/threonine kinases (e.g., cyclin dependent kinases), are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptor tyrosine kinase, plays an essential role in cell-matrix signal transduction pathways (Clark and Brugge 1995, Science 268: 233-239) and its aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55:

2752-2755). FAK was originally identified as a 125 kDa protein highly tyrosinephosphorylated in cells transformed by v-Src. FAK was subsequently found to be a tyrosine kinase that localizes to focal adhesions, which are contact points between cultured cells and their underlying substratum and sites of intense tyrosine phosphorylation. FAK is phosphorylated and, thus, activated in response to extracellular matrix (ECM)-binding to integrins. Recently, studies have demonstrated that an increase in FAK mRNA levels accompanied invasive transformation of tumors and attenuation of the expression of FAK (through the use of antisense oligonucleotides) induces apoptosis in tumor cells (Xu et al. 1996, Cell Growth and Diff. 7: 413-418). In addition to being expressed in most tissue types, FAK is found at elevated levels in most human cancers, particularly in highly invasive metastases.

Various compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. Five European patent publications, namely EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22,1994), EP 0 635 507 A1 (published January 25,1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties.

Also, World Patent Application WO 92/20642 (published November 26, 1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent

Applications WO96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published January 22,1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as

-32016201820 04 Jul2016 tyrosine kinase inhibitors that are useful for the same purpose. In addition, the following list of publications relate to bis-mono and bicyclic aryl and heteroaryl compounds that may optionally be used as tyrosine kinase inhibitors: WO 03/030909, WO 03/032997, US Patent Application Publication No. 2003/0181474, US Patent Application Publication

No. 2003/0162802, US Patent No. 5,863,924, WO 03/078404, US Patent No. 4,507146, WO 99/41253, WO 01/72744, WO 02/48133, US Patent Application Publication No. 2002/156087, WO 02/102783, and WO 03/063794.

U.S. Patent Application Publication No. 20040220177 relates to a broad class of novel pyrimidine derivatives that are kinase inhibitors, and more specifically, inhibitors of FAK. Moreover, U.S. Patent No. 7,107,335 relates more specifically to a subset of pyrimidine derivatives, i.e., those bearing a 5-aminooxindole, which are tyrosine kinase inhibitors, and more particularly, FAK inhibitors. Compounds such as these are useful in the treatment of abnormal cell growth.

Accordingly, a need exists for additional selective inhibitors of certain receptor and non-receptor tyrosine kinases, useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention provides novel sulfonyl amide derivatives that are kinase inhibitors and inhibitors of the non-receptor tyrosine kinase, FAK, Aurora (e.g., Aurora-1 and Aurora-2), Pyk, HgK, and are useful in the treatment of abnormal cell growth.

Summary of the Invention

According to a first aspect, the present invention provides a method of making a compound of Formula (I), the method comprising

reacting a compound of Formula (II) (II)

2016201820 04 Jul2016

- 3a -

with a compound of Formula (III), /

fe

R⁵ (III)

R⁴—N

H₂N-(CR²R³)„-Η B thereby providing the compound of Formula (I); wherein A is phenyl;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH;

each R¹ is independently selected from the group consisting of —H, halo, —CF —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(=CR⁹), —CR⁷(NR⁷R⁸)(=NR⁷), — NR⁷C(NR⁷R⁸)(=NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)C(O)R⁹, — C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, — OC(O)OR¹⁰, —S(O)jR¹¹, —S(O)(=NR⁷)R⁸, — (C_r C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅15 Cio)cycloalkenyl, —(C₆-Cio)bicycloalkyl, —(C₆-Cio)bicycloalkenyl, —(CiC₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, (C₅-Cio)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆20 Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R¹ is optionally independently substituted by one to three R¹²groups;

2016201820 04 Jul2016

-3bR²and R³are each independently selected from the group consisting of —H, halo, —OR¹⁰, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C_w)aryl and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, — (C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R²and R³is optionally substituted by one to three Regroups;

R⁴and R⁵are each independently selected from the group consisting of —H, — NR⁷R⁸, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅10 Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(CiC₉)heteroaryl moieties of said R⁴and R⁵is optionally substituted by one to three R¹² groups;

R⁶ is —CF₃;

R⁷and R⁸are each independently selected from the group consisting of —H, — OR¹⁰, — S(O)jR¹¹, —NO₂, — (Ci-C₆)alkyl, — (C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, —C₃Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, — (C₆-C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆C_w)aryl and —(Ci-C₉)heteroaryl moieties of said R⁷and R⁸is optionally substituted by one to three Regroups;

each R⁹is independently selected from the group consisting of —H, -halo, — NR¹³R¹⁴, — (Ci-C₆)alkyl, — (C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, — (C₃-Ci₀)cycloalkyl, — (C₅Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆30 C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆C_w)aryl and —(Ci-C₉)heteroaryl moieties of said R⁹is optionally substituted by one to three Regroups;

2016201820 04 Jul2016

-3ceach R¹⁰is independently selected from the group consisting of —H, —(C₂C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl — (C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₆-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R¹⁰is optionally substituted by one to three Regroups;

R¹¹ each is independently selected from the group consisting of —H, —NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(Ci-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆C_w)aryl and —(Ci-C₉)heteroaryl moieties of said R¹¹ is optionally substituted by one to three Regroups;

each R¹²is independently selected from the group consisting of —H, —OR¹³, — C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, — C(O)NR¹³R¹⁴, —

NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(=NR¹³), —NR¹³C(NR¹³R¹⁴)(=N—

C(O)R¹³), —NR¹³C(O)R¹⁴, — NR¹³S(O)jR¹³, — S(O)jR¹³, —CF₃, —CN, — (Ci-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, — (C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(Ci25 C₉)heteroaryl; wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl and —(CiC₉)heteroaryl of said R¹²is optionally independently substituted by one to three groups selected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH, —O((CiC₆)alkyl), —C(O)R¹⁵, — C(O)NR¹⁵R¹⁶, —S(O)jR¹⁵, and — S(O)jNR¹⁵R¹⁶, — (C₃Ci₀)cycloalkyl, — (C₂-C₉)heterocycloalkyl, —SH, — S((Ci-C₆)alkyl), —NH₂, — NH((CiC₆)alkyl) and — N((Ci-C₆)alkyl)₂;

R¹³and R¹⁴are each independently selected from the group consisting of —H, —NR¹⁵C(O)R¹⁶, —CF3, —CN, —S(O)jR¹⁵, — (Ci-C6)alkyl, — (C₂-C₆)alkenyl, —(C₂2016201820 04 Jul2016

-3dC₆)alkynyl, —C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(CiC₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, — (C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl and —(CiC₉)heteroaryl of said R¹³and R¹⁴is optionally independently substituted by one to three groups selected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH, —

O((Ci-C₆)alkyl), —C(O)((Ci-C₆)alkyl), —(C₃-Ci₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, — SH, —S((Ci-C₆)alkyl), —NH₂, — NH((Ci-C₆)alkyl) and — N((Ci-C₆)alkyl)₂;

R¹⁵and R¹⁶are each independently selected from the group consisting of —H, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂15 C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆20 C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl of said R¹⁵and R¹⁶is optionally independently substituted by one to three groups selected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH, —O((Ci-C₆)alkyl), —C(O)((Ci-C₆)alkyl), —(C₃-Ci₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((Ci-C₆)alkyl), —NH₂, — NH((Ci-C₆)alkyl) and — N((Ci-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned —(CiC₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and — (C₆-C₉)heterobicycloalkenyl in said R¹-R¹⁴groups may optionally and independently be replaced with —C(O)— or —C(S)—;

wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and — (C₆-C₉)heterobicycloalkenyl of said R¹ to R¹⁴ groups may optionally join to form a ring

2016201820 21 Feb 2018

N

NH

0'

3fCF.

Cl (VI) thereby providing a compound of the Formula (IV).

According to a third aspect, the present invention provides a compound of Formula (I) produced by the method of the first aspect.

According to a fourth aspect, the present invention provides a compound of Formula (IV) produced by the method of the second aspect.

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.

The present invention provides a compound of formula I:

/ '0

N

or a pharmaceutically acceptable salt thereof; wherein

2016201820 04 Jul2016

-3esystem selected from the group consisting of a —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl and —(C₄-C₉)heterocycloalkenyl; and wherein j is an integer from 0 to 2;

n is an integer from 1 to 3; and m is an integer from 0 to 3.

According to a second aspect, the present invention provides a method of making a compound of the Formula (IV), the method comprising

(IV) reacting a compound of the Formula (V) h₂n 'N' 'N (V)

SO₂CH₃ with a compound of the Formula (VI)

2016201820 23 Mar 2016

-4 A is a ring moiety selected from the group consisting of a:

(a) 4- to 7-membered carbocyclyl, (b) 4- to 7-membered heterocyclyl, (c) phenyl, and (d) 5- to 6-membered heteroaryl ring, wherein each of said 4- to 7-membered carbocyclyl and 4- to 7-membered heterocyclyl of said A group may optionally contain one or two olefinic bonds; and wherein one or two carbon ring atoms in each of said 4- to 7-membered carbocyclyl and 4- to 7-membered heterocyclic of said A group may independently optionally be replaced with one or two moieties independently selected from the group consisting of -C(O)-, -C(S)- and -C(=NR⁴)-;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH, C(NH₂)orN;

each R¹ is independently selected from the group consisting of -H, halo, -CF3,

-CN, -NO_Z, -NR⁷R⁸, -NR⁷C(NR⁷R⁸)(=CR⁹), -CR⁷{NR⁷R⁸)(=NR⁷), -NR⁷C(NR⁷R⁸)(=NR⁷),

-NR⁷C(O)R⁹, -C(O)NR⁷R^a, -C(O)R⁹, -C(O)C(O)R⁹, -C(O)OR¹⁰, -OC(O)R⁹, -OR¹⁰, -OC(O)OR’°, -S(O)jR¹¹, -S(O){-NR⁷)R⁸, -(Ci-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C-io)cycloalkyl, -(C₅-Cio)cycloalkenyl, -(C₆-Ci₀)bicycloalkyl, -(C₆-C₁₀)bicycloalkenyl, -(C₂-C9)heterocycloalkyl, -(C4-C₉)heterocycloalkenyl, -(Cs-C₉)heterobicycloalkyl, -(Ce20 C₉)heterobicycloalkenyl, -(Cs-CioJaryl, and -(Ci-C₉)heteroaryl; and wherein each of the foregoing -(Ci-Cg)alkyl, -(C₂-C₆)alkenyi, -(C₂-C₆)alkynyl, -(C3-Ci₀)cycloalkyl, -(C₅Cio)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C4-C₉)heterocycloalkenyl, -(Ce-C-tojaryl and -(Ci-Cg)heteroaryl moieties of said R¹ is optionally independently substituted by one to three R¹² groups;

R² and R³ are each independently selected from the group consisting of -H, halo, -OR¹⁰, -(Ci-C_e)alkyl, -(C₂-C6)alkenyl, -(C₂-C₆)alkynyl, -(C3-C₁₀)cycloalkyl, -(C5C₁₀)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C4-C9)heterocycloalkenyl, -(C_e-Ci₀)aryl and -(Ci-C₉)heteroaryl; and wherein each of the foregoing -(Ci-Cejalkyl, -(C₂-C₅)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cio)cyc[oalkyl, -(C5-C_i0)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, (C₄30 C₉)heterocycloalkenyl, -(C_s-C₁₀)aryl and -(C_rC₉)heteroaryl moieties of said R² and R³ is optionaliy substituted by one to three R¹² groups;

R⁴ and R⁵ are each independently selected from the group consisting of-H, NR⁷R^s, -(Ci-Ce)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Ci₀)cycloalkyl, -(C_sCiojcycioaikenyl, -(C₂-C₉)heterocycloalkyl, -(C4-C₉)heterocycloalkenyl, -(C₆-Ci₀)aryi and

-52016201820 23 Mar 2016

-(Ci-Cs)heteroaryl; and wherein each of the foregoing -(C-i-CeJalkyl, -(C₂-Ce)alkenyl, -(C₂-C6)alkynyl, -(C₃-Cio)cycloalkyl, -(C₅-Ci₉)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C₄C₉)heterocycloalkenyl, -(Ce-Cio)aryi and -(CrC₉)heteroaryl moieties of said R⁴ and R⁵ is optionally substituted by one to three R¹² groups:

R⁶ is selected from the group consisting of -halo, -NR⁷R^e, -OR¹⁰, -C(O)R⁹,

-CO₂R¹⁰, -CONR⁷R⁸, -S(O),R¹¹, -NR⁷CONR⁷R^s, and -NR⁸SO2R¹¹, -NO2, -CN, -CF₃, -(0,C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₂-C₃)perfluonnated alkyl, -(C₂C₆)perfluorinated alkenyl, -(C₃-C_s)perfluorinated alkynyl, -(C₃-C₇)cycloalkyl, -(C₅Cio)cycloaikenyl, -(C₆-C₁₀)bicycloalkyl, -(C₆-C₁₀)bicycloalkenyl, -(Ci-C₉)heterocyclyl, 10 (Ci-Cio)heterocycloalkenyl, -(C₆-C₉)heterobicycloalkyl, -(C₆-C₉)heterobicycloalkenyl, -(C₆-Ci₀)aryl, -(C,-C₉)heteroaryl, -(C₆-C,₀)perfluorinated aryl, and -(C_rC₉)perfluorinated heteroaryl; and wherein each of said -(CrC6)alkyl, -(C₂-C6)alkenyl, -(C₂-C₃)alkynyl, -(C₃C₇)cycloalkyl, -(C_s-C,o)cycloalkenyl, -(C₃-C₁₀)bicycloalkyl, -(C₆-C₁₀)bicycloalkenyi, -(Ci-Cg)heterocyclyi, -(C,-Cio)heterocycloaikenyl, -(C₆-C₉)heterobicycloalkyl,

-(C6-C₉)heterobicycloalkenyl, -(Ce-C,o)atyl, and -(CrC₉)heteroaryl moieties of said R⁶ is optionally substituted by one to three R^1Z groups;

R⁷ and R³ are each independently selected from the group consisting of -H,

-OR¹⁰, -S(O),R¹¹, -NO₂, -(CrC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -<C₃Cio)cycloalkyl, -(C₅-Cio)cycloalkenyl, -(C₃-Cio)bicycloalkyl, -(Ce-C,₀)bicycloalkenyl, -(C₂20 Cgjheterocycloalkyl, -(C₄-Cg)heterocycloaikenyl, -{C₃-C₉)heterobicycloalkyl, -(C₃C₉)heterobicycloalkenyl -{C₃-Ci₀)aryl, and *{Ci-C₉)heteroaryl; and wherein each of the foregoing -(CrCe)alkyl, -(C₂-C6)alkenyl, -(C₂-C₃)alkynyl, -(C₃-C,o)cycloalkyl, -{CsCio)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyi, -(Ce-Ciojaryl and -(Ci-C₉)heteroaryl moieties of said R⁷ and R^s is optionally substituted by one to three

R¹² groups;

each R⁹ is independently selected from the group consisting of -H, -halo, -NR¹³R¹⁴,-(C,-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C₁₀)cycloalky!, -(C₅Ci₉)cycloalkenyl, -(C₆-C₁₀)bicyc!oaikyl, -(C_e-C,o)bicycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C₄-C₉)heterocycloalkenyl, -(C₆-C₉)heterobicycloalkyl, -(C₆-C₉)heterobicycloalkenyl 30 (Cs-Cio)aryl, and -(C,-C₉)heteroaryl; and wherein each of the foregoing -(Ci-C₃)alkyi, -(C₂-C₃)alkenyl, -(C₂-C₃)alkynyl, -(C₃-C,o)cycloalkyl, -(C5-Cio)cycloalkenyl, -(C₂C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, -{C₃-C,₉}aryl and -(C,-C₉)heteroaryl moieties of said R⁹ is optionally substituted by one to three R¹² groups;

-62016201820 23 Mar 2016 each R¹⁰ is independently selected from the group consisting of-H, -(CrCgJalkyi, -(C₂-C₆)alkenyl, -(C₂-C₆)a!kynyi, -(C₃-C_1o)cycioalkyl, -{C₅-C,₀)cycloalkenyl, -(C₆Cio)bicycloalkyl, -(C_s-C_l0)bicycioalkenyl, -(C₂-C₉)heterocycloalkyl. -(C4C₉)heterocycloaikenyf, -(C₃-C₉)heterobicycloalkyi, -(Ce-C₉)heterobicycloalkenyl -(Cs5 CuOaryl, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(C_rC₆)aikyl, -(C₂C₆)alkenyl, -(C₂-C₅)alkynyi, -(Cs-C^jcycloalkyl, -(C₅-C₁₀)cycioalkenyl, -(C₂C₉)heterocycloaikyl, (C4-Cg)heterocycloalkenyl, -(C₆-C₁₀)aryl and -(C^Cgjheteroaryl moieties of said R¹⁰ is optionaily substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of-H, -NR¹³R¹⁴,

-C(O)R¹³, -CF₃, -(Ci-Cs)alkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, -(C₃-Cio)cycloalkyl, -(C5Cio)cycloalkenyl, -(C₆-Ci₀)bicycioaikyl, -(C₆-Cw)bicycloalkenyl, -(C₂-C₉)heterocycioalkyl, -(Ci-Cgjheterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(C6-C₉)heterobicycloalkenyi (C6-Cio)aryl, and -(CrCgjheteroaryl; land wherein each of the foregoing -(CrCeJaikyl, -(C₂-C₆)alkenyi, -(C₂-Cs)alkynyl, -{C₃-Ci₀)cycloalkyl, -(C₅-Ci₉)cycloalkenyl, -(C₂15 C₉)heterocycloalkyl, (C4-Cg)heterocycloalkenyl, -(C₆-Cio)aryi and -(Ci-C₉)heteroaryi moieties of said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of -H, -OR¹³, -C(O)R¹³,-C(O)OR¹³, -OC(O)R¹³, -OC(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹³C(O)NR¹³R¹⁴, -NR¹³R¹⁴, -NR¹³C(NR¹³R¹⁴)(=NR¹³), -NRⁱ³C(NR¹³R¹⁴)(=N-C(O)R¹³), -NR¹³C<O)R¹⁴,

-NR¹³S(O)jR¹³, -S(O)jR¹³, -CF3, -CN, -(CrC6)alkyl, -(C2-C5)alkenyl, -(C2-C6)alkynyl, -(C3Cio)cycloalkyl, -(Cs-Ciojcycloalkenyl, -(C6-Cio)bicycloalkyl, -(C6-Cio)bicycloalkenyl, -(C2C9)heterocycloalkyl, -(C4-C9)helerocycioaikenyl, -{Cs-C9)heterobicycioalkyl, -{CsC9)heterobicycloalkenyl, -(C5-Ci0)aryl, and -(CrC9)heteroaryl; wherein each of the foregoing -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C10)cycioalkyi, -(C525 Cio)cycloalkenyl, -(C6-Cio)btcycloalkyl, -(C6-Cio)bicycioaikenyl, -(C2-Cg)heterocycioalkyl, -(C4-C9)heterocycloalkenyl, -(C6-C9)heterobicycloalkyl, -{C6-C9)heterobicycloaikenyl, (C6-Cio)aryi, and -(Ci-Cg)heteroaryl of said R¹² is optionaily independently substituted by one to three groups selected from the group consisting of -halo, -CF3, -CN, -NO₂, -OH, O((CrC₆)alkyi), -C(O)R¹⁵, -C(O)NR¹⁵R¹⁶, -S(O)jR¹⁵, and -S(O)jNR¹⁵R¹⁶, -(C₃30 C_w)cycloalkyl, -(C₂-C₉)beterocycloalkyl, -SH. -S((C_rC₆)alkyl), -NH₂, -NH((C,-C₆)alkyl) and -N((C_rC₆)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of-H, -NR¹⁵C(O)R¹⁶, -CF3i -CN, -S(O)jR^1s, -{CrC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₃)alkynyl, -(C₃Cio)cycloalkyl, -{Cs-Ciojcycloalkenyl, -(Cg-C-iojbicycloalkyl, -(Ce-CioJbicycloalkenyl, -(C₂-72016201820 23 Mar 2016

C§)heterocycloalkyl, -(C₄-Cg)heterocycloalkenyl, -(C₆-Cg)heterobicycloalkyl, -(CqCg)heterobicyctoalkenyl, -(Cs-C^Jaryi, and -(CrCg)heteroaryl; and wherein each of the foregoing -{Ct-C₆)alkyl, -(CrCgjalkenyl, -(CrCeJalkynyl, -(C₃-Cio)cycloaikyl, ~(CsCio)cycloalkenyl, -(C₆-Ci₀)bicycloalkyl, -(Ce-Cio)bicycloalkenyl, -(C₂-Cg)heterocycioalkyl,

-(C₄-C₉)heterocycloalkenyl, -(C₆-C₉)heterabrcycloalkyl, -(Cs-Cg)heterobicycloalkenyi, (Cs-Ciojaryl, and -(Ci-Cg)heteroaryl of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3, -CN, -NO2, -OH, -O((Ci-C₆)alkyl), -C(O)((C_rC₆)alkyl), -(C3-C_io)cycloalkyl, -(C₂C₉)heterocycloalkyl, -SH. -StfCvCeJalkyl), -NH_Z, -NH((Ci-C_e)alkyl) and -N«C,-C_c)a!kyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of-H, {Ci-C₆)alkyI, -(C₂-C₆)alkenyi, -(C₂-Cs)alkynyl, -(C3-Cio)cycloalkyl, -(C₅-Ci₀)cycloaikenyl, -(C&-Cio)bicycioalkyl, -(C₈-Cio)bicycloalkenyi, -(C₂-C_g)heterocycloalkyi, -(C₄C₉)heterocycloalkenyl, -(C₆-C₉)heterobicycloalkyl, -(C₆-Cg)heferobicycloaikenyl, -(CeCio)aryl, and -(Ci-Cg)heteroaryi; and wherein each of the foregoing -(CrC₈)aikyl, -(C₂15 C₈)alkenyl, -(C₂-Cs)alkynyl, -(C3-Cio)cycloalkyl, -(Cs-Ciojcyclaaikenyl, -(C₈Cio)bicycloalkyl, -(Ce-Cio)brcycloalkenyl, ~(C₂-Cg)helerocycloalkyl, -(C₄C₉)helerocycloalkenyl, -(Ce-Cg)helerobicycloalkyl, -(C₈-C₉)heterobicycloalkenyl, -{CsCto)aryi, and -(CrCg)heteroaryl of said R^1sand R¹⁶ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3,

-CN, -NO2, -OH, -O((Ci-C₆)alkyt). -C(O)({CrC6)alkyl), -(C₃-C₁₀)cycloa]kyl, -{C₂C₉)heterocycloalkyl, -SH, -SHCrCeJalkyl), -NH₂, -NH((C_rC_e)alkyi) and -N((CvC_e)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned -(C1C₆)alkyi, -(C₂-C₆)alkenyl, -(C₂-C₆)aikynyl, -(C₃-Cio)cycloalkyl, -(C₅-Cio)cyctoatkenyl, -(C₆Cio)bicycioa!kyl, -(C₆-Ci₀)bicycloalkenyl, -(C₂-Cg)heterocycloalkyi, -(C₄25 Cgjheterocycloalkenyl, -(Cs-Cg)heterobicycloalkyl and -(Ce-Cgjheterobicycloalkenyl in said R'-R¹⁴ groups may optionally and independently be replaced with -C(O)- or-C(S)-;

wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned -(CvCejalkyl, -(C₂-C_e)alkenyl, -(C₂-C₅)alkynyl, -(C₃-C₁₀)cycloalkyl, -(C₅Cio)cycloalkenyl, -(Ce-Ciojbicycloalkyl, -(C₈-C₁₀)bicycloalkenyl, -(C₂-C_g)heterocycloalkyl,

-(C₄-C₉)heterocycloalkenyl, -(Ce-Cgjheterobicycioalkyl and -(C₆-C₉)heterobicycloalkeny of said R¹ to R¹⁴ groups may optionally join to form a ring system selected from the group consisting of a -{C₃-C₄o)cycloalkyl, -(C₅-Cio)cycloalkenyt, -(C₂-Cg)heterocycloalkyl, and -(C₄-C₃)heterocycloalkenyl; and wherein j is an integer from 0 to 2;

2016201820 23 Mar 2016

-δη is an integer from 1 to 3; and m is an integer from 0 to 3.

in one embodiment, the invention relates to a compound of formula I wherein A is a 4- to 7-membered carbocyclyl; and wherein said carbocyctyl may additionally contain one or two olefinic bonds.

In another embodiment, the invention relates to a compound of formula I wherein A is a 4- to 7-membered carbocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentendienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, and cycloheptadienyl.

In another embodiment, the invention relates to a compound of formula I wherein

A is a 4- to 7-membered heterocyclyl, and wherein said'4- to 7-membered heterocyclyl may additionally contain one or two olefinic bonds.

In another embodiment, the invention relates to a compound of formula i wherein A is a 4- to 7-membered heterocyclyl selected from the group consisting of azetidinyl, oxetanyl, pyrrofidynyl, dihydropyrazolyl, tetrahydropyrazolyf, dihydrofuranyl, tetra dydrofuranyi, dihydrothiophenyl, tetrahydrothiopenyl, dihydropyridinyi, tetrahydropyridinyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, fetrahydropyranyl, thiopyrianyl, dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, dihydroazepinyl, tetrahydroazepinyl, dihyrooxepinyi, tetrahydrooxepinyl, oxepanyl, dihyrothiepinyl, tetrahydrothiepinyl and thiepanyl.

In another embodiment, the invention relates to a compound of formula I wherein A is a phenyl.

In another embodiment, the invention relates to a compound of formula I wherein A is a 5- to 6-membered heteroaryl.

In another embodiment, the invention relates to a compound of formula I wherein

A is a 5- to 6-membered heteroaryl selected from the group consisting of furanyl, pyrrolyl, thiopenyl, thiazolyf, isothiazolyl, pyrazolyl, oxazoyi, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxadiazoyl, thiadiazoyl, and benzothiazole, benzooxazole.

In one embodiment, the invention relates to a compound of formula I wherein each R¹ is independently selected from the group consisting of-H, halo, -CF₃, -CN,

-NOz, -NR⁷R⁸, -NR⁷C(NR⁷R®)(=CR⁹), -CR⁷{NR⁷R^e)(=NR⁷), -NR⁷C(NR⁷R®)(=NR⁷), -NR⁷C(O)R⁹, -C(O)NR⁷R®, -C(O)R⁹, -C(O)C(O)R⁹, -C(O)OR¹°, -OC{O)R⁹, -OR¹⁰, -OC(O)OR¹⁰, -S(O)jR¹¹, and-S{O)(=NR⁷)R^b.

-92016201820 23 Mar 2016 ln another embodiment, the invention relates to a compound of formula I wherein R¹ is -S(O)jRⁿ.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -S(O)jR¹¹, and R¹¹ is selected from the group consisting of -H, -NR¹³R¹⁴ and -(Cr

C₆)alkyl; and wherein said -(C,-C₆)alkyl of said R¹¹ is optionally independently substituted by one to three R’² groups.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)OR¹⁰.

In another embodiment, the invention relates to a compound of formula I wherein 10 R¹ is -C(O)OR¹⁰ and R¹⁰ is -(Ci-Cejalkyl optionally substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)R⁹

In another embodiment, the invention relates to a compound of formula I wherein 15 R¹ is -C{O)R⁹ and R⁹ is selected from the group consisting of-NR¹³R¹⁴, -(Ci-Cgjalkyl and -(C₃-C₁₀)cycloalkyl; wherein each of said -(Ci-C_c)alkyl, and -(C₃-Cio)cycloalkyl of said R⁹ group is optionally substituted by one to three R¹² groups; and wherein two groups attached to the same tetravalent carbon atom of said -(CrCs)alkyl and -(C₃Cio)cycloalkyl of said R⁹ may optionally join to form a ring system selected from the group consisting of a -{Ca-C^Jcycloalkyl, -(C₅-Cio)cycloalkenyl, -(Ci-Cgjheterocycloalkyl, and -(C4'Cs)helerocycloalkenyl.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)R⁹, and R⁹ is -(C-i-CeJalkyl optionally substituted by a group selected from the group consisting of -NR¹³R⁵⁴, -NR^,5C(O)R¹⁵ and -CF₃.

In another embodiment, the invention relates to a compound of formula I wherein

R¹ is -C<O)R⁹, and R⁹ is -NR¹³R¹⁴,

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)R⁹, R⁹ is -NR¹³R¹⁴, and R¹³ and R¹⁴ are each independently selected from the group consisting of-H and -(CrCeJalkyl; and wherein said -(CrCe)alkyl of said R’³ and R¹⁴ groups is optionally independently substituted with one to three groups selected from the group consisting of -halo, -CF₃, -CN, -NO?, -OH, -OfiCrCeJalkyl), -C(O){(CtC₆)alkyl), -{C₃-Cw)cycloalkyl, -(C_rC₉)heterocycloalkyl, -SH, -S{(Ci-C₆)aIkyl), -NH?, -NH((Ci-C₆)alkyl> and -N((C_vC₆)alkyl)₂.

-102016201820 23 Mar 2016 ln another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)R⁹, R⁹ is -NR¹³R¹⁴, and R¹³ and R¹⁴ are each independently selected from the group consisting -H and -{Ci-C₆)alkyl; wherein said -(CrCeJalkyl of said R¹³ and R¹⁴ are each optionally independently substituted with one to three groups selected from the group consisting of -(C₃-Ci₀)cycloalkyl, -(Ca-Cgjheterocycloalkyl, -(C_G-Cio)aryl, and -(Cr Cg)heteroaryi; and wherein each of said -(C₃-CtG)cycloaikyl, -(C2-Cg)heterocycloalkyl, (Ce-Cio)aryl, and -(Ci-Cg)heteroaryl optional substituents of said -(Ci-Ce)alkyl of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF₃, -CN, -NO₃, -OH, -©((CrCejaikyl), -C(O)((Ci-C6)alkyl),

-(C3-Cio)cyc[oalkyi, -(C2-Cg)heterocycloalkyl, -SH, -S^CrCeJalkyl), -NH2, -NH{(CiCeJaikyI) and -NfiCrCeJalkyify

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -C(O)R⁹, R⁹ is -NR¹³R¹⁴, and R’³ and R¹⁴ are each independently selected from the group consisting of -(C₃-Ci₀)cycloalkyl and -(C2-C_g)heterocyc!oalkyl, -(C₆-Cio)aryt, and -(CrCg)heteroaryi; and wherein each of said -(C₃-C₁₀)cycloaikyl, -(C2Cs)heterocycloaikyl, -{Ce-Ctojaryl, and -(Ci-Cg)heteroaryJ of said R¹³and R¹⁴ is optionally independently substituted by one to three groups independently selected from the group consisting of -halo, -CF₃, -CN, -NO2, -OH, -O((Ci-Cs)alkyi), -C(O)((C_r Cs)alkyS), -(C₃-Cio)cycloalkyl, -(C2-C₉)heterocycloalkyl, -SH, -SCfCrCeJalkyl), -NH₂,

-NH((C_rC₀)alkyl) and -NtfCrC^alkylJg.

in another embodiment, the invention relates to a compound of formula I wherein

R¹ is -C(O)R⁹, and R⁹ is selected from the group consisting of-(C₃-Cio)cycloalkyl, -(C5Ciojcycloalkenyl, -(Ce-Ciojbicycloalkyi, -{C₆-Cio)bicycloalkenyl, -(C2-Cg)heterocycloalkyl, -{C4-Cg)heterocycloalkenyl, -(Ce-Cg)heterobicycloaikyl and -(Ce-Cg)heterobicycloalkenyl;

and wherein each of the foregoing -(Ci-Cs)alkyl, -<C₂-C₆)alkenyl, -(Cs-Csjalkynyl, -(C₃Cio)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C2-Cg)heterocycloatkyl and (C4Cg)heterocycloalkenyl moieties of said R® is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein

R¹ is -C(O)R⁹, and R⁹ is selected from the group consisting of-(C6-Ci₀)aryl, and -{CiCg)heteroaryl; and wherein each of the foregoing -(C6-Cio)aryl and -(C1-C9)heteroaryl moieties of said R⁹ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula 1 wherein R¹ is -NR⁷R⁸.

-11 2016201820 23 Mar 2016

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -NR⁷R®, and R⁷ and R® are each independently selected from the group consisting of-H,-CF₃ and -S(O)jR¹¹.

In another embodiment, the invention relates to a compound of formula I wherein 5 R¹ is -NR⁷R⁸, and R⁷ and R® are each independently selected from the group consisting of -(CrCg)alkyl, -(C₂-C6)a(kenyl and -(C₂-C₆)aikynyl; and wherein each of the foregoing -(Ci-C₆)aikyi, -(C₂-Ce)aikenyi and -(C₂-C6)aikynyl moieties of said R⁷ and R® is optionally independently substituted by one to three R¹² groups.

in another embodiment, the invention relates to a compound of formula I wherein 10 R¹ is -NR⁷C(O)R®.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -NR⁷C(O)R⁹ and R⁷ is selected from the group consisting of-H and -(C-t-C_s)alkyl; and wherein said -(Ci-Cejalkyl of said R⁷ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein

R¹ is -NR⁷C(O)R⁹ and R⁷ is selected from the group consisting of-H and -(C_rC_e)alkyi; and wherein said -(CrCs)alkyl of said R⁷ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein

R’ is -NR⁷C(O)R⁹, and R⁹ is selected from the group consisting of -H and -S{O)jR¹¹.

in another embodiment, the invention relates to a compound of formula I wherein

R¹ is -NR⁷C(O)R⁹, and R⁹ is selected from the group consisting of-H, -(C-t-CeJalkyl, -(C₂-C₆)alkenyl, -(C₂-Cs)alkynyt; and wherein said -{Ci-C₆)alkyl, -(C₂-C₆)aikenyl and -(Cz-Cejalkynyl of said R⁹ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -NR⁷C(O)R⁹ and R^9ls-(Ci-Ce)alkyl; wherein said -(CrCe)aikyl of said R⁹ is optionaiiy independently substituted by one to three R¹² groups; and wherein two groups attached to the same tetravaient carbon atom of said -(CrCgjalkyl of said R^s may optionally join to form a ring system selected from the group consisting of a -(C₃Cio)cyctoaikyl, -(Cs-C^ojcycioalkenyl, -(C₂-C₉)heterocycloalkyl, and -(C4Cgjheterocycloalkenyl.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -NR⁷C(O)R⁹ and R⁹is -(Ci-C₆)alkyi; and wherein said -(Ci-Ce)alkyl of said R⁹ is

-122016201820 23 Mar 2016 substituted by one to three R¹² groups independently selected from the group consisting of-OR¹³, -C(O)R¹³,-C{O)OR¹³, -0C(O)R¹³, -OC(C)OR¹³, -C(O)NR¹³R¹\ -NR¹³C(O)NR¹³R^m, -NR¹³R¹⁴, -NR’³C{NR¹³R©(=NR¹³), -NR¹³C(NRⁱ³R’©=N-C(O)R'³), -NR¹³C(O)R¹⁴, -NR¹³S(O)jR¹³, -S(O)jR¹³, -CF₃, and -CN.

In another embodiment, the invention relates to a compound of formula I wherein

R¹ is -NR⁷C(O)R⁹ and R⁹ is -(C,-C₆)aikyl, wherein said -(CrCgJalkyl of said R⁹ is substituted by one to three R¹² groups independently selected from the group consisting of -(CrCeJaikyl, -(Cj-CeJalkenyi and -(Cz-Csjalkynyl.

In another embodiment, the invention relates to a compound of formula I wherein 10 R¹ is -NR⁷C(O)R⁹ and R⁹ is -(C_rCs)alkyl; wherein said -(CrCeJalkyl of said R⁹ is substituted by one to three R¹² groups independently selected from the group consisting of-(C₃-Cio)cycloalkyl, -(Cs-Cio)cyctoalkenyl, -(Ce-Ciojbicycloalkyl, -(C₆Cio)bicycloalkenyl, -(Ci-Cgjheterocycloalkyl, -(C4-Cg}heterocycloalkenyi, -(C₆Ce)heterobicycloalkyl and -{Cg-Cgjheterobicycioalkenyl; and wherein each of the foregoing -(C₃-Cio)cycloatkyl, -(C₅-C_1Q)cyc!oalkenyl, -(C₆-C₁₀)bicycloa[kyl, -(C_sCi₀)bicycloalkenyl, -(C2-Cg)heterocycloalkyl, -(OrC^heterocycloalkenyl, -(CeCgjheterobicycloalky! and -(Ce-Cg)heterobicycloalkenyl of said R¹² is optionally independently substituted by one to three groups independently selected from the group consisting of-halo, -CF₃, -CN, -NO₂, -OH, -O((Ci-C₆)alkyl), -C(O)((CrC₆)alkyl), -(C₃20 Cio)cycloa!kyi, -(Cz-Cg)heterocycloalkyl, -SH, -S((Ci-C6)alkyl), -NH2, -NHfrCrCeJalkyl) and -N((C_rC₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -NR⁷C(O)R⁹ and R⁹ is -(Ci-Cgjalkyl; wherein said -(Ci-Cgjalkyl of said R⁹ is substituted by one to three R¹² groups independently selected from the group consisting of -(C6’Cio)aryl, and -(CrCg)heteroaryl; and wherein each of the foregoing -(C6-C₁₀)aryl and -(CrCg)heteroaryi of said R¹² is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF₃, -CN, -NO2, -OH, -0((Cr C₆)alkyl), -C(O)((CrC6}aikyl), -{C₃-Ci₀)cycloalkyl, -(C₂-Cg)heterocycloalkyl, -SH, -S((C_r C₆)aikyl), -NH₂, -NH((C_rC₆)alkyl) and -N({CrC₆)aikyl)2.

In another embodiment, the invention relates to a compound of formula t wherein each R¹ is independently selected from the group consisting of-{CrCgJalkyl, -(C2Cejalkenyl, and -(C2-C₆)alkynyl; and wherein each of the foregoing -{Ci-Cgjalkyl, -(C2Cgjaikenyt and -(Cz-Cgjalkynyi moieties of said R¹ is optionally independently substituted by one to three R¹² groups.

-132016201820 23 Mar 2016

In another embodiment, the invention relates to a compound of formula ϊ wherein R¹ is -(CrCejalkyl optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein each R¹ is -(Ci-Cgjalkyl is independently substituted with a group selected from the group consisting of R¹³, -S(O)jR¹³, and -NR¹³S(O)jR¹³.

in another embodiment, the invention relates to a compound of formula I wherein each R’ is independently selected from the group consisting of-(C3-Cio)cycloalkyl, -(C5Cio)cycloalkenyl, -(C₆-Cio)bicycloalkyi, -{C₆-Cio)bicycloaikenyl, -(C₂-C₉)heterocycloalkyl, -(C^-Cgjheterocycioalkenyl. -(C₆-C₉)heterobicycloalkyl and -(Cs-Cg)heterobicycloaikenyl;

and wherein each of the foregoing -(Cs-Ciojcycloalkyl, -(Cs-Cio)cycloalkenyl, -(C₂Cs)heterocycloaikyl and -{CrCgjheterocycioalkenyi moieties of said R¹ is optionally independently substituted by one to three R¹² groups,

In another embodiment, the invention relates to a compound of formula I wherein R¹ is selected from the group consisting of-(C₂-C₉)heterocycioalkyi; and wherein said

-(Ci-Cgjheterocycioalkyl of said R¹ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein each R¹ is independently selected from the group consisting of-(C6-C₁₀)aryl and -(C_r Cg)heteroaryi; and wherein each of the foregoing -(Ce-Cio)aryl and -(Ci-C₉)heteroaryl of said R¹ moieties is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein R¹ is -S(O)₂NR¹³R¹\

In one embodiment, the invention relates to a compound of formula 1 wherein R² and R³ are each independently selected from the group consisting of -H, -halo, and 25 OR¹⁰.

In another embodiment, the invention relates to a compound of formula I wherein R² and R³ are each independently selected from the group consisting of-H, -(C1Csjalkyl, -(C₂-Cs)aikenyl, and -(C₂-C6)alkynyl; and wherein each of the foregoing -(Cr Cs)aikyt, -(C₂-Ce)alkenyl, and -(C₂-C₆)alkynyl moieties of said R² and R³ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein R² and R³ are each independently selected from the group consisting of -H, -(C3Cio)cycloaikyl, -(Cs-Cio)cycloalkenyi, -(C₂-C₉)heterocycioalkyl, and -{C4C₉)heterocycloalkenyl; and wherein each of the foregoing -(Cs-Cfojcycloalkyi, -(C₅-142016201820 23 Mar 2016

Cio)cycfoalkenyl, -{C2-Cg)heterocycloalkyi, and -(C<-Cg)heterocyctoalkenyl moieties of said R² and R³ is optionally independently substituted by one to three R¹² groups.

in another embodiment, the invention relates to a compound of formula I wherein R² and R³ are each independently selected from the group consisting of -H, -(C₆5 C₁₀)aryl and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ce-Cwjaryl and -(Ci-Cg)beteroaryl moieties of said R² and R³ is optionally independently substituted by one to three R¹² groups, in one embodiment, the invention relates to a compound of formula I wherein R⁴ and R⁵ are each independently selected from the group consisting of-H, -{Ci-Cejalkyl,

-(C2-C₆)alkenyl, and -(Cj-CgJalkynyl; and wherein each of the foregoing -(CrC_s)alkyl, -(Cs-Cgjalkenyl and -(C₂-C₆)alkynyl moieties of said R⁴ and R⁵ is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein R⁴ and R⁵ are each independently selected from the group consisting of-H, -(Ci15 CeJalkyl, -(C3-C₁₀)cycloalkyl, -(C₅-Cio)cycloaikenyl, -(C2-Cg)heterocycloalkyl and -(C₄Cg)heterocycloaikenyl; and wherein each of the foregoing -(Ci-Ce)aikyl, -(C3Cic)cycloa!kyl, -(Cs-Cio)cycloafkenyl, -(C2-Cg)heterocycloalkyi, and -(C₄Cg)heterocycloafkeny( moieties of said R⁴ and R^s is optionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula I wherein

R⁴ and R⁵ are each independently selected from the group consisting of-H, -(C ₅C₆)alkyl, -(C₆-Ci₀)aryl and -(Ci-Cs)heteroaryi; and wherein each of the foregoing -{CiC6)aikyi, -(Cs-Cio)aryl and -(Ct-Cgjheteroaryl moieties of said R⁴ and R⁵ is optionally independently substituted by one to three R^1Z groups.

In one embodiment, the invention relates to a compound of formula I wherein the moiety

represents a moiety selected from the group consisting of:

2016201820 23 Mar 2016

-IS-

©NH and ©NH

S=~|

ΝγΝΗ τ r'

CHj'N'SOjCHj CH₃'^NSO₂CHj

In one embodiment, the invention relates to a compound of formula I wherein R⁶ is selected from the group consisting of -NR⁷R⁸, -OR¹⁰, -C(O)R⁹, -CO2R¹⁰, -CONR⁷R^e, -S(O)jR¹¹, -NR⁷CONR⁷R^s, -NR^eSO2Rⁿ-NO₂₍ -CN and -CF₃.

In another embodiment, the invention relates Io a compound of formula I wherein R⁶ is selected from the group consisting of -CF_3l -(Ci-C₆)alkyi, -(C₂-C₆)alkenyl, -(C₂Cejalkynyl, -(C₂-C₆)perfluorinated alkyl, -(C₂-CB)perfluorinated alkenyl, and -(C₃Ce)perfluorinated alkynyl; and wherein each of said -(Ci-Cg)aikyl, -(C₂-C6)aikenyl, -(C₂Ce)alkynyi moieties of said R⁶ is optionally independently substituted by one to three R^1Z groups.

In another embodiment, the invention relates to a compound of formula i wherein R° is -CF₃.

In another embodiment, the invention relates to a compound of formula I wherein R⁶ is selected from the group consisting of -(C₃-C7)cycloalkyl, -(Cs-Ci₀)cycloalkenyi, -(C6-Cio)bicycJoalkyJ, -{C6-Cio)bicycloalkenyJ, -(Ci-C₉)heterocyclyl, -(C_r CnJhelerocycloalkenyl, -(Ce-Cgjheterobicycloaikyl, and -(C₆-C9)heterobicycloalkenyt; and wherein each of said -(C₃-C₇)cycloalkyl, -(C5-C₁₀)cycioaikenyl, -(Co-Cio)btcyc(oalkyl,

-162016201820 23 Mar 2016

-(Cs-Cio)bicycloatkenyl,-(CrCg)heterocycIyl,-(CrCw)heterocycioaikenyt, -(Ce-Csjheierobicycloatkyf, and -(Ce-Cg)heterobicycloalkenyl moieties of said R⁶ is optionally independently substituted by one io three R^1Z groups.

In another embodiment, the invention relates to a compound of formula I wherein 5 R^c is selected from the group consisting of -(C₆-Cic)aryl, -(C-rCgJheteroaryl,

-(Ca-Cio)perfluorinated aryl and -(CrCg)perfluorinated heteroaryi; and wherein each of said -(Ce-Cio)aryl and -(C_rCg)heteroaryl moieties of said R^G is optionally independently substituted by one to three R¹² groups.

In one embodiment, the invention relates to a compound of formula I wherein K is

CH.

In another embodiment, the invention reiates to a compound of formula I wherein K is C(NH₂).

In another embodiment, the invention relates to a compound of formula 1 wherein

K is N.

in one embodiment, the invention relates to a compound of formula I wherein m is 1.

In another embodiment, the invention relates to a compound of formula I wherein m is 0.

In one embodiment, the invention relates to a compound of formula I wherein n is

1.

In another embodiment, the invention relates to a compound of formula I wherein n is 2.

In another embodiment, the invention relates to a compound of formula I wherein n is 3.

in one embodiment, the invention reiates to a compound of formula I wherein K is

CH, n is 1, and Rs is -CF3.

In one embodiment, the invention relates to a compound of formula I wherein K is CH, n is 2, and Rs is -CF3.

The present invention also provides a compound of formula la:

2016201820 23 Mar 2016

or a pharmaceutically acceptable salt thereof; wherein A is phenyl;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH, C(NH₂) or N;

each R¹ is independently selected from the group consisting of -H, halo, -CF3, -CN, -NOj, -NR⁷R®, -NR⁷C(NR⁷R^s)(=CR⁹), -CR⁷(NR⁷R³)(=NR⁷), -NR⁷C(NR⁷R³)(=NR⁷), -NR⁷C(O)R⁹, -C(O)NR⁷R®, -C(O)R⁹, -C(O)C<O)R⁹, -C(O)OR¹⁰, -OC(O)R⁹, -or¹⁰,

-OC(O)OR¹⁰, -S(O),R¹¹, -S{O){=NR⁷)R®, -(C,-C₈)alkyl. -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl,

-(C₃-C₁₀)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C₆-Cio)bicycloalkyl, -(C₆-Ci₀)bicycloalkenyl, -{Ci-Cgjheterocycloalkyl, -{C₄-C₉)heterocycloaikenyl, -(Ce-C_s)heterobicycloatkyi, -(C₆C^heterobicycioalkenyf, -(Ce-C₁₀)aryl, and -(Ci-Cgjheteroaryl; and wherein each of the foregoing -(CrC_s)alkyi, -(C₂-C₆)alkenyl, -(C₂-Cs)alkynyl, -(C₃-Ci₀)cycloaikyl, -(C₅15 Cio)cycloaikenyl, -(C₂-C₉)heterocycloaikyl, -(C₄-C9)heterocycloa!kenyl, -(C₅-C_1D)aryl and -(Ci-Cg)heteroaryf moieties of said R¹ is optionally independently substituted by one to three R¹² groups;

R² and R³ are each independently selected from the group consisting of-H, halo, -OR¹⁰, -(Ci-C₆)alkyl, -(C₂-C_s)alkenyl, -(C₂-C6)alkynyi, -(C₃-Cio)cycloalkyl, -(C520 Cio)cycloalkenyl, -(Ci-Cgjheterocycloalkyl, -(C₄-Cg)heterocyc(oalkenyl, -(C₆-Cio)aryi and -(C_t-C₉)heteroaryl; and wherein each of the foregoing -{CrCetalkyl, -(C₂-C₆)alkenyl, -(Ci-Cejalkynyl, -{C₃-Cio)cycloalkyl, -(Cs-Cio)cycioalkenyl, -(C₂-CB)heterocycloalkyl, (C₄~ Cgjheterocycloalkenyl, -(Ce-Cio)aryi and -(Ci-C₉)heteroaryl moieties of said R² and R³ is optionally substituted by one to three R¹² groups;

R⁴ and R⁵ are each independently selected from the group consisting of -H, NR⁷R^a, -(Ci-C₆)alkyl, -(C₂-C₆)alkeny(, -(C₂-C₆)alkynyi, -(C₃-Cio)cycloalkyl, -(C₅Cia)cycioaikenyl, -(C₂-C9)helerocycloalkyi, -(C₄-C₉)heterocycloalkenyl, -(Ce-CioJaryl and -(CrCg)heteroaryl; and wherein each of the foregoing -(Ci-CeJalkyl, -(C₂-C6)alkenyl,

-182016201820 23 Mar 2016

-(C₂-C₆)alkynyl, -{C₃-C_1o)cycioaikyl, -(C₅-C₁₀)cycloalkenyl, -(C₂-Cg)heterocycloalkyl, -(C₄Cg)heterocycloalkenyl, -(C_e-Ci_Q)aryl and -(Ci-Cg)heteroaryl moieties of said R⁴ and R⁵ is optionally substituted by one to three R¹² groups;

R⁶ is selected from the group consisting of -halo, -NR⁷R®, -OR¹⁰, -C(O)R⁹,

-CO₂R¹⁰, -CONR⁷R®, -S(0)jR¹¹, -NR⁷CONR⁷R⁸, and -NR®SO2R¹¹, -NO2, -CN, -CF₃, -(C_r

C₆)alkyl, -(C₂-C₆)aikenyl, -(C₂-C₆)aikynyl, -(C₂-C₆)perfluorinated alkyl, -(C2Cgjperfluorinated alkenyl, -(Ca-Cgjperfluorinated alkynyl, -(C3-C7)cycloalkyl, -{CsCio)cycloalkenyl, -(C₆-C₁₀)bicycloalkyt, -(C₆-Cio)bicycloalkenyl, -(CvCg)heterocyclyl, (Ci-C₁₀)heterocycloalkenyl, -(C₆-C₉)heterobicycloalkyl, -(C6-Cg)heterobicycloalkenyl,

-{C6-Cio)aryl, -(Ci-C₀)heteroaryl, -(Cs-CioJperfluorinated aryl, and -(CrCg)perfluorinated heteroaryl; and wherein each of said -(Ct-Cejalkyl, -{C₂-C6)alkenyl, -(C₂-C6)alkynyl, -(C₃Crjcycloalkyl, -(Cs-Cio)cycloalkenyi, -(C6-C₁₀)bicycloalkyl. -(C₆-Cio)btcycloa!kenyl, -(Ci-C₉)heterocyclyl, -(Ci-Ci_D)heterocycloalkenyl, -(C₆-C₉)heterobicycloalkyl, -(Ce-Cgjheterobicycloalkenyl, -(C6-C₁₀)aryi, and -(Ci-Cg)heteroaryl moieties of said R® is optionally substituted by one to three R¹² groups;

R⁷ and R⁸ are each independently selected from the group consisting of -H,

-OR¹⁰, -S(O)jR¹¹, -NO₂, -(C,-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyt, -(C₃Cio)cycloaikyi, -(C₅-C_l0)cycloalkenyl, -(C₆-C₁₀)bicycloalkyl, -(C₆-Cio)bicycloaikenyl, -(C₂Cg)heterocycloalkyl, -(C₄-Cg)heterocycioalkenyl, -(Cg-Cgjheterobicycloalkyl, -(Cs20 Cgjheterobicycloalkenyl -(C_e-C₁₀)aryi, and -(Ct-Cgjheteroaryl; and wherein, each of the foregoing -(Ci-C₆)alkyl. -(C₂-C₆)aikenyl, -(C₂-C6)alkynyl, -(C₃-C₁₀)cycloalkyl, -(CsCio)cycloa!kenyl, -(C₂-Cg)heterocycloalkyl, {C₄-Cg)heterocycloalkenyl, -(Cs-Cio)aryi and -(C-t-Cg)heteroaryl moieties of said R⁷ and R® is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of-H, -halo,

-NR¹³R¹⁴, -(CrCe)alkyl, -(C₂-C6)alkenyl, -{C₂-C₆)alkynyl, -{C₃-Cio)cycloalkyi, -(C5Cw)cycloalkenyl, -(C₆-Cw)bicycloalkyl, -(C₆-Ci₀)bicycloalkenyl, -(C₂-Cg)heterocycloalkyl, -{C₄-C₀)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(Cs-Cgjheterobicycloalkenyl (C₆-Cio)aryl, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(CrCeJalkyi,

-(C₂-C6)alkenyt, -(C₂-Cs)alkynyl, -(C₃-Cio)cycloalkyl, -(Cs-C^cycioalkenyl, -(C₂Cg)heterocycloalkyl, (C₄-Cg)heterocycloalkenyl, -(C₆-Cio)aryl and -(CrCg)heteroaryl moieties of said R⁹ is optionally substituted by one to three R¹² groups;

each R¹⁰ is independently selected from the group consisting of -H, -(Ci-Ce)alkyl, -(C₂-C₅)alkenyl, -(C₂-C6)alkynyl, -(C₃-Cio)cycloalkyl, -(C₅-C₁₀)cycloalkenyl, -(C_e-192016201820 23 Mar 2016

C₁₀)bicycloalkyl, -(C_s-C₁₀)bicycloalkenyl, -(C₂-C9)heterocycloaikyi, -(C₄Cg)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(Cg-Cgjheterobicycloalkenyl -(C₆Ciojaryl, and -(C_rC₉)heteroaryl; and wherein each of the foregoing -(Ct-C6)alkyi, -(C₂C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Ci₉)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C₂5 C₉)heterocycloalkyt, (C4-C₉)heterocycloalkenyl, -(C₆-Cio)aryl and -(CrCgjheteroaryi moieties of said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of-H, -NR¹³R¹⁴, -C(O)R¹³, -CF₃, -(CrCe)alkyl, -(C₂-Ce)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C_w) cycloalkyl, -(C₅Cio)cycloalkenyl, -(C₆-Cio)bicycloalkyl, -(C_c-C_l0)bicyc!oalkenyi, -(C₂-C₉)heterocycloalkyl.

-(C₄-Cs)heterocycloalkenyl, -(Cg-Cgjheterobicycloalkyl, -(Ce-Cg)heterobicycloalkenyl (Ce-Cio)aryl, and -{C_rCg)heteroaryl; land wherein each of the foregoing -(CrCgJalkyl, -(C₂-C₆)alkenyl, -<C₂-C₆)aikynyl, -(C₃-Cio)cycloalkyf, -(C₅-Cio)cycloalkenyl, -(C₂Cgjheterocycloalkyl, (C₄-C₉)heterocycloalkenyl, -(C₆-Ci₀)afyl and -(Ci-Cg)heteraaryl moieties of said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of -H, -OR¹³,

-C(O)R¹³, -C(O)OR¹³, -OC(O)R¹³, -OC(O)OR¹³, -C{O)NR¹³R¹⁴, -NRⁿC(O)NR¹³R^u, -NR¹³R¹⁴, -NR¹³C(NR^!3R¹⁴)(=NR¹³}, -NR¹³C{NR¹³R¹⁴)(=N-C(O)R¹³), -NR¹³C(O)R¹⁴, ~NR^l3S(O)jR¹³, -S(O)jR¹³, -CF3, -CN, -(C,-C6)alkyl, -(C2-C6)alkenyt, -(C2-C6)alkynyl, -(C3Cio)cycloalkyl, -{C5-Ci0)cycloalkenyl, -(C6-Ci0)bicycioalkyl, -{Cg-Ciojbicycloalkenyl, -{C220 Cg)heterocycloalkyl, -(Ci-Cgjheterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(C6Cgjheterobicycloalkenyl, -(C6-Cw)aryl, and -(Ci-Cg)heteroaryl; wherein each of the foregoing -(CrCgJalkyl, -(Cj-CeJalkenyl, -<C2-C6)alkynyl, -(C3-C-!o)cycloalkyl, -(C5Cio)cycloaikenyl, -(C6-C10)bicycloalkyt, -(Cs-C10)bicycloalkenyl, -(C2-C9)heterocycloalkyl, -(C4-C9)heterocycloalkenyl, -(C6-Cg)heterobicycloalkyl, -(Cs-Cg)heterobicycloalkenyt, 25 (C6-Cio)aryl, and -(CrCsJheteroaryl of said R¹² is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF3l -CN, -NO₂, -OH, O((Ci-C₆)alkyl), -C(O)R¹⁵, -C{O)NR¹⁵R¹⁶, -S(O)jR¹⁵, and -S(O)jNR¹⁵R¹⁶, -(C₃Ciojcycloalkyf, -{C₂-Cg)heterocycloalkyl, -SH, -S((C,-C₆)alkyl), -NH₂, -NH((C,-C_s)aikyl) and -N((Ci-C6)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of -H,

-NR^1SC(O)R⁵⁶, -CF3i -CN, -S(O)jR¹⁵, -(CrC₆)alkyl, -(C₂-C₆)alkenyl, -(Cz-Cgjalkynyl, -(C₃Cio)cycloalkyl, -(Cs-Ciojcycloalkenyl. -(Cg-Ciojbicycloalkyl, -(Ce-Ciojbtcycloalkenyl, -(C₂Cg)heterocycloaikyl, -(C₄-C₉)heterocycloalkenyl, -(C6-C₉)heterobicycloalkyi, -(C$C₉)heterobicycloafkenyf, -(C_s-Cio)aryl, and -(Ci-Cg)heteroaryt; and wherein each of the

-202016201820 23 Mar 2016 foregoing -(CrCg)alkyl, -{C₂-C6)alkenyl, -{C₂-Cg)atkynyl, -(C₃-Cio)cycloalkyl, -(CsCi₀)cycloalkenyl. ~(C_c-Cw)bicycloalkyl, -(Cg-Cio)bicycloalkenyl, -(C₂-C₉)heterocycloalkyl -(C,rC₉)heterocycIoalkenyJ, -(C_e-C₉)heterobicycloalkyl, -(Ce-Cg)heterobicycloalkenyl, (Ce-Cio)aryl, and -(Ci-C₉) heteroaryl of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF₃, -CN, -NO2, -OH, -O((Ci-Cs)alkyl), -C(O){(C,-C_e)alkyl), -(C₃-Cio)cycloalkyl, -(C₂C₉)heterocycloalkyl, -SH, -S((C_rC₆)alkyl}, -NH₂, -NH((C,-C_s)alky!) and -N((CrC₆)alky!)₂;

R^1S and R¹⁶ are each independently selected from the group consisting of-H, (Ci-Ce)atkyl, -(C2-C_G)alkenyl, -(C₂-C_G)alkynyl, -(C₃-Ci₀)cycloalkyl, -(C_s-Ci₀)cycloalkenyl,

-(Ce-Cio)bicycloalkyi, -(C_G-Cio)bicycioalkeny|, -(C₂-C₉)heterocycloaikyl, -(C4C₉)heterocycloalkenyl, -(Cg-Cs)helerobicycloalkyl, -(C₆-C₉)heterobicyc]oalkenyl, -(CgC₁₀)aryl, and -(Ci-C₉)heteroaryl; and wherein each of the foregoing -(CrCg)alkyl, -(C₂C₆)alkenyl, -(C₂-C_G)alkynyl, -(C₃-Cio)cycloalkyl, -(Cs-Cw)cycloalkenyl, -(C₆Cio)bicycloalkyt, -(Cg-Cio)bicyc!oalkenyl, -(C₂-C₉)heterocycloalkyl, -(C,r

C₉)heterocycloalkenyl, -(Cg-Cg)heferobicycloalkyi, -{Cg-C₉)heterobicycloalkenyl, -{CeCio)aryl, and -(Ci-C₉)heteroaryl of said R^,5and R¹⁶ is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF₃, -CN, -NO_Z, -OH, -O((C,-C₆)alkyl), -C(O)((C_rC₆)alky(), -(C₃-Cw)cycloalkyl, -(C₂C_B)heterocycloalkyl, -SH, -S((C,-C₆)alkyl), -NH₂, -NHfiCrCgJalkyl) and -N((Ci-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned -(C)Cejalkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -{C₃-C₁₀)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C_GCio)bicycloalkyl, -(C_s-Ci₀)bicyc)oalkenyl, -(C₂-Cg)heterocycloalkyl, -(C₄C₉)heterocycloalkenyl, -(Cs-C₉)heterobicycJoaikyi and -(Cg-C_s)heterobicycloalkenyi in said R¹-R¹⁴ groups may optionally and independently be replaced with -C(O)- or -C(S)-;

wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned -(C,-C₆)alkyl, -(C₂-Cg)alkenyl, -(C₂-C_G)alkynyl, -(C₃-Cio)cycloalkyl, -{C₅Cio)cycloalkenyl, -(Cg-C-ioJbicycloalkyl, -(Cg-Cio)bicycloalkenyi, -(C₂-C₉)heterocycloalkyi, -{C₄-C₉)heterocycloalkenyl, -(Cg-Cgjheterobicycloalkyl and -{Cg-Cgjheterobicycloalkeny of said R¹ to R¹⁴ groups may optionally join to form a ring system selected from the group consisting of a -(C₃-Cio)cycloalkyl. -(C₅-Cio)cycloalkenyf, -(C₂-C₉)heterocyctoalkyl, and -fC4-Cg)heierocycloalkenyl; and wherein j is an integer from 0 to 2; n is an integer from 1 to 3: and m is an integer from 0 to 3.

2016201820 23 Mar 2016

-21 In another embodiment, the invention relates to a compound of formula la wherein at least one R¹ is -C(O)OR¹⁰.

In another embodiment, the invention relates to a compound of formula la wherein at least one R¹ is -C(O)OR^1(J and R¹⁰ is -(Ct-Cejaikyl optionally substituted by one to three R¹² groups.

In another embodiment, the invention relates io a compound of formula Ia wherein at least one R¹ is -C(O)R⁹,

In another embodiment, the invention relates to a compound of formula la wherein at ieast one R¹ is -C(O)R⁹ and R⁹ is selected from the group consisting of10 NR¹³R¹⁴, -{Ct-CeJaJkyl and -(C3-C₁₀)cycloaikyl; wherein each of said -(C_rC_e)alkyl, and

-(C₃-Ci₀)cycioalkyi of said R⁹ group is optionally substituted by one to three R¹² groups; and wherein two groups attached to the same tetravaient carbon atom of said -(Cr Cgjafkyl and -(C₃-Ci_O)cycloaikyl of said R® may optionally join to form a ring system selected from the group consisting of a -(C₃-Cio)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C215 C₉)heterocycloalkyl, and -(C4-C₉)heterocycloalkenyl.

in another embodiment, the invention relates to a compound of formula la wherein at least one R¹ is -C(O)R⁹ and R⁹ is -(Ci-Ce)alkyl optionally substituted by a group selected from the group consisting of-NR¹³R¹⁴, -NR¹⁵C(O)R¹⁶ and -CF₃.

in another embodiment, the invention relates to a compound of formula la wherein at least one R¹ is -C(O)R⁹ and R⁹ is -NR¹³R¹⁴.

In another embodiment, the invention relates to a compound of formula ia wherein at least one R¹ is -C(O)R⁹, R⁹ is -NR¹³R¹⁴, and R¹³ and R¹⁴ are each independently selected from the group consisting of-H and -(CrCe)alkyl; and wherein said -(Ci-Cgjalkyl of said R¹³ and R¹⁴ groups is optionaiiy independently substituted with one to three groups selected from the group consisting of -halo, -CF₃, -CN, -NO₂, -OH, -O((Ci-C_s)alkyl), -C(O)((Ci-C₆)aikyl), -(C₃-C_t0)cycioalkyI, -(C₂-C₉)heterocycioalkyl, -SH, S((Ci-C₆)alkyl), -NH₂, -NH((C_rC₆)alkyl) and -N({C_rC6)alkyi)₂.

in another embodiment, the invention relates to a compound of formula la wherein at least one R¹ is -C(O)R⁹, R⁹ is -NR¹³R¹⁴, and R¹³ and R¹⁴ are each independently selected from the group consisting -H and -(Ci-Cejalkyl; wherein said -(C-s-CsJaikyl of said R¹³ and R¹⁴ are each optionally independently substituted with one to three groups selected from the group consisting of -{C₃-Cio)cycloaikyl, -(C₂C₉)heterocyctoalkyl, -(C6-C₁₀)aryl, and -(Ci-Ca)heteroaryt; and wherein each of said -(C₃C₁₀)cycloalkyl, -{C₂-C₉)heterocycloalkyl, -(C6-Cio)aryi, and -(Ci-Cs)heteroaryi optional

-222016201820 23 Mar 2016 substituents of said -(CrCeJalkyl of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3, -CN, -NO?, -OH, -O((C,-C₆)alkyl). -C(O)((C_rC₆)alkyl), -(C₃-Cio)cyctoaikyl, -<C₂C₉)heterocycloalkyl. -SH, -S((C,-C₆)alkyl), -NH₂, -NH((C_rC_e)alkyl) and -N((C_rC₈)alkyl)₂.

In another embodiment, the invention relates to a compound of formula la wherein m is 1.

The present invention also provides a compound of formula lb:

or a pharmaceutically acceptable salt thereof; wherein A is phenyl;

B is phenyl or a 5- to δ-membered heteroaryl;

K is CH. C(NH₂) or N;

at least one R¹ is -(CrCe)alkyl optionally independently substituted by one to three R¹² groups;

R² and R³ are each independently selected from the group consisting of-H, halo, -OR¹⁰, -(Ci-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C_to)cycloalkyl, -(C₅Cio)cyctoalkenyl, -(C₂-Cg)heterocycloalkyl, -(C₄-Cg)heterocyctoalkenyl, -(C6-Cio)aryl and -(Cj-CgJheteroaryt; and wherein each of the foregoing -(Ci-Cejalkyl, -(C₂-C6)alkenyl,

-(C₂-C₆)alkynyl, -(C₃-Ci₀)cycloalkyi, -{C_s-C_1Q)cycloalkenyi, -(C₂-C₉)heterocycloalkyl, (C₄Cg)heterocycloaikenyl, -{Ce-CioJaryl and -(CrCg)heteroaryl moieties of said R² and R³ is optionally substituted by one to three R¹² groups;

R⁴ and R^s are each independently selected from the group consisting of-H, NR⁷R^e, -(CrCe)alkyl, -(C₂-C₆)alkenyl, -{C₂-C6)alkynyl, -(C3-Cio)cycloalkyl, -(C₅25 Cio)cycloalkenyl, -(C₂-Cg)heterocycioaikyl, -(C₄-Cg)heterocycloalkenyl, -(Cs-Cio)aryl and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ct-Cejaikyl, -(C₂-C6)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cio)cycloalkyt, -(Cs-Cw)cycloalkenyl, -(C₂-Cg)heterocycloalky!, -(C₄-232016201820 23 Mar 2016

Cgjheterocycioalkenyl, -(C₆-C₁₀)aryl and -(C,-C₉)heteroaryl moieties of said R⁴ and R^s is optionally substituted by one to three R¹² groups;

R⁶ is selected from the group consisting of-halo, -NR⁷R⁸, -OR¹⁰, -C(O)R⁹, -CO2R¹⁰, -CONR⁷R⁸, -S(O),R¹¹. -NR⁷CONR⁷R⁸, and -NR⁸SO2R¹¹, -NO2. -CN, -CF₃, -(0,5 C_B)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)aikynyl, -(C₂-C_e)perfluorinated alkyl, -(C₂C₅)perftuorinated alkenyl, -(C₃-C₆)perfluorinated alkynyl, -(C₃-C₇)cycloalkyl, -(C₅Cio)cycioalkenyl, -{C_B-C,o)bicycloalkyl, -(C_B-Cio)bicycloalkenyl, -(C,-C₉)heterocyclyl, (CrC,₀)heterocycloalkenyi, -(C₆-Cg)heterobrcycioalkyl, -(C_B-Ca)heterobtcycloalkenyl₍ -(Ce-C,o)aryl, -(Ci-Cg)heteroaryl, -(C6-C,o)pertluorinated aryl, and -(Ci-C₉)perfluorinated heteroaryl; and wherein each of said -(CrC_B)alkyl, -(C₂-Cs)alkenyl, -(C₂-C₆)alkynyi, -(C₃C₇)cycloalkyl, -(C_s-C,o)cycloaikenyl, -(Ce-Cio)bicycloalkyl, -(C_B-Ci₀)bicycloaikenyI, -(Ci-Cg)heterocyclyl, -(Ci-Cio)heterocycloalkenyl, -(C₆-C₉)heterobicycloatkyl, -(Ce-Cg)heterobicycloaikenyi, -(Ce-Cio)aryi, and -(CrCg)heteroaryi moieties of said R⁶ is optionally substituted by one to three Regroups;

R⁷ and R^s are each independently selected from the group consisting of -H,

-OR¹⁰, -S(O)jR¹¹, -NO2, -(C_rC₆)alkyl, -{C₂-C₆)alkenyl, -(C₂-C_s)alkynyl, -(C₃Ci_C)cycloalkyl, -(C₅-Cio)cycloalkenyl, -{C_s-C,₀)bicycloalkyi, -(C_G-C₁₀)bicycloalkenyl, -(C₂Cg)heterocycloalkyl, -(CrCgJheterocycloalkenyl, -(Ce-Cg)heterobicycloalkyl, -(C_BCo)heterobicycloalkenyl -(C_B-Ci₀)aryl, and -(CrCg)heteroaryi; and wherein each of the foregoing -(C,-C₆)alkyi, -(C2-C_B)alkenyl, -(C₂-C_B)alkynyl, -(C3-Cio)cycloalkyl, -(C₅C,₀)cycloalkenyl, -{C2-C₉)heterocycloaikyl, (C4-Cg)heterocycloalkenyl, -(C6-Cio)aryl and -(C,-Cg)heteroaryl moieties of said R⁷ and R⁸ is optionally substituted by one to three R^1Z groups;

each R⁹ is independently selected from the group consisting of -H, -halo,

-NR¹³R¹⁴, -{C,-C_B)alkyl, -{C₂-C₆)aikenyl, -(C2-C_B)alkynyl, -(C₃-Cio)cycloalkyl, -(C_sC,o)cycloalkenyl, -(Cg-CioJbicycloalkyl, -(Cs-C,_o)bicycloalkenyl, -(C2-C_g)heterocycloalkyl, -(C4-Cg)heterocycloaikenyl, -(C₆-Cg)heterobicycloalkyl, -(Cg-Cgjheterobicycloaikenyl (Ce-Cio)aryl, and -{Gi-Cg)heteroaryl; and wherein each of the foregoing -(C,-C_B)alkyl, -(C₂-C6)aikenyl, -{C2-C_B)aikynyl, -(C₃-C,o)cycloalkyl_t -{C₅-Cio)cycloaikenyl, -(C₂30 Cgjheterocycloaikyi, (C4-C₉)heterocycloaikenyl, -{Ce-Ciojaryl and -(C_rC₉)heteroaryl moieties of said R⁹ is optionally substituted by one to three R¹² groups;

each R¹⁰ is independently selected from the group consisting of-H, -(Ci-Cs)alkyl, -(C₂-C_B)alkenyl, -(C₂-C₅)alkynyl, -(C₃-Ci_O)cycloalkyl, -(C₅-C₁₀}cycloalkenyl, -(C₆C₁₀)bicycloalkyl, -(C₆-C₁₀)bicycloalkenyl, -{C2-C₉)heterocycloalkyl, -(C4-242016201820 23 Mar 2016

Cgjheferocycloalkenyt, -(Cs-Cgjheterobicycloalkyi, -(Ce-Cg)heterobicycloalkenyl -(Ce* Cio)ary!, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ci-Cgjalkyl, -(C₂C₆)alkenyJ, -(C₂-C₆)alkynyl, -{C₃-C_l0)cycloalkyl, -{C₅-C_1o)cycloalkenyt, -{C₂Cg)heterocycloalkyi, (C^CgJheterocycloalkenyl, -(Ce-Cio)aryi and -(Ci-Cg)heteroaryi moieties of said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of -H, -NR¹³R¹⁴,

-C(O)R¹³, -CF₃₎ -(CvCeJalkyl, -(C₂-C6)alkenyl, -(C₂-C₆)alkynyl, -{C₃-Cio)cycloalkyl, -(C_sCio)cycloalkenyl, -(C6-Cio)bicycloalkyl, -(Cs-CuObicycIoaikenyl, -(C₂-Cg)heterocycloalkyl, -(C4-C₀)heterocycfoalkenyl, -(C₆-C0)heterobicycloaikyl, -(Cs-Cgjheterobicycloalkenyi 10 (Cg-Ciojaryi, and -(CrCg)heteroaiyt; land wherein each of the foregoing -(Ci-C₆)alkyl, -(C₂-C₆)alkenyl, -(Cz-C₆)alkynyl, -(C₃-Ci₀)cycloalkyl, -(Cs-Cto)cycloaikenyl, -(C₂Cg)heterocycloalkyl, (Ci-Cgjheterocycloalkenyl, -(C_G-Cio)aryl and -(CrCgJheteroaryl moieties of said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of-H, -OR¹³,

-C(O)R¹³, -C(O)OR¹³, -OC(O)R¹³, -OC(O)OR¹³, -C(O)NRⁿR¹⁴, -NR¹³C(O)NR¹³R¹⁴,

-NR¹³R¹⁴, -NR¹³C{NR¹³R¹⁴X=NR’³), -NR¹³C(NR¹³R¹⁴){=N-C(O)R¹³), -NR¹³C(O)R¹⁴, -NR¹³S{O)jR¹³, -S{O)jR¹³, -CF₃, -CN, -(C_rC_G)alkyl, -(C₂-C_G)alkenyl, -(C₂-C₆)alkynyl, -(C₃Cio)cycloalkyl, -(C5-Ci₀)cycloalkenyl, -(C₆-C₁₀)bicycloalkyl, -(Ce-Ci₀)bicycfoaikenyl, -(C₂Cg)heterocyc!oalkyl, -(C₄-C₀)heterocycioalkenyi, -(Cs-Cs)heterobicycioalkyl, -(C_G20 Cs)heterobicycloalkenyl, -(Ce-C-ioJaryl, and -(Ci-Cg)heleroaryl; wherein each of the foregoing -(CrCgJalkyl, -(C2-C6)alkenyl, -(C₂-C_G)alkynyl, -(C₃-Cn>)cycloalkyl, -(CsCio)cycioalkenyl, -(C_s-Ci₀)bicycloaikyl, -(C_G-Cio)bicycloaikenyI, -(C₂-C9)heterocycloalkyt, -(C4-Cg)heterocycloalkenyl, -{C6-Cg)heterobicycloalkyi, -(C_G-Cg)heterobicycloalkenyi, (C₆-Cio)aryl, and -(Ci-Cg)heteroaryl of said R¹² is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF₃, -CN, -NO₂, -OH, O((C_rC₆)alkyl), -C(O)R¹⁵, -C(O)NR^1sR^,e, -S(O)jR¹⁵, and -S(O)jNR¹⁵R¹⁶, -(Cr Cio)cycloalkyl, -(C₂-Cg)heterocycloalkyl, -SH, -SfiCrCeJalkyi). -NH₂, -NH((CrC₆)alkyl) and -N{(Ci-C₆)alkyi)2;

R¹³ and R¹⁴ are each independently selected from the group consisting of -H,

-NR^1SC(O)R¹⁶, -CF3, -CN, -S(0)jR¹⁵, -(C,-Cs)aikyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -{C₃C,₀)cycloalkyl, -{C5-C_w)cycloalkenyl, -(Ce-CioJbicycioalkyl, -(C_G-C_1o)bicycloalkenyl, -(C₂Cgjheterocycloalkyi, -{C₄-Cg)heterocycloalkenyl, -(C₆-Cg)heterobicycioalkyl, -(CeCgjheterobicycloalkenyl, -{C_G-Ct₀)aryi, and -(Ci-C₉)heteroaryl; and wherein each of the foregoing -(Ci-Ce)alkyl, -(C₂-C_G)alkenyi, -(C₂-C₆)alkynyl, -(C₃-Cig)cycloalkyl, -(C₅-252016201820 23 Mar 2016

Cio)cycloalkenyl, -(C_e-Ci_O)bicycloalkyJ, -(Ce-Cio)bicycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C^-Cgjheterocycloalkenyi, -(C₆-C₉)heterobicycloaikyl, -(C₆-C₉)heterobicycloa!kenyl. (C₆-C,o)aryl, and -{Ci-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF3,

-CN, -NO2, -OH, -O((C,-C₆)alkyi), -C(O)((C_vC₆)alkyl), -(C₃-C,₀)cycloalkyl, -(C₂Cg)heterocycfoalky|, -SH, -S((Ci-C₆)alkyl), -NH₂, -NH((Ci-C₉)alkyl) and -N((Ci-Ce)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of -H, (CrC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)aikynyi, -(C₃-Cio)cycloalkyi, -{Cs-Cio)cycloalkenyl, -(Ce-Ciojbtcycloalkyl, -(Ce-Ciojbicycloalkenyl, -(Ci-Cgjheterocycloafkyl, -(C410 C₉)heterocycloalkenyi, -(C6-C₉)heterobicycloalkyl, -(Ce-Cgjheterobicycloalkenyi, -(CeCio)aryl, and -{CrC₉)heteroaryi; and wherein each of the foregoing -{CrC_B)alkyl, -{C₂Cs)alkenyl, -(C2-Ce)alkynyl, -(C₃-Cio)cycloaikyf, -(C₅-Cio)cycloalkenyl, -(CgCio)bicycloalkyi, -(Ce-Cw)bicycloalkenyl, -(C2-Cg)heterocycloalkyl, -(C4C₉)heterocycloalkenyl, -(Ce-C₉)heterobicycloalkyl, -(Ce-C₉}heterobicycloalkenyi, -(C_e15 C₁₀)aryi, and -{Ci-C₉)heteroaryi of said R¹⁵and R¹⁶ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF₃,

-CN, -NO_Z> -OH, -O((C,-C₆)alkyl), -C(O)«C,-C₆)alkyl), -(C₃-C₁₀)cycloalkyl, -(C₂Cgjheterocycloalkyi, -SH, -S((C_rCs)alkyl), -NH_Z, -NH((C_rC₆)alkyi) and -N((C_rC₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned -(Ci20 C_c)alkyl, -(C₂-C6)alkenyi, -(C2-C_s)alkynyl. -(C₃-Ci₀)cycloalkyl, -{Cs-C₁₀)cycloalkenyl, -(CeCio)bicycloalkyl, -(Cs-Cio)blcycloalkenyl, -(C₂-Cg)heterocycloaikyl, -(C4C₉)heterocycloalkenyl, -(Cg-C₉)heterobicycloalkyl and -(C₆-C₉)heterobicycloalkenyl in said R¹-r¹⁴ groups may optionally and independently be replaced with -C(O)- or -C(S)-;

wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned -(Ci-Cgjaikyi, -{C₂-C6)alkenyl, -(C₂-Ce)alkynyl, -(C₃-Cio)cycloalkyl, -(C5Cio)cycloalkenyl, -(Cg-Ciojbicycloalkyl, -(C₆-C₁Q)bicycloalkenyl, -(C₂-Cg)heterocycloalkyl, -(C4-C₉)heterocycloalkenyi, -(Ce-Cg)heterobicycloalkyl and -(C₆-C₉)heterobicycloalkeny of said R¹ to R¹⁴ groups may optionally join to form a ring system selected from the group consisting of a -(C₃-C₁₀)cycloalky!, -(C_s-Cio)cycloalkenyl, -(C₂-C₉)heterocycloalkyl, and -(C«i-Cg)heterocycloaikenyl; and wherein j is an integer from 0 to 2; n is an integer from 1 to 3; and m is an integer from 0 to 3.

-262016201820 23 Mar 2016 ln another embodiment, the invention relates to a compound of formula la or 1b wherein R² and R³ are each independently selected from the group consisting of-H, halo, and -OR¹⁰.

In another embodiment, the invention relates to a compound of formula la or 1b wherein R⁴ and R⁵ are each independently selected from the group consisting of-H,

-(CrCgJalkyl, -(C2-C6)alkenyl, and -(Ca-Cejalkynyl; and wherein each of the foregoing -(Ci-C₆)alkyi, -(Ci-Cejaikenyl and -(Cz-Csjalkynyl moieties of said R⁴ and R® is optionally independently substituted by one to three R¹² groups.

in another embodiment, the invention relates to a compound of formula fa or 1b 10 wherein R® is-CF₃.

tn another embodiment, the invention relates to a compound of formula la or 1b wherein K is CH.

In another embodiment, the invention relates to a compound of formula la or 1b wherein m Is 1.

In another embodiment, the Invention relates to a compound of formula la or 1b wherein n is 1.

The present invention provides a compound of formula fc:

/

HN

N

R⁴-N (R¹)m

Ic or a pharmaceutically acceptable salt thereof; wherein the moiety R⁵

/

R⁴-N

HN-(CR'R³),

-272016201820 23 Mar 2016 represents a moiety selected from the group consisting of:

f^NH

Λη

Stz-j

N^S

CHj'^N'SO2CH3 CHj'^N‘SO2CH₃

A is a ring moiety selected from the group consisting of a:

(a) 4- to 7-membered carbocyciyl, (b) 4- to 7-membered heterocyclyl, (c) phenyl, and (d) 5- to 6-membered heteroaryl ring, wherein each of said 4- to 7-membered carbocyciyl and 4- to 7-membered heterocyclyl of said A group may optionally contain one or two oiefinic bonds; and wherein one or two carbon ring atoms in each of said 4- to 7-membered carbocyciyl and 4- to 7-membered heterocyclic of said A group may independently optionally be replaced with one or two moieties independently selected from the group consisting of -C(O)-, -C(S)- and -C(=NR⁴)-;

Kis CH, C(NH₂) ofN;

each R* is independently selected from the group consisting of -H, halo, -CF3, -CN, -NO2, -NR⁷R^s, -NR⁷C(NR⁷R⁸)(=CR⁹), -CR⁷(NR⁷R⁸)(=NR⁷), -NR⁷C{NR⁷R^b)(=NR⁷),

-282016201820 23 Mar 2016

-NR⁷C(O)R⁹, -C(O)NR⁷R⁸, -C(O)R⁹, -C(O)C(O)R^S, -C(O)OR¹⁰, -OC(O)R⁹, -or¹⁰, -OC(O)OR¹⁰, -S{O)jR¹¹, -S<O){=NR⁷)R^a, -(C,-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Ci₀)cyc!oalkyl, -{C_s-Ci_O)cycloalkenyl, -(C6-Cio)bicycloalkyl, -(C₆-Cio)bicyctoalkenyl, -{C₂-C₉)heterocyc1oalkyl, -(C.4-Cg)heterocycloalkeny!, -(Cg-Cgjheterobicycloalkyl, -(Cg5 Cg)heterobicycloalkenyl, -(Cg-Ciojaryl, and -(CrCg)heteroaryl; and wherein each of the foregoing -(CrCgJalkyl, -(Ci-Cgjalkenyl, -(C₂-Csjalkynyl, -(C₃-C₁₀)cycloalkyl, -(C₅Ci₀)cycloalkenyl, -(C₂-Cg)heterocycloalkyi, -{CU-CgJheterocycloalkenyl, -(Ce-Cho)aryl and -(Ci-Cg)heteroaryl moieties of said R¹ is optionally independently substituted by one to three R¹² groups;

R® is selected from the group consisting of -halo, -NR⁷R®, -OR¹⁰, -C(O)R⁹,

-CO_ZR¹⁰, -CONR⁷R⁸, -S(O)jR¹¹, -NR⁷CONR⁷R⁸, and -NR^aSO2R¹¹, -NO2, -CN, -CF₃, -(C, Cejalkyl, -(C₂-C₆)alkenyl, -{C₂-C_e)alkynyl, -(C₂-C_e)perfluorinafed alkyl, -(C₂C₆)perfluorinated alkenyl, -(C₃-C₆)perfluorinated alkynyl, -{C₃-C₇)cycloalkyl, -(CsCio)cycloalkenyl, -(C_e-Ci₀)bicycloalkyl, -(Ce-Ciojbicycloalkenyl, -{Ci-C₉)heterocyclyi, 15 (C_rCi₀)heterocycloalkenyl, -(C₆-Cg)heterobicycloalkyl, -(Ce-Cgjheterobicycloaikenyl, -(C_s-Cio)aryl, -(Ci-Cg)heteroaryl, -(C6-Cio)perfluorinated aryl, and -(Ci-Cg)perfluorinaied heteroaryl; and wherein each of said -(Ci-C₆)aikyi, -(Cz-Cejalkenyl, -{C₂-C6)alkynyl, -(C₃C₇)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C6-C₁₀}bicycloalkyl, -(C₆-Ci₀)bicycloalkenyl, -(Ci-Cg)heterocyclyl, -{Ci-Cio)heterocycloalkenyl, -{C₆-C_g)heterobicycloalkyl,

-(Cg-Cgjheterobicycloalkenyl, -{Cg-CwJaryl, and -(CrCg)heteroaryl moieties of said R® is optionaliy substituted by one to three Regroups;

R⁷ and R⁸ are each independently selected from the group consisting of-H, -OR¹⁰, -S(O)jR¹¹, -NO₂, -(C_rC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃CwJcycloalkyl, -(C₅-Cio)cycloalkenyl, -(C₆-C₁₀)bicycioalkyl, -{C₆-Cio)bicycloalkenyl, -(C₂25 Cgjheterocycloalkyl, -(C^-Cgjheterocycloalkenyl, -(C₆-Cg)heterobicycloalkyl, -(CgCgjheterobicycloalkenyl -(C₆-Cio)aryt, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ci-C₆)alkyl, -(C₂-C₆)alkenyi, -(C₂-C₆)alkynyl, -(C₃-Ci₀)cycloalkyl, -(CsCto)cycloalkenyi, -(C₂-Cg)heterocycloalkyl, (C^-Cglheterocycloatkenyl, -(Cg-Ciojaryl and -(CrCg)heteroaryl moieties of said R⁷ and R^a is optionally substituted by one to three

R¹² groups;

each R⁹ is independently selected from the group consisting of -H, -halo, -NR¹³R¹⁴,-(CrC₆)alkyi, -(C₂-C6)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C₁₀)cycloalkyl, -(C₅Ciojcycloalkenyl, -(Cg-Ciojbicycioalkyl, -(Cg-Cio)bicycloalkenyl, -(C₂-Cg)heterocycloalkyl, -(C4-C_g)heterocycloalkenyl, -(Cg-Cgjheterobicycloalkyl, -(Ce-Cg)heterobicycloalkenyl -292016201820 23 Mar 2016 (Ce-Ciojaryl, and -(CrCg)heteroaryl; and wherein each of the foregoing -(CrCeJaikyl, -(C₂-C₆)alkenyl, -(C₂-C₆)a!kynyl, -(C₃-C₁₀)cycloalkyl, -(C_s-Cio)cycloalkenyl, -(C₂Cg)heterocycloalkyl, (C^-Cgjheterocycioaikenyl, -{C6-C_J0)aryl and -(C_rC₉)heteroaryl moieties of said R⁹ is optionally substituted by one to three R¹² groups;

each R¹⁰ is independently selected from the group consisting of -H, -(Ct-Cs)alkyl,

-(C₂-C₆)alkenyl, -(C₂-C6)alkynyi, -(C₃-C₁₀)cycloalkyl, -(Cs-Cnjjcycloalkenyl, -(C₉Cio)bicycloalkyi, -(C_Q-C₁₀)bicycloalkenyi, -(C₂-C₉)heterocycloalkyl, -(C4C₉)heterocycloalkenyl, -(CG-Cg)heterobtcycloalkyi, -(C_e-C₉)heterobicycloalkenyl -(C₆Cio)aryl, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(CrCe)alkyl, -(C₂10 C₆)alkenyl, -(C₂-Cg)alkynyl, -{C₃-Cio)cycloalkyl, -(Cs-Cwjcycloalkenyl, -(C₂Cg)heterocycloatkyl, {C4-C₉)heterocycloalkenyl, -(Ce-Cio)aryl and -(CrC₉)heteroaryl moieties of said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of-H, -NR¹³R¹⁴, -C(O)R¹³, -CF₃, -(C,-C_e)a!kyl, -(C₂-C₆)alkenyl, -{C₂-C_B)aikynyl, -(C₃-Cw)cycloalkyl, -(C₅15 Cio)cycioaikeny(, -(Ce-Cw)bicycloalkyl, -(C₆-Cio)bicycloalkenyl, -(C₂-C₉)heterocycloalkyl, -(C4-C₉)heterocycloalkenyl, -(Ce-Cg)heterobicycloalkyi, -(Cs-C₉)heterobicycloalkenyl (Ce-Ciojaryl, and -(Ci-Cg)heteroaryl; land wherein each of the foregoing -(Ci-C_B)alkyl, -(C₂-C_B)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cio)cycloalkyl, -(Cg-Ctojcycloaikenyl, -(C₂C₉)heterocycloalkyl, (C4-C₉)heterocycloalkenyl, -(Ce-Cio)aryl and -{CvC₉)heteroaryl moieties of said R¹’ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of -H, -OR¹³,

-C(O)R’³, -C(O)OR¹³, -OC(O)R¹³, -OC(O)0R¹³, -C(O)NR¹³R¹⁴, -NR¹³C(O)NR¹³R¹⁴, -NR¹³R¹⁴, -NR¹³C(NR¹³R¹⁴)(=NR¹³), -NR¹³C(NR¹³R¹⁴)(=N-C<O)R¹³), -NR¹³C(O)R¹⁴, -NR¹³S{0)jR¹³, -S{0)jR¹³, -CF₃, -CN, -(C_rC_e)aIkyl, -(C₂-C₆)alkenyl, -(C₂-C_B)alkynyl, -(C₃25 Ciojcycloaikyl, -(Cs-Cio)cycloalkenyl, -(Cs-Ciojbicycloalkyl, -(Cs-Cio)bicycloalkenyl, -(C₂Cg)heterocycloalkyl, -(C4-C₉)heterocycloalkenyl_l -(Ce-C₉)heterobicycioalkyl, -(C_BCg)heterobicyc!oalkenyl, -{C₆-Cio)aryl, and -{Ci-C₉)heteroaryl; wherein each of the foregoing -(C_rCs)alkyl, -(C₂-C₆)aikenyl, -(C₂-C6)alkynyl, -(C₃-Cio)cycioalkyl, -(C_sCio)cycloalkenyl, -(Ce-Cn>)bicycloalkyl, -(Ce-Cio)btcycloalkenyl, -(C₂-C₉)heterocycioalkyl,

-(C4-C₉)heterocycloalkenyl, -(Cs-Cg)heterobicycloalkyl, -(C6-C₉)heterobicyctoalkenyi, (C_B-Cio)aryl, and -{CrC₉)heteroaryl of said R¹² is optionally independently substituted by one to three groups selected from the group consisting of-halo, -CF3, -CN, -NO2l -OH, O((Ci-C6)alkyl), -C(O)R¹⁵, -C(O)NR^1SR¹⁶, -S(O)jR¹⁵, and -S(O);NR¹⁵R^1G, -(C32016201820 23 Mar 2016

-30Cwjcycloalkyl, -(C₂-Cg)heterocycloalkyl, -SH, -S((CrC₆)alkyl), -NH₂, -NH((Ci-C₆)alkyl) and -N((Ci-C₆)afkyi)₂;

Rⁿ and R¹⁴ are each independently selected from the group consisting of -Η, -NR^1SC(O)R¹⁶, -CF3, -CN, -S(O)jR¹⁵, -(CrC6)alkyl, -(C₂-C₆)alkenyl, -<C₂-C₆)alkynyl, -(C₃5 Cio)cycloalkyl, -(Cs-C^cycloalkenyl, -(C₆-C₁₀}bicyctoalkyl, -(C6-Cio)bicycloalkenyl, -(C₂Cgjheterocycloalkyl, -(C^-Cgjheterocycioalkenyl, -(C₆-Cg)helerobrcycloalkyl, -(CsCg)heterobicycloa!kenyl, -(Ce-Cigjaryl, and -(Ct-Cs)heteroaryl; and wherein each ofthe foregoing -(Ci-C₆)alkyl, -(C₂-C_s)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cw)cycloalkyl, -(C₅Cio)cycloalkenyl, -(Cs-Cio)bicycloalkyf, -{C6-Cto)bicycloaikenyl, -(C₂-Cg)heterocycloalkyl,

-(C4-Cg)heterocycloalkenyl, -(C₆-Cg)heterobicycloaikyl, -{C6-C₉)heterobicycloalkenyl, (C6-Cio)aryl, and -(CrCg)heteroaryi of said R¹³ and R¹⁴ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF₃,

-CN, -NO₂, -OH, -O«Ci-C₈)alky|), -C(O)«C_rC₆)alkyl), -(C₃-C,₀)cycloalkyl, -(C₂C₉)heterocycloalkyl, -SH, -S((C_rC₆)alkyi), -NH₂, -NH((C_rC₆)alkyl) and -N((C_rC₆)alkyl)₂;

R¹⁵ and R^ie are each independently selected from the group consisting of-H, (Ci-Ce)afkyi, -(C2-C6)aikenyl, -(C2-Cs)alkynyl, -(C3-Cio)cycloatkyl, -(C5-Cio)cycloalkenyl, -(C6-Cio)bicycloalkyl, -(Ce-CioJbicyctoaikenyl, -(C2-C9)heterocycloalkyl, -(C4Cg)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(Ce-Cg)heterobicycloalkenyl,· -(C6C-io)aryl, and -{CrC9)heteroaryl; and wherein each ofthe foregoing -(Ci-Csjalkyl, -(C220 Ce)alkenyl, -(C2-Ce)alkynyl, -{C3-Cio)cyctoalkyl, -(C5-Ci0)cycloalkenyl, -(CfiCio)bicycloalkyl, -(C6-Ci0)bicycloalkenyl, -{C2-C9)heterocycloalkyl, -(C4C9)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(Cs-Cg)heterobicycloaikenyl, -(C5Cio)aryl, and -(CrC9)heteroaryl of said R¹⁵and R¹⁰ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3,

-CN, -NO₂, -OH, -O{(C_rCe)aikyl), -CiOJ^CpCeJalkyl). -(C₃-C,₀}cyc!oalkyl, -(C₂C₉)heterocycloalkyl, -SH, -S^CrCeJalkyl), -NH₂, -NH((Ci-C₆)alkyl) and -N<(Ci-C_e)aIkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned -(CiC₆)alkyl, -{C2-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Ci₀)cycloalkyl, -(C_s-C₁₀)cycloaikenyl, -(C₆Cio)bicycloaikyl, -{Cs-CioJbicycloalkenyi, -(C₂-C₉)heterocycloalkyi, -{C₄30 Cg)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyi and -(C₆-C₉)heterobicycloalkenyi in said R¹and R^s-R¹⁴ groups may optionally and independently be replaced with -C(O)- or -C(S)-;

wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned -(CrCeJalkyl, -{C₂-C6)alkenyl, -{C₂-Cs)alkynyl, -(C₃-Ci₀)cycloaikyl, -(C5-31 2016201820 23 Mar 2016

Cio)cycloalkenyl, '(C₆-Cio)bicycloalkyl, -(Ce-Cwjbicycloalkenyl, -(C2-Cg}heterocycloalkyl, -(C4-C₉)heterocycloalkenyl, -(C_e-Cg)heierobicycloalkyl and -(Cg-Cgjheterobicycloalkenyi of said R’and R⁶-R¹⁴ groups may optionally join io form a ring system selected from the group consisting of a -(C₃-C₁₀)cycloalkyl, -(Cs-Cio)cycloalkenyl, -(C₂-Cg)heterocycloalkyl, and -(C^-Cgjheterocycloatkenyl; and wherein j is an integer from 0 to 2; and m is an integer from 0 to 3.

The present invention also provides a compound of formula Id:

or a pharmaceutically acceptable salt thereof: wherein A is phenyl or a 5- to 6-membered heteroaryl;

B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl and pyrazinyl:

each R¹ is independently selected from the group consisting of -H, halo, -CF₃,

-CN, -C(O)NR⁷R^e, -C{O)R^S, -OR¹⁰, and -(Ct-C₆)alkyl; and wherein the -{Ci-C₆)alkyi moiety of said R¹ is optionally independently substituted by one to three R¹² groups;

R² and R³ are each independently selected from the group consisting of ~H and -(Ci-C₆)alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of-H and

-(C_rC₆)alkyl;

R⁷ and R⁸ are each independently selected from the group consisting of-H, -OR¹⁰, -S(O)jR¹¹, -NO₂, -(Ci-C₆)alkyl, -(C₂-C₆)aikenyl, -(C₂-C₆)alkynyi, -(CaCio)cycloalkyl, -{Cs-Ciojcycloaikenyl, -(C₆-Cio)bicycloalkyi, -(Cs-Ciojbicycloalkenyl, -(C₂25 Cg)heterocycloalkyl, -(Ci-Cgjheterocycloalkenyl, -(Cs-Cg)heterobicycloafkyl, -(CeC₉)heterobicycloalkenyl -(C₆-Ci₀)aryl, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ci-C₆)alkyt, -{C₂-C₆)alkenyt, -(C2-C_e)alkynyl, -(C₃-Cio)cycioalkyl, -(CgC^cycloalkenyl, -{C_z-Cg)heterocycloalkyl, (C^CgJheterocycloalkenyl, -(Ce-Cio)aryl and

2016201820 23 Mar 2016

-32-(Ci-C₉)heteroaryi moieties of said R⁷ and R® is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of-H, -halo, -NR¹³R¹⁴, -{Ci-Cejalkyl, -(C₂-Ce)alkenyl, -(Cj-CeJalkynyi, -{C₃-C₁₀)cycloalkyl, -(C_s5 Cio)cycloalkenyl, -(Cg-Ctojbicycioalkyl, -{C6-C₁₀)bicycloaikenyl, -(C₂-Cg)heterocyclQalkyi, -(C4-Cg)heterocycloa(kenyi, -(C₆-C₉)helerobicycloalkyl, -(Cg-Cgjheferobicycioalkenyl (C₆-Ci₀)aryl, and -(CrCg)heteroaryl; and wherein each of the foregoing -(Ci-Cs)aikyl, -{C₂-C_B)aikenyl, -(C₂-C_B)alkynyl, -(C3-Cio)cycloaikyl, -(Cs-Ciojcycioalkeny!, ~(C₂Cgjheterocycioalkyl, (C4-Cg)heterocycioalkenyl, -(C_s-Cio)aryl and -(Ci-C₉)heteroaryl moieties of said R⁹ is optionally substituted by one to three R¹² groups;

each R¹⁰ is independently selected from the group consisting of -H, -(Ci-Cg)alkyl,

-(C₂-C₆)alkenyl, -(C₂-Ce)alkynyl, -(C₃-Cio)cycloalkyl, -(Cs-Ciojcycloalkenyl, -(C@Cio)bicycloaikyl, -{C₆-Cio)bicyctoalkenyl, -(C₂-C₉)heterocycloaikyi, -(C₄Cg)heterocycloalkenyl, -(C_s-Cg)heterobicyc!oaikyl, -(C6-C₉)heterobicycloalkenyl -(C_B15 C_w)aryi, and -(Ci-C₉)heteroaryl; and wherein each of the foregoing -(C_rC_e)alkyl, -(C₂C₈)alkenyl, -(C2-C₆)alkynyl, -(C₃-Cio)cycloalkyl, -(C₅-Cio)cycloalkenyl, -(C₂C_g)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, -(C_B-C_to)aryl and -(CrC₉)heteroary! moieties of said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of -H, -NR¹³R¹⁴,

-C(O)R¹³, -CF₃. -(Ci-C₆)alkyl. -<C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C₁₀)cycloalkyl, -<C₅Cio)cyc!oalkenyl, -{C_B-Cio)bicycloalkyl, -(C_B-Cio)bicycloalkenyl, -(C2-Cg)heterocyctoaikyl, -{C₄-C₉)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(C₆-C_g)heterobicycloalkenyl {C_B-Cto)aryl, and -(CrCg)heteroaryl; land wherein each of the foregoing -(C_rC_B)aikyl, -(C₂-C_Q}alkenyl, -(C₂-C₆)alkynyl₁ -(C₃-Cw)cycloalkyi, -(C₅-C_w)cycloalkenyi, -(C₂25 Cgjheterocycloalkyi, (C4-C₉)heterocycloalkenyl, -(Ce-Cto)aryl and -(C_rC₅)heteroaryl moieties of said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of-H, -OR¹³, -C(O)R’³,-C(0)OR¹³, -OC(O)R¹³, -OC(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹³C(O)NR¹³R¹⁴, -NR¹³R^h, -NR¹³C(NR¹³R¹⁴)(=NR¹³), -NR¹³C(NR¹³R¹⁴)(=N-C(O)R¹³), -NR¹³C(O)R¹⁴,

-NR¹³S(O)jR¹³, -S{O),R¹³, -CF_3i -CN, -(CvC₆)alkyl, -(C₂-C₆)aikenyl, -{C₂-C₆)a]kynyt, -(C₃Cio)cycloalkyl, -(C₅-Cio)cycloalkenyl, -(Ce-Ciojbicycloalkyl, -(Ce-Ciojbicycloalkenyi, -(C₂C₉)heterocycioaikyl, -{C4-C₉)heterocycloalkenyl, -{C₆-C₉)heterobicycloalkyi, -(C₆C₉)heterobicycloalkenyl, -(Ce-C₁₍j)aryl, and -(C-i-C₉)heteroaryl; wherein each of the foregoing -(Ci-C_B)alkyl, -<C₂-C_B)aikenyl, -^-Cejalkynyl, -(C₃-Ci₀)cycioalkyl, -(C₅-332016201820 23 Mar 2016

Cio)cycloalkenyl, -(C6-Cio)bicycloalkyl, -(C₆-Cio)bicycloalkenyt, -(C₂-C₉)heterocycloalkyl, -(Ci-Cgjheterocycloalkenyl. -(C6-Cg)heterobicycloalkyt, -(Ce-Cgjheterobicycloalkenyl, (C6-C«i)aryl, and -(Ci-Cg)heteroaryl of said R^1Z is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3, -CN, -NO2, -OH, 5 O((C,-C6)alkyl), -C(O)R¹⁵, -C{O)NR^1SR¹⁶, -S{O)jR^1s, and -S(O)(NR¹⁵R¹⁶, -(C₃Cio)cycloalkyl, -(C_z-C₉)heterocycloalkyl, -SH, -S((Ci-C₆)alkyl), -NH₂, -NH<(C_rC₆)alkyl) and -l\|((C,-C_e)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of~H, -NR^1SC(O)R^1&, -CF3, -CN, -SfOjjR¹⁵, -(C,-C6)aJkyl, -(C₂-C_B)afkenyl, -(C₂-C_B)aikynyi, -(C₃10 Csojcycloalkyl, -{C_s-Cio)cycloalkenyl, -(C6-C₁₀)bicycloalkyl, -(C₆-C,₀)bicycloalkenyl, -(C₂Cg)heterocycloalkyl, -(C₄-Cg)heterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -(C_BCgjheterobicycloalkenyl, -(C_B-C₁₀)aryl, and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(CrCs)alkyl, -(C₂-Cs)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cio)cycloalkyl, -(CsCio)cycloalkenyl, -(C_B-C-i₀)bicycloalkyl, -(Cs-Ciojbicycloalkenyl, -(C2-Cg)heterocycloalkyl,

-(C4-Cg)heferocycloalkeny(, -(Cg-Cgjheterobicycloalkyl, -(Ce-Cgjheterobicycloalkenyl, (Ce-CioJaryl, and -(Ci-Cg)heteroaryl of said R¹³ and R¹⁴ is optionally independently , substituted by one to three groups selected from the group consisting of-halo, -CF₃,

-CN, -NO₂, -OH, -O((C_rC₆)alkyf), -C(O)((C,-C_e)alkyl), -(C₃-C₁₀)cycloalkyl, -(C₂C₉)heterocycloalkyl, -SH, -StfCrCeJalkyl), -NH₂, -NH«Ci-C_e)alkyl) and -N{(C_rC₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of-H, (CrCeJalkyl, -(C2-CB)alkenyl, -(C2-C6)alkynyl, -(C3-Ci0)cycloalkyl, -(C5-Cio)cycloalkenyl, -(C6-Cio)bicycloalky!, -{Ce-Ciojbicycloalkenyl, -(C2-Cg)heterocycloalkyl, -(C4Cgjheterocycloalkenyl, -(Ce-Cgjheterobicycloalkyl, -{Cs-Cglheterobicycloalkenyl, -(CsC,o)aryl. and -(Ci-Cg)heteroaryl; and wherein each of the foregoing -(Ct-CB)aikyI, -(C225 Cs)alkenyi, -(C2-Cs)alkynyl, -(C3-Cio)cycloalkyl, -(Cs-CioJcycIoaikenyl, -(CBCio)bicyctoalkyl, -(Cs-Cio)bicycloalkenyl, -(C2-Cg)heterocycloalkyl, -{C4Cg)heterocycioalkenyl, -(Ce-Cgjheterobicycioalkyi, -{Ce-C^heterobicycloalkenyl, -(CBC,o)aryl, and -(Ci-Cg)heteroaryl of said R^1sand R¹⁶ is optionally independently substituted by one to three groups selected from the group consisting of -halo, -CF3,

-CN, -NOz, -OH, -O({C,-C₆)aikyl). -C(O)((C,-C₆)alkyl). -(C₃-Cio)cycloalkyl, -(C₂C₉)heterocycloalkyl, -SH, -S((C,-C₆)alkyl), -NH_2l -NHfiCvCeJaikyl) and -N((Ci-C₆)alkyl)₂;

j is an integer from 0 to 2; and m is an integer from 1 to 3.

-342016201820 23 Mar 2016

In another embodiment, the invention relates to a compound of formula Id wherein A is a phenyl.

In another embodiment, the invention relates to a compound of formula id wherein the moiety

represents a moiety selected from the group consisting of:

In another embodiment, the invention relates to a compound of formula Id wherein R¹ is -C(O)NR⁷R® and R⁷ and R⁰ are each independently selected from the group consisting -H and -(C1 -C₆)aIkyi.

In another embodiment, the invention relates to a compound of formula Id wherein R¹ is -OR¹⁰ and R^1G is -(Ci-Ce)alkyI.

In another embodiment, the invention relates to a compound of formula Id wherein each R¹ is independently selected from the group consisting of -H, fluoro, chioro, -CF₃, -CN, methyl, -C(O)NH_2> -C(O)NHCH₃, -C(O)NHCH₂CH₃, -C(O)N{CH₃)₂, and -OCH₃.

In another embodiment, the invention relates to a compound of formula id wherein the moiety

HN

<R¹)_m

-352016201820 23 Mar 2016 represents a moiety selected from the group consisting of:

R1 is-C{O)NH2 or-C(O)NHCH3; and

R1a is selected from the group consisting of fluoro, chloro, methyl and -OCH3.

In another embodiment, the invention relates to a compound of formula Id wherein R² and R³ are -H.

In another embodiment, the invention relates to a compound of formula Id wherein R⁴ and R⁵ are methyl.

In another embodiment, the invention relates to a compound of formula Id 10 wherein m is 1 or 2.

In another embodiment, the invention relates to a compound of formula I wherein each R¹ is independently selected from the group consisting of-H, fluoro, chloro, -CF3, -CN, -(Ci-Ce)alkyl, -C(O)NR⁷R⁸, and -OR¹⁰.

In another embodiment, the invention relates to a compound of formula 1 wherein 15 R¹ is -C{O)NR⁷R^a and R⁷ and R® are each independently selected from the group consisting -H and -(Ci-C₆)alkyl.

In another embodiment, the invention relates to a compound of formula I wherein R², R³, R⁴ and R⁵ are each independently selected from the group consisting of-H and -(C,-C₆)alkyl. .

In another embodiment, the invention relates to a compound of formula I wherein

R² and R³ are -H.

In another embodiment, the invention relates to a compound of formula I wherein R⁴ and R⁵ are methyl.

In another embodiment, the invention relates to a compound of formula I wherein 25 R⁶ is -CF_3l K is CH, m is 1 or 2, and n is 1.

In another embodiment, the invention relates to a compound of formula I wherein the moiety

-362016201820 23 Mar 2016

R⁵

represents a moiety selected from the group consisting of:

in another embodiment, the invention relates to a compound of formula I, ia, !b,

Ic or Id wherein R¹² further includes halo.

In another embodiment, the invention relates to a compound of formula I, la or lb wherein R⁴ is selected from the group consisting of-H, -NR⁷R^e, -OR¹⁰, -(Gi-C₆)alkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, -(C3-Ci₀)cycloalkyl, -(C_s-Cio)cycloalkenyl, -(C₂Cgjheterocycloalkyl, -(GrCgJheterocycloalkenyl, -{Ce-Ciojaryl and -(CrCs)heteroaryl;

wherein each of the foregoing -(Ci-C6)alkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, -(C₃Cio)cycloalkyl, -(Cs-Cio)cycloalkenyi, -{C2-Cg)heterocycloaikyl, -(C₄Cs)heterocycloalkenyl, -(Cs-Ciojaryl and -(CrCg)heteroaryi moieties of said R⁴ is optionally substituted by one to three R¹² groups: and wherein R⁴ is not -H when B is a 5- to 6-membered heteroaryl; and R^s is selected from the group consisting of -NR⁷R⁸,

-(Ci-C₆)alkyl, -(C₂-C_e)alkenyl, -(C₂-Ce)alkynyl, -(C3-Cio)cycioalkyl, -(Cs-CioJcycloalkenyl, -(C₂-C₉)heierocycloalkyl, -(C₄-C9)heterocycloalkenyl, -(C_o-Cio)aryl and -(Cr Cg)heteroaryt; and wherein each of the foregoing -(Ci-C6)alkyl, -(C₂-Cs)alkenyl, -(C₂-C₆)alkynyl, -(C₃-Cio)cycloalkyl, -(Cs-C^cycloalkenyl, -(C₂-C9)heterocycloalkyl, -(C₄Csjheterocycloalkenyl, -(C6-C₁₀)aryl and -(C_rCg)heteroaryl moieties of said R⁵ is optionally substituted by one to three R¹² groups;

In one embodiment, the invention also relates to the compounds described as

Compounds 1-415 in Examples 1-415 in the Examples section of the subject application, and pharmaceutically acceptable salts thereof.

-372016201820 23 Mar 2016

Non-iimiting examples of compounds representing the scope of this invention include:

4-({4-[({2-[methyl(methyisulfonyl)amino]pyridin-3-yl}metbyl)amino]-5(trifluoromethyJ)pyrimidin-2-yl}amino)benzamide;

4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5(trifluoromethy0pyrimidin-2-yl}amino)benzamide;

4-{(4-({3-[methyl{methylsulfonyi)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin

2-yl]amino}benzamide;

3- ({4-{({3-[meihyl(methyisuifonyl)amino]pyrazin-2-yl}methyl)amino]-510 (trifluoromethyl)pynmidin-2-yl}amino)benzamide;

4- methoxy-3-({4-[({3-[methyI(methylsulfonyl)amino)pyrazin-2-yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;

N-methyl-4-({4-[{{3-[methyl(methylsulfonyl)amino]pyridin-2-yi)methyl)amino]-5(trifiuoromethyl)pyrimidin-2-yI}amino)benzamide;

N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yi}methyl)amino]-5(trifluoromethyl)pyrimidin-2-yl}amino)benzamide; .

3-f1uoro-4-({4-[{{2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5(tnftuoromethyl)pyrimidin-2-yl}amino)benzamide;

2-fluoro-4-({4-[({3-[methyl(methyisulfonyl)amino]pyridin-2-yi}methyl)amino]-520 (trifiuoromethyl)pyrimidin-2-yl}amino)benzamide;

2-fluoro-4-t[4-{{3-[methyl(methylsulfonyl)amino]benzyl}amino)-5(trifiuoromethyl)pyrimidin-2-y)]amino}benzamide;

2-methyI-4-({4-[({2-[methyl(methylsulfonyl)amino]pyndin-3-yl}methyl)amino]-5{trifluoromethyl)pyrimrdin-2-yl}amino)benzamide;

2-methyl-4-({4-[({3-[methyl(rnethylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5(lrifluoromethyl)pyrimidin-2-yl}amino)benzamide;

2- methyl-4-({4-[({3-(metbyl(methylsulfonyl)amino]pyrazin-2-yl}meihyl)amino]-5(trifluoromethyi)pyrimidin-2-yl}amino)benzamide;

3- methyl-4-({4-[({2-[methyl{methy!sulfonyl)amino3pyridin-3-yl}methyl)amino]-530 (lrifiuoromethyl)pyrimidin-2-yl}amino)benzamide;

3-methyl-4-({4-[({3-[methyi{methyisulfonyl)aminojpyridin-2-yi}methyl)amino]-5(irifluoromethyl)pyrimidin-2-yl}amino)benzamide;

3-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyt)amino3-5{trifluoromethyl)pyrimidin-2-yl}amino)benzamide;

-382016201820 23 Mar 2016

2-chloro-4-({4-[({2-[methyl(methyIsulfonyl)amino]pyridin-3-yl}methyl)amino]-5(trif!uoromethyl)pyrimidin-2-yl}amino)benzamide;

2- ch!oro-4-({4-[({3-[methyJ(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5(trifiuoromethyl)pyrimidin-2-yl}amino)benzamide;

2-chloro-4-({4-[{{3-[methyl(methylsulfonyl)aminojpyrazin-2-yl}methyl)amino]-5(trifluoromeihy0pyrimidin-2-ylJamino)benzamide;

3- fluoro-N-methyl~4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2yi}methyl)amino]-5-(trif!uoromethy!)pyrimidin-2-yl}amino)benzamide;

2-fluoro-N-methyl-4-({4-(({3-[methyl{methyIsulfonyl)aminoJpyrazin-210 yl}methyi)aminol-5'(trifIuoromethyl)pyrimidin-2-yl}amino)benzamide;

N,2-dimethyl-4-{{4-[{{3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;

N_l3-dimethyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide; and

N,3-dimethyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyndin-3-yl}methyl)amino]5-(tnfluoromethyf)pynmidin-2-yl}amino)benzamide; or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of this invention also include:

(R)-N-(3-((2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4ylamino)methyl)pyridirt-2-yl)-N-methylmeihane-sulfonamide;

N-(3-((2-(4-(aminomethyi)phenylamino)-5-(trifluoromethyl)pyrimidin-4ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;

N-[4-({4-[({2-[methyl{methylsulfonyl)amino]pyridin-3-yI}methyl)amino]-525 (trifluoromethyI)pyrimidin-2-yi}amlno)benzyi]acetamide;

N-(3-((2-(4-(hydroxymethyi)phenylamino)-5-(trifluoromethyl)pyrimidin-4ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;

N-(3-((2-(4-(chloromethyl)phenylamino)-5-(trifluoromethyi)pyrimidin-4ylamino)methyl)pyndin-2-yl)-N-methylmethane-sulfonamide;

N-(3-((2-{4-((1,3-dihydroxypropan-2-ylamino)methyl)phenylamino)-5(trifluoromethyl)pyrimidin-4-ylamino)methy!)pyridin-2-yl)-N-meihylmethane-sulfonamide;

tert-butyl 3-({4-K{2-[methyl(meihylsuifonyl)amino]pyridin-3-yl}methyl)amino]-5{trifluoromethyl)pyrimidrn-2-yl}amino)benzoate;

-392016201820 23 Mar 2016

3.({4.[((2-[methyl(methylsulfonyi)amirio]pyridin-3-yl}methyl)amino)-5(trifluoromethyl)pyrimidin-2-yl}amino)benzoic acid;

N-cyclopropyl-3-({4-I{{2-{methyl(methylsuifonyI)aminoJpyridin-3-yi}methyI)amino] 5-{trifluoromethy i) py rimidin-2-y l}amino)benza mide;

N-(3-({2-(4-{1-hydroxyethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4ylamino)methy Qpyrid in-2-y l)-N-methy lm etba nes u Jfonamid e;

2- fluoro-4-{{4-[({2-[methyl(methyisulfonyl)amino]pyridin-3-y[}methyl)amino]-5(trifiuoromethyl)pyrimidin-2-y!}amino)benzamide;

3- fluoro-4-({4-[({2-[methyl(methylsuJfonyl)amino}pyridin-3-yl}methyi)amino]-510 (trifluoromethyl)pyrimidin-2-yl}amino)benzamide; and

N-methyl-4-({4-[({3-[methyl(methyisulfonyl)amino]pyrazin-2-yl}methyl)amino]-5(trifiuoromethy))pyrimidin-2-yi}amino)benzamide; or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of this invention 15 also include:

2- fluoro-4-({4-[({2-[methyl{methyi$u!fonyl)amino3pyridin-3-yi}methyl)amino]-5(triffuoromethyf)pyrimidin-2-yl}amino)benzamide;

3- f1uoro-4-((4-[{{2-[methyl(methy!sulfonyi)amino]pyridin-3-yl}methyl)amino]-5(trifluoromethy!)pyrimidin-2-yl}amino)benzamide; and

N-methyl-4-({4-[({3-[methyi(methyisu!fonyi)amino3pyrazin-2-yl}methyl)amino]-5(trifIuoromethyl)pyrimidin-2-yi}amino)benzamide; or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of this invention also include:

2-fiuoro-4-({4-K{2-[methyl(methyIsulfonyl)amino]pyridin-3-yl}methyt)amino]-5~ (trifiuoromeihyl)pyrimidin-2-y!}amino)benzamide formate;

3-fluoro-4-({4-[({2-[mefhyJ{methyJsuIfonyl)amino]pyridin-3-y)}methyi)aminoJ-5(trifIuoromethyl)pyrimidin-2-yl}amino)benzamide formate; and

N-methyl-4-{{4-[({3-[methyl(methy!sulfony!)amino)pyrazin-2-yl}methyl)amino]-530 (trifluoromethyl)pynmidin-2-yl}amino)benzamide hydrochloride.

As used herein, the term alkyl, as well as the alkyl moieties of other groups referred to herein {e.g., alkoxy), may be linear or branched {such as methyl, ethyl, npropyt, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl); optionaiiy substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl,

-402016201820 23 Mar 2016

-(Ci-CsJalkoxy, -(C₆-Ci₀)aryloxy, trifluoromethoxy, difluoromethoxy or -(C_rC_s)alkyl. The phrase “each of said alkyl as used herein refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkyiamino. Preferred alkyls include (Ci-Ce)alkyl, more preferred are (Ci-C-s)alkyl, and most preferred are methyl and ethyi.

As used herein, the term halogen or “halo’ includes fluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide.

As used herein, the term alkenyl” means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, t-butenyl, 2-butenyl, and the like;

optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -(C-i-CeJalkoxy, -(C6-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or -(Ci-C₆)alkyl.

As used herein, the term alkynyl’' means straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -(Ci-Cs)alkoxy, -(C₆-Ci₀)aryloxy, trifluoromethoxy, difluoromethoxy or-(CrCeJalkyl.

As used herein, the term ‘‘carbonyl or C(O) (as used in phrases such as alkylcarbonyi, aikyl-C(O)- or alkoxycarbonyl) refers to the joinder of the >C=O moiety to a second moiety such as an alkyi or amino group (i.e. an amido group).

Alkoxycarbonylamino (i.e. alkoxy-C(O)-NH-) refers to an alkyl carbamate group. The carbonyl group is also equivalently defined herein as C(O). Alkyicarbonylamino refers to groups such as acetamide.

As used herein, the term cycloaikyl refers to a mono-carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,); optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -(C_rC6)alkoxy, -(Cs-Cio)aryloxy, trifluoromethoxy, difluoromethoxy or -(CrCeJalkyl. Cycloalkyls include -(C3-Cio)cycloalkyl.

As used herein, the term “cycloalkenyp refers to a cycloalkyl as defined above and further containing 1 or 2 double bonds (e.g., cyclopentenyl, cyciohexenyl). Cycloalkenyls include -(Cs-Cio)cycloalkenyl,

The term 4- to 7-membered carbocyclyl refers to a non-aromatic ring containing 4 to 7 carbon ring atoms, optionally containing 1 or 2 double bonds, and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro,

-41 2016201820 23 Mar 2016 trifluoromethyl, ~(Ci-C₆)aIkoxy. -((/-Cwjaryloxy, trifluoromethoxy, difluoromethoxy or -(Ci C₆)alkyJ. Non-limiting examples of 4- to 7-membered carbocyclyls include cyclopropyl, cyciobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentendienyl, cyclohexyt, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, and cycloheptadienyi.

As used herein, the term “bicycloalkyl refers to a cycloalkyl as defined above which is bridged to a second carbocyclic ring (e.g., bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5,2.0]nonanyl, etc.). Bicycloalkyls include -(CsCio)bicycloalkyl.

As used herein, the term “bicycloalkeny! refers to a bicycloalkyl as defined above 10 and further containing 1 or 2 double bonds. Bicycloalkenyls include -{CeCio)bicycloalkenyl.

As used herein, the term “(C6-C,₀)aryr means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as defined above.

As used herein, the term (Ci-C₉)heteroaryr refers io an aromatic heterocyclic group having from 1 to 9 carbon atoms and containing from 1 to 4 heteroatoms in the ring selected from the group consisting of O, S and N. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring. For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl {e.g., 1,2thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadlazolyl), thiadiazolyi (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indoiyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -(Ci25 C₆)alkoxy, -(Ce-Chojaryloxy, trifluoromethoxy, difluoromethoxy or -(Ci-Ce)alkyl.

The term “5- to 6-membered heteroaryl ring” refers to an aromatic ring containing from 1 to 5 carbon atoms ring atoms and from 1 to 4 hetero ring atoms, and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, -(Ci-C₆)alkoxy, -{C₆-Cio)arytoxy_r trifluoromethoxy, difluoromethoxy or-(Cr

C6)alkyl. Non-limiting examples of 5- to 6-membered heteroaryi rings include furanyl, pyrrolyl, thiopenyl, thiazolyl, isothiazolyl, pyrazolyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxadiazoyl, thiadiazoyl, benzothiazolyl, and benzooxazolyl.

As used herein, the term heteroatom refers to an atom or group selected from N, O, S(O)q or NR, where q is an integer from 0 to 2 and R is a substituent group.

2016201820 23 Mar 2016 ¹ -42The term “(CrCgjheterocycloalkyl’ as used herein refers to a cyclic group containing 1 to 9 carbon atoms and 1 to 4 hetero atoms. Non-limiting examples of said monocycfic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yI, imidazoiidin-1 -yl, imidazolidin-2-yi, imidazoiidrn-4-yl, pyrrolidin-1-yl, pyrrolidtn-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidln-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yi,

1.2- pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,

1.3- tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl,

1.3- tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxalhiazin-4-yl and the like; optionally W containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifiuoromethyi, -(Ci-Cs)alkoxy, -(Cs-Cio)aryioxy, trifluoromethoxy, difluoromethoxy or-(Ct-Cs)aikyl.

As used herein, the term “heterocycloalkenyr refers to a heierocycloalkyl as defined above and further containing 1 or 2 double bonds. Heterocycloalkenyls include

-(Cx-Cgjheterocycloalkenyl.

The term “4- to 7-membered heterocyclyl” refers to a non-aromatic ring containing from 1 to 6 carbon atoms ring atoms and from 1 to 4 hetero ring atoms, optionally containing 1 or 2 double bonds, and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifiuoromethyi, -(Ci-Cejalkoxy, -(Cs-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or -(CrC_s)alkyl. Non-limiting examples of 4- to 7membered heterocyclyls include azetidinyl, oxetanyl, pyrrolidinyl, dihydropyrazolyl, tetrahydropyrazolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothlophenyl, dihydropyridinyl, fetrahydropyridinyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyrianyl, dihydrothiopyranyl, tetrahydroihiopyranyi, morpholinyl, dihydroazepinyl, tetrahydroazepinyl, dihydrooxepinyl, tetrahydrooxepinyl, oxepanyl, dihyrothiepinyl, tetrahydrothiepinyl and thiepanyl.

As used herein, the term “heterobicycloalkyl refers to a bicycloalky! as defined above, wherein at least one of the carbon ring atoms has been replaced by at least one heteroatom (e.g. tropane). Heterobicycloalkyls include -(Cg-Cgjheterobicycloalkyl.

As used herein, the term “heterobicycloalkenyr refers to a heterobicycloalkyl as defined above and further containing 1 or 2 double bonds. Heterobicycloalkenyls include -(Cs-Cg)heterocycloalkenyl,

-432016201820 23 Mar 2016

Nitrogen heteroatoms as used herein refers to N=, >N and -NH; wherein -N= refers to a nitrogen double bond; >N refers to a nitrogen containing two bond connections and N refers to a nitrogen containing one bond.

The term periluorinated or perfluoro refer to a compound having 4 or more 5 fluorine groups.

The term replaced by” refers to compounds in which an element selected from the group consisting of -C(O)- and -C(S)- replaces a methylene motety in a nonaromatic cyclic ring system. For example, if a substituent is a heterocycloalkyl group, such as an azetidine group:

a methylene ring moiety may be replaced by, e.g., a ~C(O)- to form a pyrrolidinone group:

Compounds of the invention can accommodate up to three such replacements.

The present invention also includes isotopically-labeled compounds, which are identical to those recited in formulae I, la, ib, Ic, Id and il, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ^uC, ^1SN, ^1SO, ¹⁷0,³¹P, ³²P, ³⁵S, ^wF, and ^Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isoiopically25 labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with

-442016201820 23 Mar 2016 heavier isotopes such as deuterium, i.e., ^ZH, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically-labeled reagent.

The phrase “pharmaceutically acceptable salt{s), as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.

The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-320 naphthoate)] salts. The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

The invention also relates to base addition salts of the compounds of the invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such nontoxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

Suitable base salts are formed from bases which form non-toxic salts. Nonlimiting examples of suitable base salts include the aluminum, arginine, benzathine,

-452016201820 23 Mar 2016 calcium, choline, diethytamine, dioiamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:

Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the art.

This invention also encompasses compounds of the invention containing 10 protective groups. One skilled in the art will also appreciate that compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in “Protective Groups in Organic Chemistry”, edited by J.W.F. McOmie, Plenum Press (1973) and “Protective

Groups in Organic Synthesis’, 3rd edition, T.W. Greene and P.G.M. Wuts, WileyInterscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the invention (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. AH such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes ail tautomers of the present compounds.

The present invention also includes alropisomers of the present invention. Atropisomers refer to compounds of the invention that can be separated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.

The compounds of the invention may also exist in unsolvated and solvated forms. Accordingly, the invention also relates to the hydrates and solvates of the compounds of

-462016201820 23 Mar 2016 the invention. Thus, it will be understood that the compounds of formula I, and pharmaceutically acceptable salts thereof also include hydrates and solvates of said compounds of formula I, and pharmaceutically acceptable salts thereof, as discussed below.

The term “solvate’' is used herein to describe a noncovelent or easily reversible combination between solvent and solute, or dispersion means and disperse phase. It will be understood that the solvate can be in the form of a solid, slurry {e.g., a suspension or dispersoid), or solution. Non-limiting examples of solvents include ethanol, methanol, propanol, acetonitrile, dimethyl ether, diethyl ether, tetrahydrofuan, methylene chloride, and water. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The invention also relates to prodrugs of the compounds of the invention. Thus certain derivatives of compounds of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs. Further information on the use of prodrugs may be found tn Pro-drugs as Novel Delivery Systems, Vol. 14,

ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionaiities present in the compounds of the invention with

-472016201820 23 Mar 2016 certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some non-limiting examples of prodrugs in accordance with the invention include (i) where the compound of the invention contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C_r C₆)alkyJ;

(ii) where the compound of the invention contains an alcohol functionality (OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of the invention is replaced by (CrCgJalkanoyloxymethyl; and (iii) where the compound of the invention contains a primary or secondary amino functionality (-NH₂ or -NHR where R ϊί H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogen atoms of the amino functionality of the compound of the invention is/are replaced by (CrCe)alkanoyi.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Moreover, certain compounds of the invention may themselves act as prodrugs of 20 other compounds of the invention.

Also included within the scope of the invention are metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include:

(i) where the compound of the invention contains a methyl group, an 25 hydroxymethyl derivative thereof (e.g., -CH3-> -CH2OH):

(ii) where the compound of the invention contains an alkoxy group, an hydroxy derivative thereof (e.g., -OR⁷ -> -OH);

(iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (e.g., -NR³R⁴ -> -NHR³ or -NHR⁴);

(iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (e.g., -NHR³ -> -NH₂);

(v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (e.g., -Ph -> -PhOH); and

-482016201820 23 Mar 2016 (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (e.g., -CONH2 -> COOH).

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or 2/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dlarginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled In the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers 20 include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of an alcoholic solvent such as

-492016201820 23 Mar 2016 isopropanoi, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example. Stereochemistry of Organic Compounds by E. L. Eliel and S, H. Wilen (Wiley, 1994).

In one embodiment, the invention relates to compositions comprising a compound of the invention and at least one additional ingredient (hereinafter “the compositions of the invention”). It will be understood that the compositions of the invention will encompass any combination of the compound of the invention and the at least one additional ingredient, Non-limiting examples of the at least one additional ingredient include impurities (e.g., intermediates present in the unrefined compounds of the invention), active ingredients as discussed herein (e.g., an additional anti-tumor agent), pharmaceutically acceptable excipients, or one or more solvents (e.g., a . pharmaceutically acceptable carrier as discussed herein).

The term “solvent as it relates to the compositions of the invention includes organic solvents (e.g,, methanol, ethanol, isopropanoi, ethyl acetate, methylene chloride, and tetrahydrofuran) and water. The one or more solvents may be present in a non-stoichiometric amount, e.g., as a trace impurity, or in sufficient excess to dissolve the compound of the invention. Alternatively, the one or more solvents may be present in a stoichiometric amount, e.g., 0.5:1,1:1, or 2:1 molar ratio, based on the amount of compound of the invention.

In one embodiment, the at least one additional ingredient that is present in the composition of the invention is an organic solvent

In another embodiment, the at least one additional ingredient that is present in the composition of the invention is water.

In one embodiment, the at least one additional ingredient that is present in the composition of the invention is a pharmaceutically acceptable carrier.

-502016201820 23 Mar 2016

In another embodiment, the at least one additional ingredient that is present in the composition of the invention is a pharmaceutically acceptable excipient.

In one embodiment, the composition of the invention is a solution, in another embodiment, the composition of the invention is a suspension.

In another embodiment, the composition of the invention is a solid.

In another embodiment, the composition of the invention comprises an amount of the compound of the invention effective for treating abnormal cell growth.

In yet another embodiment, the invention relates to a composition comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier.

In another embodiment, the invention relates to a composition comprising a therapeutically effective amount of the compound the invention as defined above, a pharmaceutically acceptable carrier and, optionally, at least one additional medicinal or pharmaceutical agents (hereinafter “the pharmaceutical compositions of the invention''). In a preferred embodiment, the at least one additional medicinal or pharmaceutical agent is an anti-cancer agent.

In another embodiment, the invention relates to a composition useful for treating abnormal cell growth in a mammal comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier.

The invention also relates to methods of making the compounds of the invention.

In one embodiment, the invention relates to a method for making a compound of formula I comprising allowing a compound of formula

Cl to react with a compound of formula NH

-51 2016201820 23 Mar 2016 to provide the compound of formula I.

In another embodiment, the invention relates to a method for making the compounds of the invention comprising allowing a compound of formula

to react with a compound of formula

When preparing compounds of the invention in accordance with the invention, il is open to a person skilled in the art to routinely select the form of the intermediate compound which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The invention also relates to intermediate compounds that are useful for making the compounds of the invention.

In one embodiment, the invention relates to intermediate compounds having the formula If:

II wherein A, K, R¹, R⁶ and m are as defined above for the compound of formula I.

-522016201820 23 Mar 2016

The invention also relates to methods for the treatment of abnormal cell growth in a mammal. In one embodiment, the invention relates to a method for the treatment of abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of the invention that is effective in treating abnormal cell growth.

In another embodiment, the abnormal cell growth is cancer.

In another embodiment, the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.

The invention also relates to methods for the treatment of cancer solid tumors in a mammal. In one embodiment, the invention relates to the treatment of cancer solid tumor in a mammal comprising administering to said mammal an amount of a compound of the invention that is effective in treating said cancer solid tumor.

in another embodiment, the cancer solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin {melanoma), endocrine, uterine, testicular, or bladder, in another embodiment, the invention relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the invention that is effective in treating abnormal ceil growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

A particular aspect of this invention is directed to methods for treating or preventing a condition that presents with low bone mass in a mammal (including a

-532016201820 23 Mar 2016 human being) which comprise administering to a mamma! in need of such treatment a condition that presents with low bone mass treating amount of a compound of the invention or a pharmaceutically acceptable salt of said compound of the invention. This invention is particularly directed to such methods wherein the condition that presents with tow bone mass is osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods for treating osteoporosis in a mammal (including a human being) which comprise administering to a mammal in need of such treatment an osteoporosis treating amount of a compound of the invention or a pharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating a bone fracture or an osteoporotic fracture in a mammal which comprise administering to a mammal in need of such treatment a bone fracture treating or an osteoporotic fracture treating amount of a compound of the invention or a pharmaceutically acceptable salt of said compound.

The term osteoporosis includes primary osteoporosis, such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing syndrome (due to corticosteroid use), acromegaly, hypogonadism, dysosteogenesis and hypophospatasemia.

Detailed Description of the Invention

Synthesis of 2,4-Diamino Pyrimidines

The compounds of the invention can be prepared by the following general methods and by methods described in detail in the Experimental Section.

Non-limiting methods for making the sulfonyl amides of the invention are depicted tn Schemes 1 -6 below. For sake of clarity, only the pyrimidine derivatives of the compounds of formula I are depicted in the Schemes (i.e., where K of the compound of formula I is CH). However, the same methods can be used for making the 1,2,4-triazine derivatives compounds of formula i (i.e., where K is N).

Scheme 1 shows one method for preparing 2,4-diamtno pyrimidines.

-542016201820 23 Mar 2016

Scheme 1

A1-S

In Scheme 1, the amino group of an amino-nitroaryl compound of structure A1-1 5 is protected (PG = protecting group such as BOC) to form the protected compound A12. The nitro group of A1-2 can then be selectively reduced to the corresponding aniline

A1-3, using, e.g., hydrogen in the presence of a palladium-supported catalyst. Reaction of aniline A1-3 with 2,4-dichloro-5-(trifluoromethyI)pyrimidine in the presence of an appropriate zinc salt (e.g., ZnBr₂) provides the corresponding C-2 addition product A1-4.

Reaction of compounds of formula A1-4 with amines of formula A1-? under basic conditions provides compound of formula I having the structure A1-5. Other compounds of formula I can be prepared by selectively deprotecting A1-5 to provide the aminoalkyl compound of formula I having the structure A1-6,

Scheme 2 depicts a non-limiting method for making amide derivatives of the compound of formula I.

-552016201820 23 Mar 2016

Scheme 2

A1-6 Α2-Ϊ

In Scheme 2, an aminoalkyl such as the compound of formula I having the structure A1-6 can be reacted with an acid halide (e.g., acetyl chloride) under basic conditions to provide the amide derivative of the compound of formula I having the structure A2-1.

Scheme 3 represents another general non-limiting method of making compounds of formula t.

Scheme 3

OH OH

A3-4 A3-S

In Scheme 3, an hydroxyalkyl-aniline of formula A3-1 is reacted with 2,4-dichloro5-(trifluoromethyl) pyrimidine in the presence of a zinc salt (e.g., ZnBr₂) to provide the corresponding C-2 addition product A3-2. Treatment of the A3-2 with an amine of formula A3-6 provides hydroxyalkyl derivatives of the compound of formula I having the structure A3-3. Compound A3-3 may further be selectively converted to a compound of formula I where the hydroxy! group is replaced for another reactive functional group (e.g., alkyl halide or alkyl sulfonate). For example, in Scheme 3, the hydroxyialkyl

-562016201820 23 Mar 2016 compound of formula A3-3 is reacted with thionyi chloride to provide the chloroalkyl compound of formula I having the structure A3-4. Compound A3-4 may further be reacted with amines (e.g., HNR⁷R^fi) to provide aminoalkyl derivatives of the compounds of formula I having the structure A3-5. If desired, the compounds of structure A3-5 can be used as a starting material to prepare other compounds of formula I.

Scheme 4 represents yet another general non-limiting method for making compounds of formula I.

Scheme 4

R’ θ A4-6 A4-S

In Scheme 4, the acid group of a nitrobenzoate compound of structure A4-1 is protected to form the protected compound A4-2. The nitro group of A4-2 can then be selectively reduced to the corresponding aniline A4-3, using, e.g., hydrogen in the presence of a palladium-supported catalyst. Reaction of aniline A4-3 with 2,4-dichloro15 5-(trifluoromethyl)pyrimidine in the presence of an appropriate zinc salt (e.g., ZnSr₂) provides the corresponding C-2 addition product A4-4. Treatment of the chloropyrimidine compounds of formula A4-4 with amines of formula A4-7 provides benzoateprotected compounds of formula I having the structure A4-5. Selective deprotection of

-572016201820 23 Mar 2016 compound A4-5 can provide benzoic acid derivatives of the compound of formula I having the structure A4-6. The benzoic acid derivatives of formula A4-6 may be further reacted with an amine to provide the amide derivatives of the compound of formula I having the structure A4-6.

Scheme 5 depicts yet another genera! non-limiting method for making compounds of formula I,

Scheme 5

R® R®

A5-1 AS-2

R*

A5-4 in Scheme 5, an aniline amide compound of structure A5-1 is be reacted with 2,4-dichioro-5-(trifluoromethyI)pyrimidine in the presence of a zinc salt (e.g., Zn8r₂) to provide the corresponding C-2 addition product A5-2. Treatment of the chloro pyrimidine compounds of formula A5-2 with an amine of formula A5-3 provides amide derivatives of the compounds of formula I having the structure A5-4. The amide derivatives of formula A5-4 may be used as a starting material to provide other compounds of formula I.

In Schemes 1 and 3-5, the 2,4-dichloro-5-(trifluoromethy!)pyrimidine first formed a C-2 addition product (“the C4-chloro intermediate). The C-4 group was then added by allowing the C4-chloro intermediate to react with an aralkylamino reagent. Scheme 6 depicts another non-limiting method for making the compounds of the invention where the first formed intermediate is the C-4 addition intermediate (“the C2-chioro intermediate”).

-582016201820 23 Mar 2016

Scheme 6

XX^CF‘ 'TX’* jX &

Cl N Cl

A6-1 'SO,R^s 'jam

A6-3

0Γ

HN N NH (ft S@f^Ns.w

Optionally ReFunctionalizc R¹

HN^N *{R’)^m

A6-S ^N^NH R⁴ (ft '{R’)m

A6-6 in Scheme 6, 2,4-dichloro-5-(triftuoromethyl)pyrimidine is reacted with an aralkyiamino reagent of formula A6-2 to provide the 2-chloro-pyrimidine addition product A6-3. Reaction of A6-3 with an amino reagent of formula A6-4 provides the compound of formula ! having the structure A6-5. Depending on the substituent groups R¹, the compounds of formula A6-5 can be further reacted as described above in Schemes 1-5 to provide additional compounds of formula I.

Arylalkylamines or heteroarylalkylamines (e.g., A1-7 in Scheme 1) that are attached to the 4 position of the pyrimidine core (or the 5 position of the 1,2,4-triazine core) may be prepared from the corresponding nitrile by catalytic hydrogenation using catalysts such as Pd/C or Raney Nickel or by lithium aluminum hydride reduction, (see Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, 1979); or by methods described herein in the Examples section.

ch,

Ν..

SO₂CH,

H/ Pd on Carbon

Inert Solvent

NH,

CHj

N 'SO₂CHj

The nitrite starting materials can be either purchased or prepared from the corresponding aiyl/heteroaryl bromide, iodide or triflate and Zn(CN)₂ using Pd coupling conditions found in Tschaen, D, M., et. al Synthetic Communications (1994), 24, 6, pp 887-890,

CHj

N-SOjCHj

Zn{CN>2/ Pd

Inert Solvent

CH,

N-SO₂CHj

-592016201820 23 Mar 2016

Appropriately protected amines may be converted to different amines of formula A1-7 {see Scheme 1) according to methods familiar to those skilled in the art as, for example, N-aikyiation of a suIfanilide under phase transfer using conditions as described by Brehme, R. Synthesis, (1976), pp113-114.

“^C'O

SOJCHJ

CT5

NaOH/PTC

SOjCHj

Inert Solvent

As understood by those skilled in the art, the chemical transformation to convert an aryl halide or triflate or heteroaryl halide or tritiate to an aromatic or heteroaromatic amine may be carried out using conditions currently outlined in the literature, see

Hartwig, J, F.: “Angew. Chem. int. Ed.” (1998), 37, pp. 2046-2067, Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S.L.; “Acc. Chem. Res.”, (1998), 31, pp 805-818, Wolfe, J. P.; Buchwald, S.L; “J. Org. Chem.”, (2000), 65, pp 1144-1157, Muci, A. R.; Buchwald.

S. L.; “Topics in Current Chemistry” (2002), pp131-209 and references cited therein. Further, as understood by those skilled in the art, these same aryl or heteroaryl amination chemical transformations may alternatively be carried out on nitrile (or primary amide) precursors which provide amines after nitrile (or amide) reduction.

Other methods for making the intermediate compounds (e.g. A1-7 in Scheme 1) can be found in U.S. Patent Appl, Publ. No. 20040220177, U.S. Patent No. 7,109,335, U.S. Patent No. 7,10,9,337, and PCT/IB2006/003349, the entire contents of each of the foregoing references being expressly incorporated herein by reference.

As noted above, amines comprising the ring moiety A (e.g., A6-4 in Scheme 6) are attached to the 2 position of the pyrimidine core (or the 3 position ofthe 1,2,4-triazine core). Such amino-ring groups are commercially available or can be made by methods known to those skill in the art. For example, amines comprising alky!-, hydroxyl-, carboxyl-, and halo-substituted ring moieties are commercially available. In addition, certain of these commercially available amines such as, e.g,, the halo- and hydroxylsubstituted ring compounds, can be reacted to form other compounds of the invention using the methods described above, in the Examples section, or known to those skilled in the art. Such reactions can be carried out prior to the reaction with pyrimidine core.

Alternatively, such reactions can be carried out after the cyclic amine is attached to the C2 position of the pyrimidine core.

-602016201820 23 Mar 2016

This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable sait, solvate or prodrug thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In one embodiment the method comprises comprising administering to a mammal an amount of a compound of the invention that rs effective in treating said cancer solid tumor. In one preferred embodiment the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.

in another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

-61 2016201820 23 Mar 2016

This invention aiso relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cel! growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, cofon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid giand, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers, in another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.

The invention also contemplates a pharmaceutical composition for treating abnormal cell growth wherein the composition includes a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and another anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, ceil cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and antiandrogens.

This invention also relates to a method for the treatment of a disorder associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the invention, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating said disorder in combination with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-622016201820 23 Mar 2016 related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordeteila pertussis, and group A Streptococcus.

This invention also relates to a method of {and to a composition for) treating abnormal cell growth in a mammal which comprise an amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors,

MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-ll (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of the invention in the methods and pharmaceutical compositions described herein. Examples of useful COX-ll inhibitors include CELEBREX™ (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of useful matrix metalloproteinase inhibitors are described in WO Θ6/33172 (published October 24, 1996), WO 96/27583 (published March 7,1996), European Patent Publication No. EP0818442, European Patent Publication No. EP1004578, WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29,1998), WO 98/34918 (published August 13,1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO

98/30566 {published July 16,1998), European Patent Publication 606,046 (published July

13,1994), European Patent Publication 931,788 (published July 28,1999), WO 90/05719 (published May 331,1990), WO 99/52910 (published October 21,1999), WO 99/52889 (published October 21,1999), WO 99/29667 (published June 17, 1999), PCT International Publication No. WO99/007675, European Patent Application No.

99302232.1 (filed March 25,1999), Great Britain patent application number 9912961.1 (Filed June 3,1999), United States Patent No, 7,030,242, United States Patent No. 5,863,949 (issued January 26,1999), United States Patent No. 5,861,510 (issued January 19,1999), and European Patent Publication 780,386 (published June 25,1997), ail of which are herein incorporated by reference in their entirety. Preferred MMP-2 and

-632016201820 23 Mar 2016

MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrixmetalloproteinases (/,e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list:

3- [[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(l-hydroxycarbamoyl-cyclopentyl)aminoj-propionrc acid;

3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.13octane3-carboxyiic acid hydroxyamide;

(2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesutfonyi]-3-hydroxy-3-methyipiperidine-2-carboxyiic acid hydroxyamide;

4- [4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic 15 acid hydroxyamide;

3- [[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)amino]-propionic acid;

4- [4-{4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3-[4-(4-chloro-phenoxy)-benzenesulfonylamino3-tetrahydro-pyran-3-carboxylic acid hydroxyamide;

(2R, 3R) 1 -[4-{4-fluoro-2-methyl-benzyloxy)-benzenesuIfonyl]-3-hydroxy-3methyl-piperidine-2-carboxylic acid hydroxyamide;

3-[[4-(4-fluoro-phenoxy)-benzenesulfony)]-(1-hydroxycarbamoyl-1-methyl-ethyl)25 aminoj-propionic acid;

3-[[4-{4-fluoro-phenoxy)-benzenesuifonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran4-yl)-amino]-propionic acid;

3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino3-8-oxabicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;

3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxabicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; and

3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide;

-642016201820 23 Mar 2016 and pharmaceutically acceptable salts, solvates and prodrugs of said compounds.

VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 {Sugen Inc. of South San Francisco, California, USA), can also be combined with a compound of the invention. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT international Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 5,834,504 (issued November 10,1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United

States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11,1998), U.S. Patent No. US 6,653,308 (issued November 25, 2003), WO 99/10349 (published March 4,1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26,1997), WO 98/54093 (published December 3,1998), WO 98/02438 (published January 22,1998), WO 99/16755 (published April 8,1999), and WO

98/02437 (published January 22, 1998), all of which are herein incorporated by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland, Washington, USA); Avastin, an anti-VEGF monoclonal antibody of Genenlech, Inc. of South San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome pic), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), may be administered in combination with a compound of the invention. Such erbB2 inhibitors include Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22,1998), WO

99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO

98/02437 (published January 22,1998), WO 97/13760 {published April 17,1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24,1996), and United States Patent 5,877,305 (issued March 2,1999), each of which is herein incorporated by reference in its entirety, ErbB2 receptor inhibitors useful in the present invention are also described in United States Patent No. 6,465,449, and in

United States Patent No. 6,284,764, both of which are herein incorporated by reference in their entirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda) and GW572016 (Glaxo-Weilcome).

-652016201820 04 Jul2016

Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. More recently, five European patent publications, namely EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30,

1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published November 26,

1992), refers to certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors that are useful in inhibiting abnormal cell proliferation. World Patent Applications WO96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors that are useful for the same purpose. Other patent applications that refer to anti-cancer compounds are World Patent Application WO 00/44728 (published August 3, 2000), EP 1029853A1 (published August 23, 2000), and WO 01/98277 (published December 12, 2001) all of which are incorporated herein by reference in their entirety.

Other antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed

December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31,2000); 09/202796 (filed July 10, 1999); 09/384339 (filed August 26, 1999) and 09/383755 (filed August 26, 1999) and the compounds disclosed and claimed in the following United States provisional patent applications:

60/168207 (filed November 30, 1999) granted as patent number 6,596,735; 60/170119 (filed December 10, 1999) granted as patent number 6,596,735; 60/177718 (filed

January 21,2000) granted as patent number 6,479,513; 60/168217 (filed November 30, 1999) granted as patent number 7,019,147 and 60/200834 (filed May 1,2000) granted as patent number 6,844,357. Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety.

A compound of the invention may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of

-662016201820 23 Mar 2016 enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4} antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the “Background section, supra. Specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998) which is herein incorporated by reference in its entirety.

A compound of formula I may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, oxaliplatin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylrnethyl)-N-methylamino]-2-thenoyl)-L-glufamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example anti-estrogens such as Nolvadex (tamoxifen) or, for example anti-androgens such as Casodex (4'-cyano-3-(4-fluorophenylsulphonyi)-2-hydroxy~2-methyi-3'(trifiuoromethyl)propionanilide).

The compounds of the present invention may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, the compounds of the present invention may be used with cytotoxic agents, e.g., one or more selected from the group consisting of a camptothecin, irinotecan HCi (Camptosar), edotecarin, SU-11248, epirubictn (Ellence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinations thereof. Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

-672016201820 23 Mar 2016

The compounds of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with the compounds of the invention.

® Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolaciol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaptatin, lobaplatin, nedaptatin, oxaliplatin orsatrplatin;

• Antimetabolites include but are not limited to, methotrexate, 6mercaptopurine riboside, mercaptopurine, 5-fIuorouracii (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynyicytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-Nmethylamino]-2-thenoyl)-L-glutamic acid;

» Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin;

» Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercaiciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozote (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4-fluorophenyisulphonyl)-2-hydroxy-2mefhyl-3'-(trifiuoromethyl)propionanilide) and combinations thereof;

« Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel;

-682016201820 23 Mar 2016 • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, beiotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof;

® Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1 a or interferon gamma-n1. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), moigramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge;

• Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, or ubenimex;

· Other anticancer agents include aiitretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol. exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, i-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin;

* Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat. removab, Revlimid, squalamine, ukrain and Vitaxin;

• Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaiiplatin;

• Camptothecin derivatives include but are not limited to camptothecin, 10hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan;

Tyrosine kinase inhibitors are tressa or SU5416;

*692016201820 23 Mar 2016 * Antibodies include Herceptin, Erbitux, Avastin, or Rituximab; and » Interferons include interferon alpha, interferon alpha-2a, interferon, alpha2b, interferon beta, interferon gamma-1 a or interferon gamma-n1.

“Abnormal ceil growth, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms {e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of the FAK protein tyrosine kinases, and thus are all adapted to therapeutic use as antiproliferative agents (e.g.. anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stop or prevent proliferationalion of blood vessels) in mammals, particularly in humans. In particular, the compounds of the present invention are useful in (he prevention and treatment of a variety of human hyperproliferative disorders such as malignant and benign tumors of the liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). It is, in addition, expected that a compound of the present invention may possess activity against a range of leukemias and lymphoid malignancies.

In one preferred embodiment of the present invention cancer is selected from tung cancer, bone cancer, pancreatic cancer, gastric, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, gynecological, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, squamous cell, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the

-702016201820 23 Mar 2016 kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain, pituitary adenoma, or a combination of one or more of the foregoing cancers.

In a more preferred embodiment cancer is selected a solid tumor, such as, but 5 not limited to, breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular, and bladder.

The compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions or activation or signalling events related to various protein tyrosine kinases, are involved.

Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbS tyrosine kinases are involved.

In addition, the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention.

A particular aspect of this invention is directed to methods for treating or preventing a condition that presents with low bone mass in a mammal (including a human being) which comprise administering to a mammal in need of such treatment a condition that presents with low bone mass treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

This Invention is particularly directed to such methods wherein the condition that presents with low bone mass is osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods for treating osteoporosis in a mammal (including a human being) which comprise, administering to a mammal in need of such treatment an osteoporosis treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating a bone fracture or an osteoporotic fracture in a mammal which comprise administering to a mammal in need of such treatment a bone fracture treating or an osteoporotic fracture treating amount of a Formula I compound or a pharmaceutically acceptable salt of said compound.

-71 2016201820 23 Mar 2016

The term “osteoporosis includes primary osteoporosis, such as senile, postmenopausal and juvenile osteoporosis, as well as secondary osteoporosis, such as osteoporosis due to hyperthyroidism or Cushing syndrome (due to corticosteroid use), acromegaly, hypogonadism, dysosteogenesis and hypophospatasemia,

The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating is defined immediately above.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. The daily dosage of the compound of formula (l)/salt/solvate (active ingredient) may be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg,

The present invention also encompasses sustained release compositions.

As noted above, the compounds of the invention are useful for treating abnormal cell growth such, e.g., cancer. Without being limited by theory, Applicants believe that the compounds of the invention are useful for treating or preventing abnormal cell growth by inhibiting the FAK kinases.

In Vitro and In Vivo Assays

As noted above, the compounds of the invention are useful as inhibitors of receptor tyrosine kinases such as, e.g., FAK, Aurora-1, Aurora-2, HgK and Pyk.

Methods for determining the in vitro and in vivo activity of these compounds inhibitors of receptor tyrosine kinases are described below:

A. In-vitro Activity of FAK:

-722016201820 23 Mar 2016

The in viiro activity of the compounds of the compounds of the invention may be determined by the following procedure. More particularly, the following assay provides a method to determine whether compounds of the compounds of the invention inhibit the tyrosine kinase activity of the catalytic construct FAK(410-689). The assay is an EL.ISA5 based format, measuring the inhibition of poly-glu-tyr phosphorylation by FAK(410-689). The assay protocol has three parts:

I. Purification and cleavage of His-FAK(410-689)

II. FAK410-689 (a.k.a. FAKcd) Activation

III. FAKcd Kinase ELISA 10 Materials:

-Ni-NTA agarose (Qiagen)

-XK-16 column (Amersham-Pharmacia)

-300 mM Imidizole

-Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.)

-Antibody: Anti-Phosphotyrosine HRP-ConJugated Py20 (Transduction labs)

-FAKcd: Purified and activated in house

-TMB Microwell Peroxidase Substrate (Oncogene Research Products #CL07)

-BSA: Sigma #A3294

-Tween-20: Sigma #P1379 20 -DMSO: Sigma #D-5879

-D-PBS: Gibco #14190-037 Reagents for Purification:

-Buffer A: 50mM HEPES pH 7,0 500mM NaCI

0,1mM TCEP

CompleteTM protease inhibitor cocktail tablets (Roche)

-Buffer B: 25mM HEPES pH 7.0 400mM NaCI

0.1 mM TCEP

-Buffer C: 10mM HEPES pH 7.5

200mM Ammonium Sulfate O.lmMTCEP

Reagents for Activation:

-732016201820 23 Mar 2016

-FAK(410-689): 3 tubes of frozen aliquots at 150pt/tube for a total of 450μΙ at 1.48 rrtg/ml (660pg)

-His-Src{249-524): -0.74 mg/ml stock in 10mM HEPES, 200mM (NH4)2SO4 -Src reaction buffer (Upstate Biotech):

100 mM Tris-HCI pH7.2

125mM MgCI2 25 mM MnCI2 2mM EDTA 250 μΜ Na3VO4

2 mM DTT

-Mn2+/ATP cocktail (Upstate Biotech)

75mM MnCI2

500 μΜ ATP 20mM MOPS pH 7.2

1mM Na3VO4

25mM -glycerol phosphate 5mM EGTA

1mM DTT -ATP: 150mM stock

-MgCI2: 1 M Stock

-DTT: 1M stock

Reagents for FAKcd Kinase ELISA:

-Phosphorylation Buffer:

50mM HEPES, pH 7.5

125mMNaCI

48mM MgCI2

-Wash Buffer: TBS τ 0.1% Tween-20.

-Blocking Buffer:

Tris Buffer Saline

3% BSA

0.05% Tween-20, filtered -Plate Coating Buffer:

50mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer Saline (DPBS).

-ATP: 0.1 M ATP in H2O or HEPES, pH7

-742016201820 23 Mar 2016

Note: ATP Assay Buffer:

Make up as 75 uM ATP in PBS, so that 80 pi in 120 pi reaction volume=50pM final ATP concentration.

1. Purification of His-FAKcd(410-689):

1. Resuspend 130 g bacutovirus cell paste containing the over expressed HisFAKcd410-689 recombinant protein in 3 volumes (400ml) of Buffer A.

2. Lyse cells with one pass on a microfluidizer.

3. Remove cell debris by centrifugation at 4°C for 35 minutes at 14,000 rpm in a Sorval SLA-1500 rotor.

4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTA agarose (Qiagen).

5. Incubate the suspension with gentle rocking at 4”C for 1 hour.

6. Centrifuge suspension at 700 x g in a swinging bucket rotor.

7. Discard the supernatant and resuspend the agarose beads in 20.0 ml of Buffer A.

8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connected to a

FPLCTM.

9. Wash the agarose-beads with 5 column volumes of Buffer A and elute off the column with a step gradient of Buffer A containing 300mM Imidizole.

10. Perform a buffer exchange of the eluted fractions into Buffer B.

11. Following buffer exchange, pool the fractions and add thrombin at a 1:300 (w/w) ratio and incubated overnight at 13°C to remove the N-terminal His-tag (HIS-FAK410698 a FAK410-689 (a.k.a. FAKcd)).

12. Add the reaction mixture back onto the Ni-NTA column equilibrated with Buffer A and collect the flow-through.

13. Concentrate the flow-through down to 1.7 ml and load directly onto a Superdex

200 HiLoad 16/60 prep grade column equilibrated with Buffer C, The desired protein elutes between 85 - 95 ml.

14. Aliquot the FAKcd protein and store frozen at -SO'C.

11. FAK activation

1. To 450ul of FAK(410-689) at 1.48 mg/ml (660pg) add the following:

30μΙ of 0.037 mg/ml (1μΜ) His-Src(249-524)

30μΙ of 7.5 mM ATP

12plof20 mM MgCI2

10μί Mn2+/ATP cocktail (Upstate Biotech.)

-752016201820 23 Mar 2016

4μΙ of 6.7mM DTT

60μΙ Src Reaction Buffer {UpState Biotech.)

2. incubate Reaction for at least 3 hours at room temperature

At time tO, almost all of the FAK{410-689) is singly phosphorylated. The second 5 phosphorylation is stow. At t120 (t = 120 minutes), add 10μI of 150 mM ATP.

TO = (Start) 90% singly phosphorylated FAK(410-689) (1 PO4)

T43 = (43 min) 65% singly phosphorylated (1 PO4), 35% doubly phosphorylated (2 PO4)

T90 = (90 min) 45% 1 PO4, 55% 2 PO4 10 T150 = 15% 1 PO4, 85% 2 PO4

T210 = <10% 1 PO4, >90% 2 PO4 desalted sample

3. Add 180 μΐ aliquots of the desalted material to NiNTA spin column and incubate on spin column

4. Spin at 10k rpm (microfuge), for 5 minutes to isolate and collect flow through (Activated FAK(410-689)) and remove His-Src (captured on column)

III. FAKcd Kinase ELISA

1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10 pg/weli: Prepare 10 pg/mi of pGT in PBS and aliquot 100 μΙ/well. Incubate the plates at 37°C overnight, aspirate the supernatant, wash the plates 3 times with Wash Buffer, and flick to dry before storing at 4°C.

2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocks are subsequently diluted to 60X of the final concentration in 100% DMSO, and diluted 1:5 in Kinase Phosphorylation Buffer.

3. Prepare a.75 μΜ working ATP solution in Kinase phosphorylation buffer. Add 80 μΙ to each well for a final ATP concentration of 50 μΜ.

4. Transfer 10 μΙ of the diluted compounds (O.SIog serial dilutions) to each well of the pGT assay plate, running each compound in triplicates on the same plate.

5. Dilute on ice, FAKcd protein to 1:1000 in Kinase Phosphorylation Buffer.

Dispense 30 μΙ per well.

6. Note: Linearity and the appropriate dilution must be pre-determined for each batch of protein. The enzyme concentration selected should be such that quantitation of the assay signal will be approximately 0.8-1.0 at OD450, and in the linear range of the reaction rate.

7. Prepare both a No ATP control (noise) and a No Compound Control (Signal):

-762016201820 23 Mar 2016

8. (Noise) One blank row of wells receives 10 pi of 1:5 diluted compounds in DMSO, 80μΙ of Phosphorylation buffer (minus ATP), and 30 μΙ FAKcd solution.

9. (Signal) Control wells receive 10 μΙ of 1:5 diluted DMSO (minus Compound) in Kinase phosphorylation buffer, 80 μΙ of 75 uM ATP, and 30 μΙ of 1:1000 FAKcd enzyme.

10. Incubate reaction at room temperature for 15 minutes with gentle shaking on a plate shaker.

11. Terminate the reaction by aspirating off the reaction mixture and washing 3 times with wash buffer.

12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250 pg/ml (1:1000 of Stock) in blocking buffer. Dispense 100 μΙ per well, and incubate with shaking for 30 minutes at 25°.

13. Aspirate the supernatant and wash the piate 3 times with wash buffer.

14. Add 100 μΙ per well of room temperature TMB solution to initiate color development. Color development is terminated after approximately 15-30 sec. by the addition of 100μΙ of 0.09M H2SO4 per well.

15. The signal is quantitated by measurement of absorbance at 450nm on the BioRad microplate reader or a microplate reader capable of reading at OD450.

16. Inhibition of tyrosine kinase activity would result in a reduced absorbance signal. The signal is typically 0.8-1.0 OD units. The values are reported as ICSOs, μΜ concentration.

FAK Inducible cell-based ELISA: Final Protocol

Materials:

Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#! [email protected]

USD)

FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD)

ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003 @60/25mg USD)

UBI aFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @ 289,00

USD)

Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs #115-035146 @95/1.5ml USD)

SuperBlock TBS (Pierce Product#37535ZZ @99 USD)

Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

-772016201820 23 Mar 2016

TMB Peroxidase substrate (Oncogene Research Products #CLG7-100m! @40.00

USD)

Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50g USD)

MTT substrate (Sigma # M-2128 @25.95/500mg USD)

Growth Media: DMEM+10%FBS, P/S, Glu, 750 pg/ml Zeocin and 50 pg/ml

Hygromycin (Zeocin InVrtrogen #R250-05 @ 725 USD and Hygromycon fnViirogen #R220-05 @ 150 USD)

Mifepristone InVitrogen # H110-01 @ 125 USD

CompleteTM EDTA-free Protease inhibitor pellet Boehringer Mannheim #1873580

FAK cell-based Protocol for selectivity of kinase-dependent phosphoFAKY397 Procedure:

An inducible FAK cell-based assay in ELISA format for the screening of chemical matter to identify tyrosine kinase specific inhibitors was developed. The cell-based assay exploits the mechanism of the GeneSwitchTM system (InVitrogen) to exogenously control the expression and phosphorylation of FAK and the kinasedependent autophosphorylation site at residue Y397. '

Inhibition of the kinase-dependent autophosphorylation at Y397 results in a reduced absorbance signal at OD450. The signal is typically 0.9 to 1.5 OD450 units with the noise failing in the range of 0.08 to 0.1 OD450 units. The values are reported as IC50s, μΜ concentration.

On day 1, grow A431*FAKwt in T175 flasks. On the day prior to running the FAK cell-assay, seed A431«FAKwt cells in growth media on 96-wel! U-bottom plates. Allow cells to sit at 37°C, 5% CO2 for 6 to 8 hours prior to FAK induction. Prepare

Mifepristone stock solution of 10 pM in 100 % Ethanol. The stock solution is subsequently diluted to 10 X of the final concentration in Growth Media. Transfer 10 pi of this dilution (final concentration of 0.1 nM Mifepristone) into each well. Allow celis to sit at 37°C, 5% CO2 overnight (12 to 16 hours). Also, prepare control wells without Mifepristone induction of FAK expression and phosphorylation.

On day 2, coal Goat Anti-Rabbit plate(s) with 3.5 pg/ml of phosphospecific

FAKpY397 polyclonal antibody prepared in SuperBlock TBS buffer, and allow plate(s) to shake on a plate shaker at room temperature for 2 hours. Optionally, control wells may be coated with 3.5 pg/mi of control Capture antibody (Whole Rabbit IgG molecules) prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 times using

-782016201820 23 Mar 2016 buffer. Block Anti-FAKpY397 coated plate(s) with 200 pi per well of 3%BSA/0,5%Tween Blocking buffer for 1 hour at room temperature on the piate shaker. While the plate(s) are blocking, prepare compound stock solutions of 5 mM in 100 % DMSO. The stock solutions are subsequently serially diluted to 100X of the final concentration in 100%

DMSO. Make a 1:10 dilution using the 100X solution into growth media and transfer 10 μΐ of the appropriate compound dilutions to each weil containing either the FAK induced or urtinduced control A431 cells for 30 minutes at 37°C, 5% CO2, Prepare RIPA lysis buffer (50 mM Tris-HCI, pH7.4,1% NP-40, 0.25% Na-deoxycholaie, 150 mM NaCl, 1 mM EDTA, 1 mM Na3VO4, 1 mM NaF. and one CompleteTM EDTA-free protease inhibitor pellet per 50 ml solution). At the end of 30 minutes compound treatment, wash off compound 3 times using TBS-T wash buffer. Lyse cells with 100 pl/well of RIPA buffer.

To the coated plate, remove blocking buffer and wash 3 times using TBS-T wash buffer. Using a 96-weli automated microdispenser, transfer 100 pi of whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397 coated plate(s) to capture phosphoFAKY397 proteins. Shake at room temperature for 2 hours. Wash off unbound proteins 3 times using TBS-T wash buffer. Prepare 0.5 pg/mi (1:2000 dilution) of UBI aFAK detection antibody in 3%BSA/0.5% Tween blocking buffer. Dispense 100 pi of UBI aFAK solution per well and shake for 30 minutes at room temperature. Wash off excess UBI aFAK antibody 3 times using TBS-T wash buffer. Prepare 0.08 pg/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase (Anti-2MHRP) conjugated antibody. Dispense 100 pi per well of the Anti-2MHRP solution and shake for 30 minutes at room temperature. Wash off excess Anti-2MHRP antibody 3 times using TBS-T wash buffer. Add 100 pi per well of room temperature TMB substrate solution to allow for color development. Terminate the TMB reaction with 100 pi per well of TMB stop solution (0.09M H2SO4) and quantitate the signal by measurement of absorbance at 450 nm on the BioRad micropiate reader.

Additional FAK cell assays are hereby Incorporated by reference from W02004/027018.

In a preferred embodiment, the compounds of the present invention have an in vitro activity as determined by a kinase assay, e.g,, such as that described herein, of less than 500 nM. Preferably, the compounds have an IC50 of less than 25 nM in the kinase assay, and more preferably less than 10 nM. In a further preferred embodiment, the compounds exhibit an IC50 in a FAK cell based assay, e.g,, such as that described

-792016201820 23 Mar 2016 herein, of less than 1 μΜ, more preferably less than 100 nM, and most preferably less than 25 nM.

Administration of the compounds of the present invention (hereinafter the “active compound(s)”) can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenai routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and recta! administration.

The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active compound may be applied as a sole therapy or may involve one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-IN-(3,4-dihydro-2-methyl-4oxoquinazolin-6-yimethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example interferon; and anti-hormones, for example antiestrogens such as Nolvadex® (tamoxifen) or, for example anti-androgens such as Casodex® (4'-cyano-3-(4-fluorophenyIsulphonyl)-2-hydroxy-2-methyl-3'(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for

-802016201820 23 Mar 2016 topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceuticat composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the iike. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium tauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the acltve compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company,

Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist

-81 2016201820 23 Mar 2016 as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated herein by reference in their entireties.

Examples Genera! Methods:

HPLC:

Where HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as foilows. The column used is a ZORBAX™ RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. The samples are run on a Hewlett Packard1100 system. A gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes. The system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes. The flow rate over this period is a constant 3 mL / minute.

Preparation of Intermediates:

The groups attached to the 4 position of the pyridine core were prepared by the methods described below for compounds B1-B19.

Preparation of N-(3-aminomethvl-phenvi)-N-methvl-rnethanesulfonamide acetate (B1):

CHj

I o

Stepl. Preparation of N-(3-cyano-phenyl)-methanesulfonamide (B1-1): A solution of 3-amino benzonitrile (10 g, 84.64 mmol) in pyridine (160 mL) was cooled to 0’C and methane sulphonyl chloride (8.6 ml, 74.8 mmol) was added. The reaction mixture was allowed to warm to 25°C and stirred for about 20 hours. The reaction mixture was then concentrated, and the resultant residue was dissolved in ethyl acetate (EtOAc) (250 mL), washed with 2N HOI (50 mL), brine (25 mL)_t and dried over anhydrous Na₂SO₄. The solution was then concentrated io provide (B1-1) as a brown

-822016201820 23 Mar 2016 solid. Yield: 17,1 g. ¹HNMR (d₆-DMSO) 8:10.25(s, 1H), 7.45-7.65(m, 4H) and 3,1 (s, 3H), Mass: <M-1) 195 calculated for C8HsN₂O₂S.

Step. 2. Preparation of N-(3-cyano-phenyl)-N-meihyl-methanesuifonamide (B12): A mixture of benzyltriethylammonium chloride (BTEAC) (2.44 g, 10.7 mmol) and B15 1 (21 g, 107.1 mmol) in tetrahydrofuran (THF) (250 mL) and 40% NaOH solution (250 mL) was cooled to 10°C, treated with methyl iodide (8.6 mL, 139.0 mmol), and allowed to warm to 25^eC. After about 20 hours the THF was removed by distillation, and the concentrated mixture was extracted with dichloromethane (DCM) (3x200 mL). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated, The resultant residue was then purified by column chromatography (60-120 mesh silica gel; 20% EtOAc in hexane as eluting solvent) to provide B1-2 as a white solid. Yield: 20 g, 89.3%. ¹HNMR (d_e-DMSO) δ: 7.9(s, 1H), 7,7-7.84(m, 2H), 7.52-7.65{m, 2H), 3.3(s, 3H) and 3.02(s, 3H). Mass: (M+1) 211 calculated for C9H10N2O2S,

Step 3. A solution of B1-2 (20 g, 95.12 mmol) in THF(100 mL) and acetic acid (400 mL) was charged to a Parr reactor. The contents of the reactor were then treated with 10% Pd/C (10.12 g) and hydrogenated at 50 Psi hydrogen pressure and 25°C for 4 hours. The contents ofthe reactor were filtered through a bed of Celite® and washed with ethanol (50 mL). The combined filtrates were then concentrated under reduced pressure, and the resultant residue was azeotroped with EtOAc (3 x 50 mL). The resultant oily mass was dissolved in EtOAc and allowed stand at 25°C for about 20 hours. The resultant white solids were collected by filtration and dried to provide B1 as the acetate salt. Yield: 15.2 g, 60%. ¹HNMR (de-DMSO) δ: 7.2-7.45(m, 4H), 4.65.65{broad, 4H), 3.75(s, 2H), 3.2(s, 3H), 2,95(s, 3H) and 1.9(s, 3H). Mass: (M+1) 215 calculated for C9H₁₄N₂O₂S. HPLC Purity: 99.1%.

Preparation of N-(3-aminoroeihvi-pyrazin-2-vh-N-methvl-methane sulfonamide acetate (B2):

Step 1. Preparation of N-(3-cyano-pyrazin-2-yl)-N-methyl-methane sulfonamide 30 (B2-1): A solution of chloropyrazine-2-carbonitrile (4.2 g, 30.21 mmol) in acetonitrile

-832016201820 23 Mar 2016 {200 ml) at 25^eC was treated sequentially with Cs₂CO₃ (13.7831 g, 42.293 mmol) and N-methyl-methane sulfonamide (3.957 g, 36.25 mmol). The mixture was then heated to BO’C. After about 20 hours the mixture was cooled to 25° and filtered. The solids were washed with EtOAc (3 x 25 mL) and the combined filtrates were concentrated. The resultant residue was treated with water (50 mL) and extracted with EtOAc (3x75mL). The combined organic layers were washed with water (50 mL). brine, dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (100-200 mesh silica gei; 40% EtOAc in petroleum ether as eluting solvent) to provide B2-1 as a pale brown liquid, Yield: 4.7 g, 73.43%). ’HNMR (CDCIs) δ: 8.92(d, 2H), 3.4(s. 3H) and 3.25(s, 3H). Mass: (M+1) 213 calculated for C7HsN₄O₂S. (Note: The product contained unreacted N-methanesuIfonamide as an impurity. The product was used without further purification to prepare B2 in the step described below.

Step 2. A suspension of B2-1 (5.345 g, 23.21 mmol) in 2N methanolic NH₃ (566.7 mL) in a Parr reactor was treated with 10% Pd/C (395 mg, 3.78 mmol), and the contents of the reactor were hydrogenated at 45 Psi hydrogen pressure and 25°C for 3 hours. The contents of the reactor were then filtered through a bed of Celite®, washed with methanol (MeOH), and concentrated. The resultant residue was treated with EtOAc (25 mL) and acetic acid (1.5 g), stirred at 25°C, and concentrated. The resultant residue was treated with EtOAc (100 mL) and allowed to stand at 25°C for about 20 hours. The resultant solids were collected, washed with EtOAc, and dried to provide B2. Yield: 3,5 g, 64,3%. IR (cm'¹}: 3453, 3222, 2937, 3859, 1641,1560, 1405, 1340 and 1155. ’HNMR (d₆-DMSO) δ: 8.7(s, 1H), 8.5{s, 1H), 5.3-5.8(broad, 2H), 4.0(s, 2H), 3.2(s, 3H), 3.12(s, 3H) and 1.84(s, 3H). Mass: (M+1) 217 calculated for C7H₁₂N₄O₂S.

Preparation of Ν-(2-8ηΊίηο['ηο1ΐΊνΙ-ρΚβηνΙ)-Ν-Γη6ίίΊνΙ-π^Ιΐ3ηβ5υ1ίοπ3η'^Θ acetate (B3):

Step 1. Preparation of N-(2-cyano-phenyl)-N-dimethanesutfonamide (B3-1): A solution of 2-amino benzonitrile (10 g, 8.46 mmol) in pyridine (250 mL) at 25°C was treated drop-wise over 30 minutes with methane sulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was then stirred at 25°C for about 20 hours and

-842016201820 23 Mar 2016 concentrated The resultant residue was dissolved in EtOAc (200 mL), washed with 2 N HCt (200 mL) and brine (30 mL), and dried over anhydrous sodium suifate. The solution was then concentrated to provide B3-1 as a yellow solid. Yield: 20.7 g, 89%. ¹HNMR (de-DMSO) 6: 8.06(d, 1H), 7.82-7.85{m, 2H), 7.7-7.75(m, 1H), 3.62(s, 6H).

Step 2. Preparation of N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (B3-2): A solution of B3-1 (4 g, 1.45 mmol) in THF (30 mL) at 25^eC was treated with 40% NaOH solution (30 mL) and BTEAC (0.331 g, 0.145 mmol) and stirred vigorously for 30 minutes. The mixture was then treated with methyl iodide (2.48 g, 1.7 mmol) and stirred at 25’C for about 20 hours. The THF was removed under reduced pressure and the mixture extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide B3-2 as a pale yellow solid. Yield: 3g, 96%. ¹HNMR (CDC!₃) S: 7.62-7.8(m, 2H), 7.55-7.56(m, 1H), 7.4-7.52(m, 1H), 3.4(s, 3H) and 3.15(s, 3H). Mass: (M-1) 209 calculated for C₃H₁₀N₂O₂S. The product was used without further purification to prepare

B3 in the step described below.

Step 3. A solution of B3-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL) and THF (25 mL) was charged to a Parr shaker. The contents of the reactor were treated with 10% Pd/C (1.01 g) and hydrogenated at 60 Psi hydrogen pressure and 25°C for 3.5 hours. The contents of the reactor were then filtered through a bed of

Celite® and washed with MeOH (20 mL). The combined filtrates were then concentrated. The resultant residue was azeotropedwith toluene (2x20 mL) and EtOAc (20 mL) and dried under vacuum to provide B3 as a white solid. Yield: 1.9 g, 95%. ¹HNMR (ds-DMSO) δ: 7.5-7.62(m, 1H), 7.25-7.5{m, 3H), 3.92-5.6(broad, 3H), 3.8(s,

2H), 3.16(5, 3H), 3.04(5, 3H) and 1.9(s, 2H). Mass: (M+1) 215 calculated for

CgHnNzOiS. HPLC Purity: 98.8%.

Preparation of N-f2-aminomethvi-pyridin-3-vl)-N-methyl-methanesulfonamide acetate salt (B4):

HHj AcOH

Step 1. Preparation of 6-chloro-pyridin-3-ylamine (B4-1): A solution of2-chloro30 5-nitro pyridine (30 g, 189 mmol) in MeOH (600 mL) was charged to a Parr reactor. The contents of the reactor were treated with Raney nickel (2 g) and hydrogenated at 60 Psi

-852016201820 23 Mar 2016 hydrogen pressure and 25°C for 16 hours. The contents of the reactor were then filtered through a Celite® bed and washed with MeOH ¢100 mL). The combined filtrates were concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel column; 10% MeOH in CHCI₃ as eluting solvent) to provide B4-1 as a pale yellow solid. Yield: 19 g, 78%. 'HNMR <CDCI₃) δ: 7.85(d, 1H), 7.1(d, 1H), 6.95(dd, 1H) and 3.52-3.98(broad s, 2H).

Step 2. Preparation of N-(6-chloro-pyridin-3-yl)-methanesulfonamide (B4-2): A solution of B4-1 (38 g, 295.7 mmol) and pyridine (28 g, 354 mm) in DCM (874 mL) at 10°C was treated drop-wise over 30 minutes with methane sulphonyl chloride (37.2 g,

325 mmol). The reaction mixture was allowed to warm to 25°C, and stirred at 25°C for hours. The mixture was then treated with DCM (300 mL) and washed with water (1500 mL) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resultant residue was washed with petroleum ether (80 mL), filtered, and dried to provide B4-2 as an off-white solid. Yield: 36 g, 60%. ¹HNMR (ds-DMSO) S:

10.12(5, 1H), 8.22(d, 1H), 7.65(dd, 1H), 7.46(d, 1H) and 3.08(s, 3H).

Step 3. Preparation of N-(6-chloro-pyridrn-3-yl)-N-methyl-methanesulfonamide (B4-3): A solution of B4-2 (13 g, 62.8 mmol), BTEAC (1.42 g, 6.2 mmol) and 40% aq. NaOH (117 mL) in THF (117 mL) at 0°C was treated drop-wise over 30 minutes with methyl iodide (10.6 g, 75.3 mmol). The reaction mixture was allowed to warm to 25’C and stirred for an additional 3 hours. The mixture was then treated with THF (100 mL), and the resultant organic layer was collected. The aqueous layer was extracted with EtOAc (2 x 100 mL), and the combined organic layers were washed with 1N NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated.

The resultant residue was then triturated with petroleum ether to provide B4-3 as a pale yellow solid. Yield; 12 g, 86%. ’HNMR (CDCI₃) 5: 8.4(d, 1H), 7.72(dd, 1H), 7.35{d,

1H), 3.38(s, 3H) and 2,88 (s, 3H). Mass: (M+1) 221 calculated for C₇H₉CIN₂O₂S.

Step 4. Preparation of N-(6-chloro-1-hydroxy-pyridin-3-yl)-N-methylmethanesulfonamide (B4-4): A solution of B4-3 (15 g, 68.1 mmol) in DCM (172 mL) was cooled to 0°C and treated slowly over 10 minutes with a solution of 77% rrt30 chloroperoxybenzoic acid (MCPBA) (27.9 g, 124 mm) in DCM (200 mL). The rate of addition was controlled so that the temperature of the reaction mixture did not exceed 3 to 5’C. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 20 hours. The mixture was then cooled to 0’C and treated with 1N NaOH (300mL). The resultant organic layer was collected and washed with 1N NaOH (100mL) and 10%

-862016201820 23 Mar 2016 sodium sulfite (100mL). The organic layer was then dried over anhydrous NaiSOa and concentrated to provide B4-4 as a white crystalline solid. Yield: 8 g, 49%. ¹HNMR (d®DMSO) 6: 8.55(s, 1H), 7.85(d, 1H), 7.46(dd, 1H), 3.26(s, 3H) and 3.1(s, 3H). Mass: (M+1) 237 calculated for C7HHCIN2O3S.

Step 5. Preparation of N-(6-chloro-2-cyano-pyridin-3-yl)-N-methyImethanesulfonamide (B4-5): Dimethylsulfaie (3.2 mL) was cooled io 0°C and treated portion-wise with B4-4 (8 g, 33.6 mmol) over 3 hours. The resultant suspension was allowed to warm to 25° and maintained at 25°C for 16 hours. The resulted gummy mass was then washed with diethyl ether. The resultant white residue was dissolved in water (37.6 mL) and added drop-wise over 30 minutes to an aqueous solution of sodium cyanide (6.5 g, 134.4 mm) at 10°C. The reaction mixture was allowed to warm to 25°C, and it was maintained at 25°C for 16 hours. The resultant brown solids were collected and dissolved in EtOAc (200 mL). The organic solution was then washed with water (500 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was concentrated, and the resultant residue was purified by column chromatography (silica gel; 10% MeOH in CHCI3 as eluting solvent) to provide B4-5 as a white solid. Yield: 2.5 g, 30%. ¹HNMR (d₆-DMSO) 3: 8.38(d, 1H), 8.02(d, 1H), 3.3(s, 3H) and 3.28(s, 3H).

Step 6. A solution of B4-5 (2.5 g, 10.2 mmol) in a mixture of THF (80 mL) and acetic acid (200 mL) was charged to a Parr reactor. The contents of the Parr reactor were then treated with 10% Pd/C (2.4 g, 22.4 mmol) and hydrogenated at 60 Psi hydrogen pressure and 25°C for 16 hours. The contents of the reactor were filtered through a Celite® bed and washed with MeOH (100 mL). The combined organic filtrates were concentrated, and the resultant residue was azeotroped with EtOAc (2x50 mL). The resultant solids were collected and dried to provide B4 as an off-white solid.

Yield: 2.0 g, 95%. IR (cm’¹): 3438, 3245, 2994, 2601, 1590,1467, 1328,1151 and 1047, ’HNMR (d₆-DMSO) δ: 8.65(d, 1H), 8.25-8.55(broad s, 2H), 8.15<d, 1H), 7.57.7(m, 1H), 4.0-4.42(5, 2H), 3.25(s, 3H) and 3.14(8, 3H). Mass: (M+1) 216 calculated for C8H13N3O2S.

Preparation of N-f3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfon3mide acetate (B5);

NHj CH.COOH v°

CH,

-872016201820 23 Mar 2016

Step 1. Preparation of N-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (B5-1): A solution of 2-chtoro-3-cyano-pyridine (10 g, 72.4 mmol) in acetonitrile (200 ml) at 25°C was treated with N-methyl-methanesulfonamide (14 g, 128.2 mmol) and Cs₂CO₃ (33 g, 101.2 mmol). The reaction mixture was slowly heated to 80°C and maintained at 80’C for 8 hours. The reaction mixture was then cooled to 25C, filtered through a Celite® bed, and concentrated. The resultant residue was treated with water (300 mL) and extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, treated with carbon, and filtered. The filtrate was then concentrated, and the resultant residue was triturated with ether (100 ml). The resultant solids were collected and dried to provide S5-1 as an off-white solid. Yield: 7 g, 46%. ¹HNMR (CDCI₃) 8: 8.6-8.72(m, 1H), 8.02-8.12(d. 1H), 7.37.45(m, 1H), 3.4(s, 3H) and 3.2(s, 3H). Mass: (M+1) 212 calculated for C_eH₉N₃O₂S. HPLC purity: 99.9%.

Step 2. A solution of B5-1 (10 g, 47.3 mmol) in ethanol was charged to a Parr reactor, and the contents of the reactor were treated with 300 mL of a 2M ammonia solution in ethanol and 5% Pd/C (1.2 g). The contents of the reactor were then hydrogenated at 60 Psi hydrogen pressure and 37°C for 3 hours and then at 30°C for 20 hours. The contents of the reactor were filtered through a Celite® bed and concentrated. The resultant residue was treated with EtOAc, cooled to 20°C, and treated with acetic acid (10 mL). The mixture was then stirred for 10 minutes and concentrated. The resultant residue was dissolved in EtOAc (150 mL) in a glass flask. The walls of the flask were then scratched, and white solids began to form. The solids were collected and washed with EtOAc followed by petroleum ether. The solids were then dried to provide B5. Yield: 11 g, 85%. ¹HNMR (CDCI₃) 5: 8.3-8.5(m, 1H), 8.04(d,

1H). 7.4-7.55(m, 1H), 6,02-7.15(broad, 3H), 3.85(s, 2H), 3.14<cl, 6H), 1.9(ε, 3H). Mass:

(M+1) 216 calculated for C₈Hi₃N3O₂S.

Preparation of N-f2-Aminomethvl-phenvD-N-methvl-rnethanesulfonamide acetate (B6):

HjN η CH₃ CHjCOjH

AAz

U

Stepl. Preparation of N-(2-Cyano-phenyl)-N-djmethanesulfonamide (B6-1): A solution of 2-amino benzonitrile (10 g, 8.46 mmol) in pyridine (250 mL) was treated

-882016201820 23 Mar 2016 drop-wise at 25°C over 30 minutes with methane sulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was then stirred at 25°C for 20 hours and concentrated. The resultant residue was dissolved in EtOAc (200 mL) and washed with 2 N HCI (200 mL) and brine (30 mL). The solution was dried over anhydrous sodium sulfate and concentrated to provide B6-1 as a yellow solid. Yield: 20.7 g, 89%. ^NMR (d₆-DMSO): δ 8.06(d, 1H), 7.82-7.85(m, 2H), 7.7-7,75(m, 1H), 3.62(s, 6H). The product was used without further purification to prepare B6-2 in the step described below.

Step 2. Preparation of N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide (B62): A solution of BG-1 (4 g, 1.45 mmol) in THF (30 mL) was treated with 40% NaOH (30 mL) and BTEAC (0.331 g, 0.145 mmol) at 25’C and stirred vigorously for 30 minutes. The mixture was then treated with methyl iodide (2.48 g, 1.7 mmol) and stirred at 25*C for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with OCM (3 x 50 mL). The combined organic layers were v/ashed with brine, dried over anhydrous sodium sulfate, and concentrated to provide

BG-2 as pale yellow solid. Yield: 3 g, 96%. ¹H NMR(CDCI₃): δ 7.62-?.8(m, 2H), 7.557,56(m, 1H), 7.4-7.52{m, 1H), 3.4{s, 3H) and 3.15(s, 3H). Mass: (M-1) 209 calculated for C9H10N2O2S. The product was used without further purification to prepare B6 in the step described below.

Step 3. A solution of B6-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL) and THF (25 mL) was charged to a Parr reactor. The contents of the reactor were treated with Pd/C (1.01 g) and hydrogenated at 60 Psi hydrogen pressure and 25°C for 3.5 hours. The mixture was then filtered through a bed of Celite® and washed with methanol (20 mL). The combined filtrates were concentrated, and the resultant residue was azeotroped with toluene (2x20 mL) followed by EtOAc (20 mL). The residue was then dried under reduced pressure to provide B6 as a white solid, Yield: 1.9 g, 95%. ¹HNMR (ds-DMSO): δ 7.5-7.62(m, 1H), 7.25-7.5(m, 3H), 3.92-5.6(broad, 3H), 3.8(s, 2H). 3.16(s, 3H), 3.04(s, 3H) and 1.9(s, 2H), Mass: (M+1) 215 calculated for C9H14N2O2S. HPLC Purity: 98.8%.

Preparation of N-(2-Aminomethyl-phenyl)-methanesulfonamide acetate (B7):

h₃n.

CHjCOjH

-892016201820 23 Mar 2016

Step 1. Preparation of N-(2-cyano-phenyl)-methanesulfonamide (B7-1): A solution of B6-1 (4 g, 14.8 mmol) in THF (29.26 mL) was treated with 40% aqueous NaOH (29.26 mL) and BTEAC (0.331 g, 1,45 mmol) and stirred at 25’C for 20 hours. The reaction mixture was then concentrated, and the resultant residue was diluted with water (100 mL) and neutralized with 6N HCI (30 mL). The mixture was extracted with DCM (200 mL), and the organic layer was washed with water (150 mL) and brine, The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide B7-1 as a white solid. Yield: 2.8 g, 92%. ’HNMR(CDCI3): δ 7.7~7.76(m, 1H), 7.6-7.65(m, 1H), 6.8-6.98(broad, 1H) and 3.14(s, 3H). Mass: (M-1) 195 calculated for

C_eH₈N₂O2S.

Step 2. A solution of B7-1 (2 g, 10.19 mmol) in a mixture of THF (133 mL) and acetic acid (250mL) was charged to a Parr reactor. The contents of the reactor were then treated with 10% Pd/C (2 g) and hydrogenated at 60 Psi hydrogen pressure and 25°C for 4 hours. The reaction mixture was filtered through Celite® bed and concentrated. The resultant residue was diluted with toluene (20 mL) and concentrated. The resultant residue was then diluted with EtOAc (20 mL) and concentrated to provide B7 as white solid. Yield: 2 g, 98%. ’HNMR (ds-DMSO): δ 7.32-8.6(broad, 4H), 7,257.32{m, 1H), 7.1-7.32(m, 2H), 6.82(t, 1H), 3.9(s, 2H), 2.85<s, 3H) and 1.9(s, 3H). Mass: (M+1) 201 calculated for C_eHi₂N₂O₂S. HPLC Purity: 98.9%.

Preparation of N-(2-Aminomethvl-3-rrtethvl-pheny[)-methanesulfonamide acetate (B8):

CH;

Step 1. Preparation of N-(2-cyano-3-methyl-phenyi)-N-dimethanesuifonamide (B8-1): A suspension of 2-amino-6-methyl benzonitrile (35 g, 265.5 mmol) in pyridine (600 mL) was cooled to about 0“C to -5°C and slowly treated with mesyl chloride (30 mL, 397.71 mmol) over 10 minutes. The reaction mixture was allowed to warm to 26°C and stirred at 25°C for 20 hours. The reaction mixture was concentrated and the resultant residue was diluted with EtOAc (600 mL). The organic solution was then washed with water (100 mL), 2N HCI (100 mL), and saturated brine (100 ml). The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide B8-1 as a mixture of di- and mono-mesylated products. Yield: 49 g. The

-902016201820 23 Mar 2016 product was used without further purification to prepare B8-2 in the step described below.

Step 2. Preparation of N-(2-cyano-3-methy)-phenyl)-methanesulfonamide (B8-2): A solution of B8-1 (35 g, 166.6 mmol) in THF (300 mL) was treated with 40% aq. NaOH solution ¢300 mL) and BTEAC (1.84 g, 8.09 mmol) at 25°C and stirred for 1 hour. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (500 mL). The aqueous layer was acidified with 2N HCI and extracted with DCM (250 mL). The combined organic layers were washed with water (100 mL) and brine (50 mL). The organic solution was then dried over anhydrous sodium sutfafe and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gel; 3% MeOH in CHCI₃ as eluting solvent) to provide B8-2 as a brown solid. Yield: 24 g. ’HNMR (d₆-DMSO): 5 9.98(s, 1H), 7.6(f, 1H), 7.26-7.4(m, 2H), 3.1(s, 3H), 2.5(s. 3H). Mass: (M-1) 209 calculated for C₉H₁₀N₂O₂S.

Step 3. A solution of B8-2 (10 g, 47.6 mmol) in acetic acid (75 mL) and THF (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (6 g). The reaction mixture was then hydrogenated at 50 Psi hydrogen pressure and 25°C for 16 hours.

The reaction mixture was filtered through a Celite® bed and washed with ethanol (3 x 20 mL). The combined filtrates were concentrated, and the resultant residue was codistilled with EtOAc (100 mL). The resultant brown oil was dissolved in EtOAc (100 mL) and allowed to stand at 25°C for 20 hours. The resultant white solids were collected and dried to provide B8. Yield: 11 g. ¹HNMR (d₆-DMSO): δ 7.65-8.65{broad, 3H),

7.15(d, 1H), 7.05(t, 1H), 6.68{d, 1H), 3.9(ε, 2H), 2.8(ε, 3H), 2,26(s, 3H) and 1.9(s, 3H). Mass: (M+1) 215 calculated for C9H14N2O2S, HPLC Purity: 98.6%.

Preparation of N-(2-Aminomethvl-3-methyl-phenvl)-N-methyl25 methanesulfonamide acetate (B9):

HjN.

CM.

CMj

I 0 ^N>/

CMj

CHjCOjH

Step 1. Preparation of N-(2-cyano-3-methyl-phenyl)-N-methytmethanesulfonamide (B9-1): A solution of B8-1 (15 g, 71.42 mmol) in THF (150 mL) was treated with 40% aq. NaOH (150 mL) and BTEAC (1.6 g, 7.14 mmol) at 25°C and stirred for 10 minutes. The reaction mixture was then cooled to 10’C and treated with methyl iodide (5.78 mL, 85.7 mmol). The reaction mixture was allowed to warm to 25°C

-91 2016201820 23 Mar 2016 and stirred at 25°C for 20 hours. The reaction mass was concentrated, and the resultant residue was diluted with DCM (600 mL). The organic solution was then washed with water (100 mL) and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated. The resultant residue was then purified by column chromatography (60-120 mesh silica gel; 2% MeOH in CHCb as eluting solvent) to provide B9-1 as paie brown solid. Yield: 20 g, 98%. ’HNMR (d₆-DMSO): δ 7.65(d, 1H), 7,56(d, 1H), 7.45(d, 1H), 3.25(s, 3H), 3.14(s, 3H) and 2.5(s, 3H). Mass: (M+1) 225 calculated for Ck)Hi₂N₂O₂S.

Step 2. A solution of B9-1 (10 g, 47.6 mmol) in a mixture of THF (100 mL) and 10 acetic acid (300 mL) was charged to a Parr reactor and treated with Pd/C (6 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25°C for 6 hours. The reaction mixture was filtered through a bed of Celite® and washed with ethanol (3 x 30 mL). The combined filtrates were concentrated, and the resultant residue was co-distilied with EtOAc (100 mL). The resultant brown oil was taken into

EtOAc (100 mL) and stirred at 25°C for 16 hours. The resultant white solids were coilected, washed with EtOAc (2 x 25 mL), and dried to provide BS. Yield: 11.6 g, 89%. ’HNMR (de-DMSO): δ 7.15-7.36(m, 3H), 4.64-5.45(broad, 3H), 3.76(d, 2H), 3.15(s, 3H), 3.05(s, 3H), 2.42(s, 3H) and 1.9(s, 3H). Mass: (M+1) 229 calculated for Ci₀Hi₆N₂O₂S. HPLC Purity: 97.4%.

Preparation of N“(2-Aminoroethvl-5-methyl-phenv0-methanesulfonamide acetate (B10):

H

I 0

-CHjCOjH |*°

CH,

CH,

Step 1. Preparation of 2-amino-4-methyt-benzonitrile (B10-1): A solution of 4methyt'2-nitrobenzonitrile (10 g, 61.72 mmol) in ethanol (200 mL) was charged to a Parr reactor and treated with 10% Pd/C (1 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure 25°C for 90 minutes. The reaction mixture was filtered through a Celite® bed and washed with ethanol. The combined filtrates were the concentrated to provide B10-1. Yield: 8.5 g. ’HNMR (CDCI₃): δ 7.28(s, 1H), 6.5-6.62(m, 2H), 4.2-4.42(broad, 2H) and 2.3(s, 3H). Mass: (M-1) 132 calculated for

CeH8N₂. The product was used without further purification to prepare B10-2 in the step described below.

-922016201820 23 Mar 2016

Step 2. Preparation of N-^-cyano-S-methyl-phenyO-methanesulfonamide and N(2-cyano-5-methyl-phenyl)-N-(methylsulfonyl)methanesulfonamide (B10-2): A solution of B10-1 (8.5 g, 64.39 mmol) in pyridine (50 mL) was cooled to 0’C and treated dropwise with mesyl chloride (8.85 g, 77.22 mmol) over 15 minutes. The reaction mixture was allowed to warm to 25°C, and it was stirred at 25°C for 20 hours, The reaction mixture was then concentrated, and the resultant residue acidified with 2N HCl (50 mL) and extracted with EtOAc (200 mL). The resultant organic layer was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B10-2 as a mixture of both mono and di mesylated product. Yield: 9.2 g. The product was used without further purification to prepare B10-3 in the step described below.

Step 3. Preparation of N-(2-cyano-5-methyl-phenyl)-methanesuIfonamide (B103): A solution of B10-2 (17 g, 80.95 mmol) in a mixture of THF (70 mL) and 40% NaOH solution (70 mL) was treated with BTEAC (1.84 g, 8.09 mm) at 25°C and stimed at 25°C for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (300 mL). The aqueous layer was acidfied with 2N HCl and extracted with DCM (200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel; 30% EtOAc in DCM as eluting solvent) to provide B10-3 as a pale brown solid. Yield: 16 g, 97%. ¹HNMR (d₆-DMSO): δ 7.9(d, 1H), 7.7(s, 1H), 7.55(d, 1H), 3.62(s, 6H) and 2.45(s, 3H). Mass: (M-1) 209 calculated for CgHioN₂0₂S.

Step 4. A solution of B10-3 (17 g, 80.95 mmol) in a mixture of THF (250 mL) and acetic acid (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (8 g), at 25°C. The reaction mixture was then hydrogenated at 50Psi hydrogen pressure and 25ⁱC for 4 hours. The mixture was filtered through a Celite® bed and washed with ethanol (3 x 20 mL). The combined filtrates were concentrated and the resultant residue was azeotroped with EtOAc (2 x 20 mL). The resultant brown-colored oil was taken Into

EtOAc (50mL) and allowed to stand at 25°C for 20 hours. The resultant white solids were collected and dried to provide B10. Yield; 15.1 g, 71.2%. 'HNMR (d₆-DMSO): δ 7.62-8.2(broad, 3H), 7.02-7.18(m, 2H), 6.7(d, 1H), 3.85(s, 2H), 2.88(s, 3H), 2.25{s, 3H) and 1.9(s, 3H). Mass: (M+1) 215 calculated for C₉H,₄N₂O₂S. HPLC Purity: 99.7%.

-932016201820 23 Mar 2016

Preparation of N-(2-Aminomethyl-5-methyl-phenyl)-N-methy[methanesulfonamide acetate (B11);

HjN

CHj

Step 1. Preparation of N-(2-cyano-5-methyl-phenyl)-N-methyi5 methanesulfonamide (B11-1): A solution of B10-2 (10 g, 47.61 mmol) in a mixture of THF (100 mL) and 40% aq. NaOH solution (100 mL) at 25°C was treated with BTEAC (1.1 g, 4.7 mmol) and methyl iodide (8.78 g, 61.89 mmol). The reaction mixture was then stirred at 25°C for 20 hours. The THF was removed under reduced pressure, and the concentrated mixture was extracted with DCM (300 mL). The organic layer was washed with water (100 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel; 10% EtOAc in CHCI₃ as eluting solvent) to provide B11-1 as a brown solid. Yield; 10.3 g, 96%. ¹HNMR (CDCIj): 8 7.62(d, 1H), 7.38(s, 1H), 3.38(5, 3H), 3.1 (s, 3H) and 2.45(s, 3H). Mass: (M-1)

223 calculated for C_wHi2N₂O2S.

Step 2. A solution of B11-1 (4 g, 17.85 mmol) in acetic acid (150 mL) was charged to a Parr reactor and treated with Pd/C (2 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25°C for 6 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (2 x 20 mL). The combined filtrates were concentrated, and the resultant brown solid was azeotroped with EtOAc (3 x 25 mL). The resultant solid was taken into EtOAc (25 mL) at stirred at 25^eC for 20 hours. The resultant solids were collected and dried under reduced pressure to provide B11. Yield: 2.7 g, 53%. ¹HNMR (d₆-DMSO): δ 7.45(d, 1H), 7.3(s, 1H), 7.2<d,

1H), 5.04-5.7(broad, 2H), 3.75-3.92(brosd, 2H), 3.15(s, 3H), 3.05(s, 3H), 2.3(s, 3H) and

1.9(s, 2H). Mass: (M+1) 229 calculated for C,₀Hi_BN₂O2S. HPLC Purity; 97.7 %.

Preparation of N-(2-Aminomethvl-6-methvl-phenvl)-N-methvlmethanesulfonamide trifluoroacetate (B12):

'CFjCOjH

-942016201820 23 Mar 2016

Step 1. Preparation of potassium di-tert-butyl iminodicarboxylate (B12-1): A solution of di-tert-butyl iminodicarboxylate (56 g, 258 mmol) in ethanol (200 ml) was coofed to 15^eC and treated over 30 minutes with a solution of KOH (17g) in ethanol (150 mL). The reaction mixture was allowed to warm to 25°C, and it was stirred at 25°C for 4 hours. The reaction mixture was then concentrated, and the resultant residue was diluted with diethyl ether (300 mL) and stirred for 3 hours. The resultant solids were collected and immediately dried under reduced pressure to provide B12-1 as a white crystalline solid. Yield: 57 g, 82%. ¹HNMR (d₆-DMSO): δ 1.35(s, 18H). Mass: (M-1) 216 calculated for CioHi₉N0₄,

Step 2. Preparation of 1-chloromethyl-3-methyl-2-nitro-benzene (B12-2): A solution of 3-(methyl-2-nitro-phenyl)-methanot (12 g, 71.78 mmol) in DCM (500 mL) was cooled to -5^OC and treated with dimethylaminopyridine (DMAP) (11.4 g, 93.3 mm) followed by treatment with a solution of tosyl chloride (17.79 g, 93.3 mmol) in DCM. The reaction mixture was stirred at -5°C for 30 minutes. The reaction mixture was then allowed to warm to 25°C, and it was stirred at 25°C for 20 hours. The reaction mixture was diluted with DCM (100 mL) and washed with 1N HCI (2 x 50 mL), saturated NaHCOg (2 x 25 mL), and brine. The organic solution was then dried over anhydrous MgS0₄ and concentrated. The resultant residue was purified by column chromatography (silica gel column; 15% EtOAc in hexane as eluting solvent) to provide

B12-2 as a pale greenish-yellow oil. Yield: 14 g, 89%. ¹HNMR (CDCb): δ 7.35-7.46(m,

2H). 7.26-7.35(m, 1H), 4.6(s, 2H) and 2.36(s, 3H),

Step 3. Preparation of 3-methyl-2-nitro-benzyl di-tert-butyl iminodicarboxylate (B12-3): A solution of B12-2 (14 g, 75.6 mmol) in N-methylpyrrolidinone (NMP) (135 mL) was cooled to -5°C and treated with B12-1 (29.7 g, 116.4 mmoi) over 20 minutes.

The mixture was then heated at 50°C for 4 hour. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (4 x 250 mL). The combined organic layers were washed with water (300 mL) and brine. The organic solution was then dried over anhydrous MgSO₄and concentrated. The resultant residue was purified by column chromatography (silica gel; 20% EtOAc in hexane as eluting solvent) to provide B12-3 as an-off white solid. Yield: 21 g, 76%. ’HNMR (CDCI₃): S 7.35(1,1H), 7.1-7.25(m, 2H), 4.76(s, 2H), 2.3(s, 3H) and 1.42(s, 18H).

Step 4. Preparation of 2-amino-3-methyl benzyl di-tert-butyl iminodicarboxylate (B12-4); A solution of B12-3 (20 g, 54.64 mmol) in ethanol (500 mL) was charged to a Parr reactor and treated with 10% Pd/C (7 g). The contents of the reactor were then

-952016201820 23 Mar 2016 hydrogenated at 55 Psi hydrogen pressure and 25^eC for 5 hours. The reaction mixture was filtered through a Celite® bed and concentrated to provide B12-4 as a pale greenish-yellow oil (19 g). ¹HNMR (CDCi₃): δ 7.1 (d, 1H), 6.96(d, 1H), 6.6(t, 1H), 4.7{s, 2H), 4.3-4.5(broad, 2H), 2.15(s, 3H) and 1.45(s, 18H).

Step 5. Preparation of di-BOC 3-methyl-2-(methylsulfonamido)benzylamine (B12-5): A solution of B12-4 (20 g, 59.6 mmol) in pyridine (150 mL) was cooled to 0°C and treated over 25 minutes with mesyl chloride (6.15 mL, 79.4 mmol). The mixture was allowed to warm to 25°C, and it was stirred at 25°C for 20 hours. The reaction mixture was diluted with EtOAc (300 mL) and washed with 1N HCI solution. The aqueous layer was collected and extracted with EtOAc (100 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO₄. The organic solution was then concentrated, and the resultant residue was taken into petroleum ether and stirred for 1 hour. The resultant solids were collected and dried under reduced pressure to provide B12-5 as an off white solid. Yield: 22 g, 89%. ¹HNMR (CDCi₃): δ 7.9(s, 1H), 7.35(d, 1H), 7.05-7.25(m, 2H), 4.9(s, 2H), 3.1(s, 3H), 2.45(s, 3H) and 1.45{s, 18H). Mass: (M-1) 413 calculated for CigHaoNiOeS.

Step S. Preparation of di-BOC 3-methyl-2-(N-methylmethan-2ylsulfonamidojbenzylamtne (B12-6): A solution of B12-5 (22 g, 53.14 mmol) in THF (58.6 mL) was cooled to 15°C and treated with 40% aq NaOH solution (58.6 mL) followed by BTEAC (1.25 g, 5.5 mm). The mixture was stirred for 15 minutes and the treated over 20 minutes with methyl iodide (4.2 mL, 67,4 mmol). The reaction mixture was allowed to warm to 25’C, and it was stirred at 25’C for 20 hours. The reaction mixture was then diluted with water (300 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with water (3 x 400 mL) and brine, dried over anhydrous MgSO₄, and concentrated. The resultant residue was dissolved in petroleum ether in a glass flask, and the wall of the flask was scratched to induce solids formation. The resultant solids were collected and dried to provide B12-6 as a pale yellow solid. Yield: 20 g, 88%. ’HNMR (CDCI₃): δ 7.1-7.25(m, 2H), 7.04(d, 1H), 5.05(d, 1H), 4.B(d, 1H), 3.25(s,3H), 3.1(s, 3H), 2.36(s, 3H) and 1.45(s, 18H).

Step 7, A solution of B12-S (13 g, 30.3 mmol) in DCM (35 mL) was cooled to 0°C and treated with trifluoroacetic acid (TFA) (70 mL), The reaction mixture was allowed to warm to. 25’C, and it was stirred at 25’C for 2 hours. The reaction mixture was concentrated, and the resultant residue was azeotroped with EtOAc (2 x 100 mL). The resultant residue was diluted with a mixture of DCM and pentane (1:1) in a glass flask,

-962016201820 23 Mar 2016 and the wall of the flask was scratched. The contents of the flask were stirred for 1 hour, and the resultant precipitate was collected and dried to provide B12 as an off white solid. Yield; 9 g, 87%. ’HNMR (d₆-DMSO): δ 8.3-8.45(broad, 2H), 7.38-7.5(m, 3H), 4.2(s, 2H), 3.14{s, 6H), and 2.44(s, 3H). Mass: (M+1) 229 calculated for

C_1DH₁₆N₂O₂S. HPLC Purity: 97.5%,

Preparation of N-(2-Aminomethyl-4-methyl-phenyi-N-methyl-methanesulfonamide trifluoroacetate (B13):

Step 1. Preparation of di-BOC-5-methyl-2-nitrobenzylamrne (B13-1): A solution of 2-chloromethyl-4-methyI-1-nitro-benzene (20 g, 107.5 mmol) in NMP (140 mL) was cooled to 0’C and treated over 30 minutes with potassium di-tert-butyl iminodicarboxylate (40 g, 156 mmol). The reaction mixture was allowed to warm to 25°C, and it was stirred at 25’C for 20 hours. The reaction mixture was then diluted with water (150 mL) and extracted with EtOAc (2 x 500 mL). The resultant organic layer was washed with water (250 mL) and brine, and dried over anhydrous MgSO< The organic solution was then concentrated, and the resultant residue was purified by column chromatography (silica gel; 20% EtOAc in hexane as eluting solvent) to provide B13-1 as a pale yellow solid. Yield: 29 g, 73%. ’HNMR (CDCl₃): δ 7.98(d, 1H), 7.2(d, 1H), 7.1(s, 1H), 5.15(s, 2H), 2.4{s, 3H) and 1.44(s, 18H).

Step 2. Preparation of di-BOC 2-amino-5-methylbenzylamine (B13-2): A solution of B13-1 (29 g, 79.23 mmol) in ethanol (500 mL) was charged to a Parr reactor and treated with Pd/C (9 g). The contents of the reactor were then hydrogenated 55 Psi hydrogen pressure and 25’C for 2 hours. The reaction mixture was filtered through a Celite® bed and concentrated to provide B13-2 as an oil. Yield: 26 g. ’HNMR (CDCI₃):

δ 7.02(s, 1H), 6.85(d, 1H), 6.55(d, 1H) 4.7(s, 2H), 4.02-4.38(broad, 2H), 2.22(s, 3H) and 1.46(s, 18H).

Step 3. Preparation of di-BOC 5-meihyl-2-(methyIsu!fonamido)benzyIamine (B13-3): A solution of B13-2 (26 g, 77.38 mmol) in pyridine (165 mL) was cooled to 0’C and treated over 20 minutes with mesyl chloride (12.18 g, 106.4 mmol) was added over a period of 20 min. The mixture was allowed to warm to 25^eC, and it was stirred at

25’C for 20 hours. The reaction mixture was then diluted with EtOAc (350 mL) and

-972016201820 23 Mar 2016 washed with 1N HCI solution (2 x 250 mL). The resultant organic layer was washed with brine, dried over anhydrous MgSCU, and concentrated. The resultant residue was treated with petroleum ether and stirred at 25°C for 1 hour. The resultant solids were then collected and dried under reduced pressure to provide B13-3 as a pale yellow solid. Yield: 23 g, 71%, ¹HNMR (CDCI₃): δ 8.7(s, 1H), 7.45(d, 1H), 7.1 (d, 1H), 4.72{s, 2H), 2.96(s, 3H), 2.3{s, 3H) and 1.46(5, 18H). Mass: (M-1) 413 calculated for Ci₉H₃oN₂0₆S.

Step 4. Preparation ofdi-BOC 5-methyl-2-(N-methyimethan-2ylsuffonamtdo)benzylamine (B13-4): A solution of B13-3 (22 g, 53.14 mmol) in THF (70 mL) was cooled to 0°C and treated with 40% aq. NaOH solution (70 mL) followed by BTEAC (1.5 g, 6.6 mmol). After 15 minutes the mixture was treated with methyl iodide (9.51 g, 67.4 mmol) over a period of 20 minutes. The reaction mixture was allowed to warm to 25°C, and it was stirred at 25°C for 20 hours. The reaction mixture was then diluted with DCM (800 mL). The organic layer was collected and washed with water (2 x

200 mL) and brine, and dried over anhydrous MgSO₄. The organic solution was concentrated, and the resultant residue was triturated with petroleum ether to provide B13-4 as a pale yellow solid. Yield: 20 g, 88%. *HNMR (CDCI₃): δ 7.0-7,4(m, 3H), 4.85-5.1(d, 2H), 3.25(s, 3H), 2.92(s, 3H), 2.35(s, 3H) and 1.45(s, 18H).

Step 5. A solution of B13-4 (15 g, 35.04 mmol) in DCM (45 mL) was cooled to

0“C and treated over 30 minutes with TFA (90 mL). The mixture was then allowed to warm to 25°C. After 3 hours the mixture was concentrated, and the resultant residue was azeotroped with EtOAc (2 x 200 mL). The resultant residue was diluted with a mixture of DCM and ether (8:2) and stirred for 1 hour. The resultant precipitate was collected and dried under reduced pressure to provide B13 as an off-white solid. Yield:

12 g, 98%. ’HNMR (d_e-DMSO): δ 7.98-8.2(broad, 2H), 7.5(d, 1H), 7.4(s, 1H), 7.3(d,

1H), 3.96~4,28(broad, 2H), 3.2(s, 3H), 3.05(s, 3H) and 2.35{s, 3H). Mass: (M+1) 229 calculated for CioH₁₆N₂0₂S.

Preparation of N-(3-Aminomethvi-6-rnethvl-pyridin-2-vl-N-roethvlmethanesulfonamide acetate (B14):

-982016201820 23 Mar 2016

Step 1. Preparation of N-(3-cyano-6-methyi-pyridin-2-yl)-N-methytmethanesuifonamide (B14-1): A solution of 2-chloro-6-methyl-nicotinonitriIe {20 g,

131.5 mmol) in acetonitrile (300 mL) at 25°C was treated with HN(CH₃)SO₂Me (13.1 mL, 124.1 mmol) and Cs₂CO₃ (60 g, 184.0 mm). The reaction mixture was then stirred at

80°C for 15 hours. The reaction mixture was allowed to cool to 25°C and filtered. The resultant filtrate was concentrated and diluted with EtOAc (600 mL). The organic solution was then washed with water (2 x 250 mL) and brine, and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was recrystatlized with ether to provide B14-1 as an off white solid. Yield: 18.5 g,

62.5%. ¹HNMR(CDCI₃): δ 7.9{d, 1H), 7.16-7.26(m, 1H), 3.28(s, 3H), 3.24(s, 3H) and

2.22(s, 3H). Mass: (M+1) 226 calculated for C₉H„N₃O₂S.

Step 2. A solution B14-1 (10 g, 44.4 mmol) in a mixture of THF (100 mL) and acetic acid (900 mL) was charged to a Parr reactor and treated with 10% Pd/C (9 g,

84.9 mmol). The contents of the reactor were then hydrogenated at 55 Psi hydrogen pressure and 40°C for 4 hours. The reaction mixture was then filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc (100 mL) and stirred for 3 hours. The resultant solids were collected and dried under reduced pressure to provide B14 as an off-white solid. Yield: 10 g, 98%. ¹HNMR (dg-DMSO): δ 7.9(d, 1H), 7.3(d, 1H), 7.0-7.25(broad, 2H), 3.82(s, 2H), 3.06-3.18(d, 5H), 2.45(s, 3H) and 1.82-1.96(m, 5H). Mass: (M+1) 230 calculated for C₉H_1SN₃O₂S. HPLC Purity: 98.1%.

Preparation of N-(3-Aminomethyl-5-methvl-pyridin-2-vl)-N-methylmethanesulfonamide acetate (B15):

Step 1. Preparation of 5-methyi-nicotinic acid (B15-1): A solution of 3,5 iutidine (100 g, 934.57 mmol) in water at 25°C was treated portion-wise over 5 hours with KMnQ« (221.1 g, 1401.86 mmol). The reaction mixture was then heated at 45^OC for about 20 hours. The reaction mixture was filtered and washed with water, The resultant filtrates were concentrated, and the resultant residue was diluted with ethanol (3 x 500 mL), boiled, and filtered. The filtrate was then concentrated under reduced pressure to

-992016201820 23 Mar 2016 provide B15-1 as a white solid. Yield; 76 g, 59.4%. ¹HNMR (D₂O): δ 8,6-8.7(s, 1H), 8.3-8.4(m, 1H), 7.92(s, 1H) and 2.3(s, 3H). Mass: (M+1) 138 calculated for C₇H₇NO₂.

Step 2. Preparation of 5-methyl-nicolinamide (B15-2): A suspension of B15-1 (70 g, 510 mmol) in thionyi chloride (350 mL) was heated at 80°C for 20 hours. The resultant clear solution obtained was allowed to cool to 25°C and concentrated. The resultant residue was diluted with 1,2 dichloroethane (1.5 L), cooled to -5’C, and treated with NH₃ gas via bubbler until the mixture was saturated. The mixture was allowed to warm to 25°C, stirred for 3 hours, and concentrated. The resultant brown solid was taken in EtOAc (3 x 800 mL), refluxed for 20 min, and filtered. The resultant filtrate was then concentrated to provide B15-2 as a brown solid. Yield: 52 g, 75%. ’HNMR (de-DMSO): δ 8.85-8.9(s, 1H), 8.55(s, 1H), 8.05-8.18(m, 1H), 8.02(s, 1H), 7.487.65(s, 1H) and 2.35{s, 3H). Mass: (M+1) 137 calculated for C₇H₃N₂O.

Step 3, Preparation of 1-Hydroxy-5-methyl-nicotinamide (B15-3); A solution of B15-2 (35 g) in acetic acid (200 mL) was cooled to 10°C and treated over 10 minutes with H₂O₂ (40% solution in water, 200 mL). The reaction mixture was allowed to warm to 25°C and then heated at 80°C for 20 hours. The reaction mixture was cooled to 0°C, treated with 20% sodium sulfite solution (200 mL) and basified with 35% NH4OH (200 mL), The mixture was then allowed to warm to 25°C and stirred for an additional 2 hours. The resultant solids were collected and dried under reduced pressure to provide

B15-3 as a white solid. Yield: 30.1 g. ¹HNMR (d₆-DMSO); δ 8.45(s, 1H), 8.3(s, 1H),

7.6(s, 1H), 4.42-4.7(broad m, 2H), 2.3(s, 3H). Mass: (M-1) 153 calculated for C₇HtoN₂0₂.

Step 4. Preparation of 2-chloro-5-methyl-nicotinonitrile (B15-4): Neat POCI3 (120 mL) was cooled to about 10'C and treated portion-wise over 10 minutes with BIS25 3. The reaction mixture was then heated at 60°C for 2 hours. The reaction mixture was concentrated, cooled to about 10’C, basified with saturated Na₂CO₃, and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (50 mL), and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was purified by column chromatography (siiica gel; 35% EtOAc in hexane as eluting solvent) to provide to B15-4 as a white solid. Yield: 3.5 g, 68%. ’HNMR (d_s-DMSO): δ 8.42(s, 1H), 7.82(s, 1H) and 2.4(s, 3H).

Mass: (M+1) 153 calculated for C₇H₅CIN2.

Step 5. Preparation of N-(3-cyano-5-methyl-pyridin-2-yI)-N-methylmethanesulfonamide (B15-5): A suspension of B15-4 (16 g, 0.1049 mmol) in

- 1002016201820 23 Mar 2016 acetonitrile (150 mL) at 25⁶C was treated with CS2CO3 (51.3 g, 0.157 mmol) and Nmethyl methane sulphonamide (12.5 g, 0.115 mmol). The reaction mixture was then heated at 80°C for 20 hours. The reaction mixture was filtered through a Celite® bed and washed with acetonitrile (3 x 50 mL). The combined filtrates were concentrated, and the resultant residue was diluted with EtOAc (500 mL) and washed with water (3 x 100 mL). The resultant organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by column chromatography (silica gel; 40% EtOAc in hexane as eluting solvent) to provide B15-S as pale yellow solid. Yield; 15.1 g, 62.8%. ¹HNMR (de-DMSO): 8 8.65(ε, 1H),

8.3{s, 1H), 3 3.22-3.26(5, 3H),.15-3.22(s, 3H) and 2.36(s,3H). Mass: (M+1) 226 calculated for CaHnN₃O₂S,

Step 6. A solution of B15-5 (15 g) in a mixture of acetic acid (200 mL) and THF (200 mL) was charged to a Parr reactor and treated with Pd/C (4 g). The contents of the reactor were then hydrogenated at 50 Psi hydrogen pressure and 25°C for 5 hours. The mixture was filtered through a Celite® bed and washed with ethanof (50 mL). The filtrate was concentrated under reduced pressure, and the resultant residue was purified by column chromatography (silica gel; 5% MeOH in CHCI3 as eluting solvent) to provide B15 as a reddish brown solid. Yield: 12.3 g, 98%. IR (cm‘¹): 3450, 3264, 2937, 2161, 1706, 1633, 1548, 1413, 1321 and 1151. ^ΊΗΝΜΡ (de-DMSO): δ 8.3(s, 1H), 7.9(s, 1H),

7.02-7.25(broad s, 2H), 3.92(s, 2H), 3.15(d, 6H), 2.4(s, 3H), 1.92(s, 3H). Mass: (M+1)

CgHisNsOzS. (Note: Few drops of triethytamine was added to the mobile phase during the process of silica gel column purification.)

Preparation of N-(3-Aminomethvi-4-methvl-pyridin-2-vl)-N-methvlmethanesulfonamide (B16):

Step 1. Preparation of N-(3-cyano-4-methyi-pyridin-2-yl)-N-methylmethanesulfonamide (B16-1): A suspension of 2-ch!aro-4-methyf-nicotinonitrile (4 g,

26,2 mmol) (see WO 02/30901), N-methyl methane sulphonamide ¢3.43 g, 31.4 mmol) and CsCO₃ (12 g, 36.7 mmol) in acetonitrile (40 mL) was heated at 60°C for 20 hours.

The reaction mixture was filtered through a Celite® bed and washed with acetonitrile (40 mL), The combined filtrates were concentrated, and the resultant residue was diluted

- 101 2016201820 23 Mar 2016 with EtOAc (100 mL). The organic solution was washed with water (100 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated, and the resultant residue was stirred in methanol. The resultant solids were collected and dried under reduced pressure to provide B16-1 as a white solid. Yield: 1.6 g, 26%. ’HNMR (CDCI₃): 6 8.46(d, 1H), 7.25<m, 1H), 3.26(5, 3H), 3.18(s, 3H) and 2.6(s, 3H). Mass: (M+1) 226 calculated for CgHnN3O₂S.

Step 2. A solution of B16-1 (5 g, 22.1 mmol) in 2N ethanolic ammonia (250 mL) was charged to a Parr reactor and treated with 10% Pd/C (5 g, 47 mm). The contents of the reactor were then hydrogenated at 60 Psi hydrogen pressure and 25°C for 6 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (50 mL). The combined filtrates were concentrated, and the resultant oily residue was triturated with diethyl ether (20 mL). The resultant white solids were collected and dried to provide B16 as a white solid. Yield: 5 g, 90%. ’HNMR (de-DMSO): δ 8.46(d, 1H), 8.2-8.38(broad s, 2H), 7.42(d, 1H), 4.55-4.9(broad s, 4H), 4.15-4.3(broad s, 2H), 325(s, 3H), 3.1 (s, 3H) and 2,5(s, 3H). Mass: (M+1) 230 calculated for C₀H,₅N₃O₂S. HPLC Purity: 95.03%.

Preparation of N-(5-aminomethyl-2-methvl-pvfridin-4-vi)-N-methvlmethansulfonamide acetate (B17):

Step 1. Preparation of 2,4-dihydroxy-6-methyl-nicotinic acid ethyl ester (B17-1):

Sodium metal pieces (33 g, 1434 mmol) were slowly added to dry ethanol (800 mL) at 25^ffC and stirred until all the sodium pieces had reacted. The resultant suspension was then treated over 15 minutes with malonic acid diethyl ester (140 g, 875 mmol) followed by treatment over 15 minutes with ethyl-3-aminocrotonate (110 g, 850 mmol). The reaction mixture was then heated at 110°C for 20 hours and concentrated. The resultant residue was cooied to 15°C, dissolved in water (800 mL), and stirred for 15 minutes. The mixture was neutralized with a mixture of AcOH:H₂O (1:1) until a pH of 67 was achieved. The mixture was then stirred an addition 20 minutes. The resultant solids were collected, washed with petroleum ether (300 mL), and dried under reduced pressure to provide B17-1 as an off-white soiid. Yield: 60.3 g, 35%. ’HNMR (de-1022016201820 23 Mar 2016

DMSO): δ 12.6(s, 1H), 11.38(s, 1H), 5.8(s, 1H), 4.25(q, 2H), 2.14{s, 3H) and 1.25(t, 3H). Mass: (M+1) 198 calculated for CgHnNCU.

Step 2. Preparation of 2,4-dichioro-6-methyl-nicotinic acid ethyl ester (B17-2): A suspension of B17-1 (36 g, 182.2 mmol) in N,N-bis(2-hydroxyethyI) 2-propanolamine (DEiPA) (38 mL) was cooled to 0°C and slowly treated with POCI₃ (250 mL). The resultant clear solution was allowed to warm to 25°C and then heated at 15°C for 20 hours. The reaction mixture was concentrated, and the resultant residue was poured into crushed Ice, The chilled mixture was then basified with saturated Na₃CO₃ until a pH of 8 was achieved. The organic iayer was collected, and the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by chromatography (silica gel; 2% EtOAc in petroleum ether as eluting solvent) to provide B17-2 as a pale yellow solid. Yield: 24 g, 55%. 'HNMR (ds-DMSO): δ 7.2(s, 1H), 4.45(q, 2H), 2.52(s, 3H) and 1.42(1, 3H). Mass: (M+1) 236 calculated for

CgHgClzNOi.

Step 3. Preparation of 2-chloro-4-methoxy-6-methyl-nicotinic acid ethyl ester (B17-3): A solution of B17-2 (30 g, 128.2 mmol) in methanol (102 mL) was cooled to 0°C and treated portion-wise over 30 minutes with NaOMe (8.5 g, 157.4 mmol). The reaction mixture was then heated at 60°C for 5 hours. The reaction mixture was cooled to 25°C, filtered, and concentrated. The resultant residue was diluted with DCM (350 mL), filtered through a Celite® bed, and washed with DCM. The combined filtrates were concentrated, and the resultant residue was purified by chromatography (silica gel; 6% EtOAc in petroleum ether as eluting solvent) to provide B17-3 as a pale yellow solid. Yield: 20.62 g, 70%. ’HNMR{CDCI₃): δ 6.66(s, 1H). 4.4(q, 2H), 3.95(s, 1H), 3,92(s,

3H), 2,52(s, 3H) and 1.38(t, 3H). Mass: (M+1) 230 calculated C₁₀Hi2CINO₃.

Step 4. Preparation of 4-methoxy-6-methyi-nicotinic acid ethyl ester (B17-4): A mixture of B17-3 (27 g, 117.3 mmol) and potassium acetate (11.0 g, 112 mmol) in isopropanol (IPA) (500 mL) was charged to a Parr reactor and treated with Pd/C (9.5 g, 70.15 mmol). The contents of the reactor were then hydrogenated at 55 Psi hydrogen pressure and 25^eC for 4 hours. The mixture was filtered through a Celite® bed and concentrated. The resultant residue was purified by chromatography (silica gel; 8% EtOAc in petroleum ether as eluting solvent) to provide B17-4 as a green viscous liquid. Yield: 23 g, 90%. ¹HNMR(CDCI₃): δ 8.84(s, 1H), 6.75(s, 1H), 4.35(q, 2H), 3.98(5, 3H), 2.6{s, 3H) and 1.4(t, 3H). Mass: (M+1) 196 calculated for C₁₀Hi₃NO₃.

- 1032016201820 23 Mar 2016

Step 5. Preparation of 6-methyl-4-oxo-1 ,4-dihydro-pyridine-3-carboxylic acid hydrochloride (B17-5): A suspension of B17-4 (50 g, 256 mmol) in concentrated HCI (600 mL) was heated at 110°C for 20 hours. The reaction mixture was then concentrated, and the resultant residue was washed in this order with ethanol (150 mL),

DCM (2 x 300 mL), and a mixture of DCM:Et₂O (1:1). The resultant solids were collected and dried fo provide B17-5 as an off-white solid. Yield: 40 g. IR (cm¹): 3449, 3095. 2890, 1674, 1647, 1565, 1470, 1428, 1345, 1257, 1186 and 1028. ¹HNMR (d_cDMSO): δ 11.4-12.7 (b, 2H), 8.45(s, 1H), 6.64(s, 1H) and 2.4(s, 3H). Mass: (M+1) 154 calculated for C7H7NO3,

Step 6. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methyl ester (B17-6): A solution of B17-5 (40 g, 261.4 mmol) in methanol (600 mL) was cooled to 0°C and treated drop-wise over 20 minutes with SOCI₂ (100 mL), The reaction mixture was allowed to warm to 25’C, heated at 7Q°C for 20 hours, and concentrated. The resultant residue was washed with ethanol (100 mL), filtered and dried to provide B17-6 as a gummy solid. Yield: 40 g. ¹HNMR (CDCI3): δ 8.8(s, 1H), 6,7(s, 1H), 3.9(s, 3H) and 2.45(s, 3H). Mass: (M+1) 168 calculated for C₀H₉NO₃. The product was used in the preparation of B17-7 below without further purification.

Step 7. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid amide (B17-7): A suspension of B17-6 (40 g, 239.5 mmol) in aqueous NH₃ (800 mL) was heated at 50°C for 20 hours. The reaction mass was then concentrated, and the resultant residue was washed with a mixture of diethyl ether.DCM (8:2) (300 mL). The resultant solids were collected and dried under reduced pressure to provide B17-7 as an off-white solid. Yield. 40 g. ¹HNMR (d₀-DMSO): 6 12.1 (b, 1H), 9.4 (s, 1H), 8.3(s, 1H), 7.4(s, 1H), 8.25(s, 1H) and 2.25 (s, 3H). Mass: (M+1) 153 calculated for C₇H₀N₂O₂.

Step 8. Preparation of 4-Chloro-6-methyI-nicotinonitrile (B17-8): A suspension of

B17-7 (20 g, 131.5 mmol) in POCf₃ (62 mL, 580 mmol) was heated at 110’C for 15 minutes. The mixture was allowed to cool to 25’C and treated portion-wise over 20 minutes with PCI5 (38.12 g, 183.4 mmol). The mixture was then heated at 110°C for 1 hour and concentrated. The resultant residue was diluted with EtOAc (100 mL), cooled to 10’C, and quenched with aqueous Na₂CO₃ (200 mL). The mixture was then extracted with EtOAc (3 x 250 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resultant residue was purified by chromatography (silica gel; 4-5% EtOAc in petroleum ether as eluting solvent) to provide B17-8 as an off-white puffy solid. Yield: 7.5 g, 37%. ¹HNMR

-1042016201820 23 Mar 2016 (CDCb): δ 8.75(s, 1 H>. 7.38 <s, 1H), 2.65(s, 3H). Mass: (M+1) 153 calculated for c₇h₅cin₂.

Step 9. Preparation of N-(5-Cyano-2-methyl-pyridin-4-yl)-N-methylmethanesulfonamide (B17-9): A solution of B17-8 (7 g, 46.8 mmol) in acetonitrile (165 mL) at 25°C was treated sequentially with Cs₂CO₃ (19 g, 58.2 mmol) and HN(Me)SO₂Me (8.9 mL, 95 mmol). The mixture was heated at 60^eC for 20 hours and concentrated.

The resultant residue was diluted with EtOAc (300 mL) and water (100 mL), and stirred for 10 minutes. The organic layer was collected, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated. The resultant residue was purified by chromatography (silica gel; DCM as eluting solvent) to provide B17-3 as a solid. Yield: 9 g, 87%.

’HNMR (CDCfe): δ 8.8(s, 1H), 7.3(d, 1H), 3.4 (s, 3H), 3.18(s, 3H) and 2.65(s, 3H).

Mass: (M+1) 226 calculated for CqHuN₃O₂S.

Step 10. A solution of B17-9 (7.5 g, 33.3 mmol) in EtOH-NH₃ (300 mL) was charged to a Parr reactor and treated with Pd/C (5 g). The contents of the reactor were hydrogenated at 60 Psi hydrogen pressure and 25°C for 4 hours. The mixture was filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc:acetic acid (1.1 eq.) and concentrated. The resultant gummy orange-colored liquid was then diluted with a mixture of ether and EtOAc in a glass flask, and the wall of the flaks was scratched. The resultant solids were collected to provide B17 as an offwhite solid. Yield: 4.4 g, 42%. IR {cm'¹); 3484, 3343, 3166, 2975, 1644, 1601, 1560, 1505, 1412,1313,1136 and 1058. ¹HNMR <d_s-DMSO): δ 8.62(s, 1H), 7.4(s, 1H), 4.75.3(broad, 3H), 3.82(5, 2H), 3.14(d, 2H), 2.45(s, 3H) and 1.9(s, 3H). Mass: (M+1) 230 calculated 230 for C9H₁₅N₃O₂S.

Preparation of N-(3-Aminomethvi-4-methyl-phenyl)-N-methylmethanesulfonamide acetate (B18):

hh₂ ch₃

CHjCOjH

Step 1. Preparation of 5-amino-2-methyl-benzonitrile (B18-1): A stirred suspension of 2-methyt-5-nitro benzonitrile (20 g, 123.45 mmol) in a mixture of dioxane (640 mL), ethanol (480 mL) and water (160 mL) at 25^OC was treated with NH4CI (26.4 g,

493.8 mmol) followed by treatment with iron powder (34.4 g, 617,2 mmol). The mixture

-1052016201820 23 Mar 2016 was then heated at 80°C for 16 hours, The mixture was filtered through a Celite® bed and concentrated. The resultant residue was diluted with EtOAc (600 mL), washed with water (150 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B18-1 as an orange solid. Yield:

18.2 g. ¹HNMR(CDCI₃): δ 7.08(d, 1H), 6.84-6.9(m, 1H), 6.75-6.82(m, 1H), 3.65-3.82(m,

2H) and 2.4(s, 3H). Mass: (M+1) 133 calculated forC₈HaN2. The product was used below to prepare B18-2 without further purification.

Step 2. Preparation of N-(3-cyano-4-methyl-phenyl)-metbanesulfonamide (B182): A solution of B18-1 (18 g, 136.36 mmol) in pyridine (150 mL) was cooled to 0°C and treated with mesyl chloride (12.6 mL, 163.63 mmol). The mixture was allowed to warm to 25^SC, stirred for 20 hours, and concentrated. The resultant residue was diluted with EtOAc (500 mL), and washed with 2N HCI (50 mL), water (100 mL), and brine (50 mL). The organic solution was then dried over anhydrous sodium sulfate and concentrated to provide B18-2 as a yeliow solid. Yield: 25.1 g, 87.3%. ¹HNMR(CDCI₃): δ 7.5(s, 1H),

7.3-7.45(m, 2H), 7.1-7.25(m, 1H), 3.05(s, 3H) and 2.5(s, 3H). Mass: (M+1) 209 calculated for C9H10N2O2S,

Step 3. Preparation of N-(3-cyano-4-methyl-pheny!)-N-methyl· methanesulfonamide (B18-3): A solution of B18-2 (25 g, 119.04 mmol) in a mixture of THF (200 mL) and 40% NaOH solution (200 mL) at 25°C was treated with BTEAC (2.7 g, 11.9 mmol) and stirred vigorously for 20 minutes. The mixture was then treated with methyl iodide (8.89 mL, 142.8 mmol), stirred for 20 hours, and concentrated. The resultant residue was extracted with DCM (500 mL) and washed with water (100 mL) and brine (50 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gel; 40% EtOAc in hexane as eluting solvent) to provide B18-2 as a white solid. Yield: 26.2 g, 97%. ¹HNMR(CDCI₃): δ 7.55-7.65(m, 1H), 7.5-7.54{m, 1H), 7.37.4(m, 1H), 3.34(5, 3H), 2.85{s, 3H) and 2.55(s, 3H). Mass: (M+1) 225 calculated for C10H12N2O2S.

Step 4. A solution of B18-3 (28 g, 124.4 mmol) in acetic acid (500 mL) and THF (200 mL) was charged to a Parr reactor and treated with 10% Pd/C (8 g). The contents of the reactor were then hydrogenated at 50 PSi hydrogen pressure and 25°C for 4 hours. The mixture was filtered through a Celite® bed and washed with ethanol (50 mL). The combined filtrates were concentrated, and the resultant residue was azeotroped with EtOAc (3 x 50 mL). The resultant oily residue was dissolved in EtOAc

-1062016201820 23 Mar 2016 (200 mL) and maintained at 25°C for 20 hours. The resultant solids were collected and dried to provide B18 as a white solid. Yield: 2.9 g, 81%. ¹HNMR (de-DMSO): 5 7.42{s, 1H), 7.15(s, 2H), 5.7-5.98(broad, 3H), 3.72(s, 2H). 3.2{s. 3H), 2.96(8, 3H), 2.25(s, 3H) and 1.86(s, 3H). Mass: (M+1) 229 calculated for CioHisN₂0₂S, HPLC Purity: 99.9%.

Preparation of N-(5-Aminomethvl-2-methyl-pvrimidin-4-vl)-N-methvlmethansulfonamide acetate (B19):

NK}

CHjCOjK

N N I

QaeSssQ

Step 1. Preparation of4-hydroxy-2-methylsu!fanyl-pyrimidine-5-carboxylicacid ethyf ester (B19-1): A mixture of water (410 mL) and a 50% NaOH solution (115.98 g,

2899 mmol) was cooled to 0°C and treated with 2-methyl 2-thio pseudo urea sulfate (100 g, 359 mmol). The resultant clear solution was treated with a solution of ethoxy methylene malonate (155.38 g, 719 mmol) in ethanol (251 mL) and stirred until the reaction mixture was turbid. The mixture was then allowed to warm to 25“5, and it was allowed to stand at 25°C for 20 hours. The resultant solids were collected, washed with ethanol (2 x 50 mL), and dried under reduced pressure to provide B19-1 as a pale yellow solid. Yield: 58 g, 75%. ¹HNMR (d₆-DMSO): δ 8.25(s, 1H), 4.12(q, 2H), 2.32(5, 3H) and 1.24(t, 3H).

Step 2. Preparation of 4-chloro-2-methyisulfany!-pyrimidine-5-carboxyiic acid ethyl ester (B19-2): Neat POC1₃(120 mL) was cooled to 10°C and treated portion-wise over 4 hours with B19-1 (50 g, 232 mmol) without exceeding a temperature of 25°C. The mixture was then heated at 65°C. After 3 hours the mixture was cooled to 10°C, poured into crushed ice (350 g), treated drop-wise with water (676 mL) under vigorous stirring. The resultant solids were collected and dried under reduced pressure to provide B19-2 as a pale yellow solid. Yield: 22 g, 40%. ’HNMR (CDCi₃): δ 8.95(5, 1H).

4.44(q, 2H), 2.62{s, 3H) and 1.42 (t, 3H).

Step 3. Preparation of 4-chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (B19-3): A solution of B19-2 (40 g, 172 mmol) in methanol (720 mL) was cooled to 0’C and treated with a slurry of oxone (317.9 g, 517 mmol) in distilled water (720 mL). The mixture was allowed to warm to 25°C and stirred at 5 hours. The mixture was filtered, and the solids were washed with DCM (500 mL). The resultant organic layer was collected, and the aqueous layer was extracted with DCM (3 x 200

-1072016201820 23 Mar 2016 mL). The combined organic tayers were then washed with brine, dried over anhydrous sodium sulfate, and concentrated to provide B19-2 as a white solid. Yield: 31 g, 68%. IR (cm'¹): 3015, 2932, 1734, 1550, 1445, 1391, 1325, 1258, 1222, 1142 and 1067. ¹HNMR (CDCI₃): § 9.28{s, 1H), 4.5(q, 2H), 3.4(s, 3H) and 1.45(1, 3H). Mass: (M+1) 265 calculated for CsHgClNzO^S.

Step 3. Preparation of 4-chioro-2-methyl-pyrimrdine-5-carboxylic acid ethyl ester (B19-3): A solution of B19-2 (40 g, 151 mmol) in THF (700 mL) was cooled to 0°C and treated drop-wise over 2 hours with a 3 molar solution of methyl magnesium chloride in THF (54 mL, 166 mmol). The mixture was allowed to warm to 25°C and maintained for at 25^eC for 4 hours. The mixture was added to water (500mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, and concentrated to provide B19-2 as a brown liquid. Yield: 30 g, 98%. IR (cm'¹): 2983, 2934, 2868, 1736, 1574, 1523. 1434, 1373, 1269, 1181 and 1070.¹HNMR (CDCI₃): δ 9.1(s, 1H),4.5(q, 2H), 2.74(s, 3H) and 1.5(t, 3H).

Step 3. Preparation of 4-(metbanesulfonyl-methyl-amino)-2-methyl-pyrimidine-5carboxylic acid ethyl ester (B19-3): A solution of N-methyl methane sulphonamide (18.2 g, 180 mmol) in acetonitrile (420 mL) was cooled to 0^DC and treated with cesium carbonate (68 g, 225 mmol). The mixture was then treated over 2 hours with B19-2 (30 g, 150 mmol), The mixture was allowed to warm to 25°C, and it was maintained at 25°C for 20 hours. The mixture was then filtered, and the solids were washed with washed with EtOAc (200 mL). The combined filtrates were further diluted with EtOAc (500 mL), washed with water (2 x 500 mL) and brine, and dried over anhydrous sodium sulfate.

The organic solution was then concentrated to provide B19-3 as an orange solid. Yield: 18 g, 44%. ¹HNMR (d₆-DMSO): δ 8.94(s, 1H), 4.3(q, 2H), 3.25-3.3(m, 6H), 2.65(s, 3H) and 1.3(t, 3H). Mass: (M+1) 274 calculated for Ci₀H₁₅N₃O4S.

Step 4. Preparation of 4-(methanesulfonyl-methyl-amino)~2-methyl-pyrimidine-5carboxylic acid amide (Bi9-4); A suspension of B19-3 (10 g, 36 mmol) in 25% ΝΗ4ΟΗ (100 mL) was heated at 32°C for 20 hours. The mixture was concentrated under reduced pressure, and the resultant residue was triturated with EtOAc. The mixture was then filtered and concentrated. The resultant residue was purified by column chromatography (60-120 mesh silica gei; 10% MeOH in CHCt₃as eluting solvent) to provide B19-4 as a white solid. Yield: 3 g, 33%. ’HNMR (d₆-DMSO): δ 8.75(s, 1H),7.95(s, 1H), 7.7{s, 1H),3.3-3.42(m, 3H), 3.25(s, 3H) and 2.65(s, 3H). Mass: (M+1) 245 calculated for CBH12N4O3S,

-1082016201820 23 Mar 2016

Step 5. Preparation of N-(5-cyano-2-methyl-pyrimidin-4-yl)-N-methylmethanesulfonamide (B19-5): A solution of B19-4 (5.2 g, 22.3 mmol) and pyridine (3.36 g, 42.6 mmol) in 1.4 dioxane (78 ml) was cooled to 0°C and treated drop-wise over 10 minutes with TFA (5,8 g, 27.7 mmol). The mixture was allowed to warm to 25°C. After

4 hours the mixture was diluted with EtOAc (100 mL) and washed with water (2 x 200 mL). The aqueous layer was collected and washed with EtOAc (2 x 100 mL). The combined organic layers were then washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resultant residue was then washed with petroleum ether and dried to provide B19-5 as a pale yellow solid. Yield: 3.5 g. 76%.

¹HNMR (CDCI₃): 8 8.84(s, 1H), 3.54(s, 3H), 3.4(s, 3H) and 2.75(s, 3H). Mass: (M-1) 225 calculated for C₀HioN₄O2S.

Step 6. A solution of B19-5 (5 g, 22 mmol) in 2N methanolic ammonia (350 mL) was charged to a Parr reactor and treated with 10% Pd/C (3.75 g, 35 mmol). The contents of (he reactor were then hydrogenated at 48 Psi hydrogen pressure and 25°C for 1 hour. The mixture was filtered through a Celite® bed and washed with methanol (200 mL). The combined filtrates were concentrated, and the resultant residue was diluted with EtOAc (25 mL) and acetic acid (1.3 g, 21 mmol). The mixture was stirred for 30 minutes, and the resultant solids were collected to provide B19 as a white solid.

Yield: 4.2 g, 80%. IR (cm¹): 3433, 3381, 3017, 2930,1720, 1591, 1555, 1446, 1331,

1148 and 1058. ¹HNMR (ds-DMSO): 8 9.05(s, 1H), 8.5-8.7(broad s, 2H), 4.14(s, 2H),

3.24(s, 3H), 3.15(s, 3H) and 2.66 (s, 3H). HPLC Purity: 99.9%.

4-Chioro-pyrimidine intermediates were prepared by methods similar to that described below for compound B20.

Preparation of 4-(4-chloro-5-ftrifiuoromethvl)pvrimidin-2-ylamino)-N25 methylbenzamide (B20):

A solution of 2,4-dichloro-5-triffuorometbyl-pyrimidine (8.63 mmol) in 1:11BuOH/DCE (10 mL) was cooled to 5°C, treated with solid ZnBr₂ ¢22.5 mmol), and stirred at 5°C for 30 minutes. The resultant solution was maintained at 5“C and treated first with solid 4-amino-N-methyJ-benzarrtide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25^eC, and it was mixed at 25°C for 20

-1092016201820 23 Mar 2016 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol I DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20, Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 ¹H NMR (500 MHz, d₆-DMSO) δ ppm 10.89 (s, 1 H), 8.87 (s, 1 H), 8.34 (d,

7=4,67 Hz, 1 H). 7.73 - 7.89 (m, 3 H), 2.78 (d, 7=4.67 Hz, 3 H).

Example 1 (R)-tert-butyl 1-(4-(4-({2-{N-methylmethan-5-ylsulfonamido)pyridin-3yl)methylamfno)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyi)ethylcarbamate (1)

Step 1: Preparation of (R)-tert-butyl 1-(4-nitrophenyl)ethylcarbamate (C1).

(R)-1-(4-nitrophenyl)ethanamine hydrochloride salt (1.0g, 4.9mmol), tertbutoxycarbonyl (BOC) anhydride (1.18g, 5.43mmol), and 10,0mL of 1M sodium bicarbonate solution were dissolved in DCM (15 mL) and allowed to stir at 25“C for 24h. The organic layer was collected, and the aqueous layer was washed with DCM. The combined organic layers were then washed with water and 0.1 N HCI, dried over MgSO₄, filtered, and concentrated to provide C1 as a white solid. Yield: 1.2g, 92%, GCMS=266. ¹H NMR (500 MHz, d₆-DMSO) δ: 8.15 (d, 2H). 7.56 (d, 1H), 7.52 (d, 2H), 4.68 (m, 1H), 1.32 (s, 9H), 1,27 (d. 3H).

Step 2: Preparation of (R)-tert-butyl 1-(4-aminophenyl)ethylcarbamate (C2)

-110 2016201820 23 Mar 2016

A solution of Cl (1.0g, 3.8mmol) in MeOH (20 mL) was charged to a Parr reactor, and the contents of the reactor were treated with 10% Pd/C (SOOmg, 0.376mmol). The contents of the reactor were then hydrogenated at 45 Psi hydrogen pressure and 25^eC for 4 hours. The contents of the reactor were filtered through Celite® and washed with DCM. The combined filtrates were concentrated to provide C2 as a sticky orange residue. Yield: 690mg, 78% yield. GC_MS = 236. ¹H NMR (500 MHz, d₆-DMSO) δ: 7.07 (d, 1H), 6,88 (d, 2H), 6.43 (d, 2H), 4.85 (s, 2H>, 4.40 (m, 1H), 1.31 (s, 9H), 1.18 (d,

3H).

Step 3. Preparation of (R)-teri-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2ytamino)phenyl)ethylcarbamate (C3)

C2 (690mg, 2.92mmol) was dissolved in 10mL DCE:t-BuOH (1:1 vohvol), and the resultant solution was treated with ZnBr₂ (1.97g, 8.76mmoi) and 2,4-dichloro-5(trifluoromethyl)pyrimidine (748mg, 3,45mmot). The resultant mixture was then treated drop-wise with TEA (406ml, 2.92mmol), and the mixture was allowed to stir at 25°C for about 20 hours. The reaction mixture was concentrated, and the resultant residue was treated with EtOAc, The resultant solution was washed with water and brine, and dried over MgSO₄. The mixture was then filtered, concentrated, and purified by column chromatography eluting with 22% EtOAc/Heptane. The product-containing eluents were combined and concentrated to provide C3 as a white solid. Yield: 680mg, 56%. MS415.2. Ή NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53 (d, 2H). 7.31 (d, 1H), 7.23 (d. 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25 (d, 3H).

2016201820 23 Mar 2016

-111 Step 4. Compound C3 {100 mg, 0.24 mmol), B5 (88.5mg, 0.264mmol), and diethylamine (DIEA) (0.127ml, 0.960mmol) were dissolved in 1,2-dichloroethane (DCE):t-BuOH (1:1vol:vol) (1.2 mL). The resultant solution was heated at 80^eC for about 20 hours, cooled to 25°C, treated with EtOAc, and washed with water. The organic phase was collected, and the aqueous phase was washed with EtOAc. The combined organic layers were dried over MgSO^, filtered, and concentrated to provide 1 as a sticky residue. MS⁴ 596.8. ’H NMR (500 MHz, d₆-DMSO) δ: 9.50 (s, 1H), 8.41 (m, 1H), 8.22 (s, 1H), 7.61 (m, 2H), 7.35 (m, 3H), 6.99 (d, 2H), 4.76 (d, 2H), 4.47 (m. 1H), 3.14 (s, 3H), 3.11 (s, 3H), 1.33 (s, 9H), 1.21 (d, 3H). The product was used in the preparation of compound 2 in Example 2 below without further purification.

Example 2

Preparation of (R)-N-(3-((2-(4-(1-aminoethyl)phenylamino)-5(trifluoromethyl)pyrimidin-4-ylamino)meihyi)pyridin-2-yl)-N-methyimethanesulfonamide hydrochloride (2)

A solution of 1 (I43mg, 0.24mmol) in THF (0.3mL) was treated with 4N HCI in dioxane (0.240ml, 0,96mmol), and stirred at 25°C for about 20 hours. The reaction mixture was then triterated with EtOAc and filtered, and the filtrate was concentrated to provide the HCI salt form of 2 as a white solid. Yield: 128mg, 94% yield. MS 494.0.

’H NMR (500 MHz, d₆-DMSO): δ 10.2 (s, 1H), 8.40 (m, 4H), 8.12 (s, 1H), 7.67 (d, 1H), 7.45 (m, 3H), 7.27 (d, 2H), 4.84 (d, 2H), 4.28 (m, 1H), 3.16 (s, 3H), 3,14 (s, 3H), 1.45 (d, 3H), FAK IC₅₀: <0.000595 μΜ (Table 1, Example 354)

Example 3

Preparation of tert-butyl 4-(4-«2-(N-methylmethan-5-ylsuifonamido)pyridin-3yl)methylamino)-5-(trif|uaromethyi)pyrimidin-2-ylamino)benzylcarbamate (3)

-1122016201820 23 Mar 2016

Step 1: Preparation of tert-butyl 4-nitrobenzyicarbamate (C4).

A stirred solution of (4-nitrophenyl)methanamine hydrochloride (10g, 53.0mmoi) tn THF (150mL ) and water (13mL) was cooled to 0°C and treated with BOC anhydride (11,6g, 53.0mmol) and DIEA (27.7mL, 159mmol). The reaction mixture was stirred for about 20 hours as it was allowed to warm to 25°C. The mixture was then concentrated, and the resultant residue was dissolved in EtOAc. The resultant solution was washed with 1N HCI, saturated sodium bicarbonate, and brine. The organic phase was then dried over MgSO₄, filtered, and concentrated to provide C4 as an off white solid. Yield: 14.0g, 99%. ¹H NMR (400 MHz, d_e-DMSO) 5: 8.16 (d, 2H), 7.55 (t, 1H), 7.46 (d, 2H), 4.21 (d,2H), 1.36 (s,9H).

Step 2. Preparation of tert-butyl 4-aminobenzylcarbamate (C5)

C4 (7.0g, 27.7mmol) was dissolved in dioxane (325mL), ethanol (240mL), and water (160mL). The resultant solution was then treated with Fe(0) powder (7.12g, 127.4mmol) and ammonium chloride (5.33g, 99.7mmol), and the resultant mixture was stirred at 70’C for 4 hours. The reaction mixture was coofed to 25°C, filtered through Celite®, and washed with EtOAc. The organic solvents were evaporated, and the resultant aqueous residue was extracted with EtOAc, The combined organic layers

2016201820 23 Mar 2016

-113 were dried over MgSO^, filtered, and concentrated to provide C5 as a yellow soiid. Yield: 6.52g, 99% yield. ¹H NMR {400 MHz, dg-DMSO) δ: 7.146 (t, 1H), 6.87 (d, 2H), 6.48 (d, 2H), 4.95 (s, 2H), 3.92 (d, 2H), 1.38 (s, 9H).

Step 3. Tert-butyl 4-(4-chloro-5-(trifiuoromethyt)pyrimidin-25 ylaminojbenzylcarbamate (C6)

Compound C6 was prepared as a white solid in a manner similar to that described in Step 3 of Example 1 except that C5 {1.30g, 5.86mmol) was used instead of C2. Yield: 1.37g, 49%. MS’401.1. Ή NMR (400 MHz, dg-DMSO) δ: 10.6 (s,1H),

8.75 (s, 1H), 7.56 (d, 2H), 7.34 (t 1H), 7.18 (d, 2H), 4.05 (d, 2H), 1.36 (s, 9H).

Step 4. Compound 3 was prepared as a white solid in a manner similar to that described in Step 4 of Example 1 except that C6 (1.2g, 2.98mmol) was used instead of C3, and the resultant crude product was purified by column chromatography, eluting with 45-55% EtOAc/Heptane. Yield: 1.17g, 68%. MS* 582.3. ¹H NMR (500 MHz, dg15 DMSO) δ: 9.57 (s, 1H), 8.42 (s, 1H), 8.58 (s, 1H), 7.64 (m, 2H), 7.35 (m, 4H), 6.94 (d. 2H), 4.80 (d, 2H), 3.98 (d, 2H), 3.16 (s, 3H), 3.14 (s, 3H), 1.39 (s, 9H).

Example 4

Preparation of N-(3-((2-(4-(aminomethyl)phenylamino)-520 {trifluoromethyi)pyrimidm-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (4)

-1142016201820 23 Mar 2016

The HCt sail form of 4 was prepared as a white solid in a manner similar to that described for preparing 2 in Example 2 except that 3 (1.0g, 1.72mmof) was used instead of 1.

The salt form of 4 was dissolved in DCM, and was washed with saturated sodium bicarbonate. The organic phase was then dried over NaaSO^ filtered, and concentrated to provide the free-base form of 4 as a foamy white solid. Yield: 904mg, 99%. MS* 482. 'H NMR (500 MHz, d_rDMSO) 5: 9.50 (s, 1H). 8.44 (d, 1.H), 8,25 (s, 1H), 7.66 (d, 1H), 7.57 (t, 1H), 7.38 (m, 3H), 7.04 (d, 2H), 4.80 (d, 2H), 3.58 (d, 2H), 3.17 (s, 3H), 3.13 (s, 3H). FAK ICso: 0.00059 μΜ (Table 1, Example 104)

Example 5

Preparation of N-(4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3yl)meihyiamino)-5-{trifIuoromethyl)pyrimidin-2-ylamino)benzyl)acetamide (5)

The free-base form of 4 (80mg, 0.166mmol), acetic anhydride (0.019ml, 0,199mmol), and DIEA (0.043ml, 0.249mmoi) were dissolved in THF (0.5ml) and stirred at 25°C for 24 hours. The reaction mixture was then treated with EtOAc and washed with 1N NaOH. The resultant organic layer was dried over MgSO^, filtered, and concentrated to provide 5 as a white solid. Yield: 63mg, 73%. MS* 524.5. ¹H NMR (500 MHz, de-DMSO) δ: 9.55 (S, 1H), 8.44 (d, 1H), 8,25 (s, 1H), 8.22 (t, 1H), 7.60 (m, 2H), 7,38 (m, 3H). 6.96 (d, 2H), 4.80 (d, 2H), 4.11 (d. 2H). 3.16 (s, 3H), 3.13 (s, 3H), 1.85 (s, 3H). FAK IC₅₀: 0.0006 pM

Example 6

-1152016201820 23 Mar 2016

Preparation of N-{3-{(2-(4-{hydroxymethyl)phenyiamino)-5{trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (6)

Step 1. Preparation of (4-(4-ch[oro-5-(trifluoromethyl)pyrimidin-2ytamino)piienyi)mefhanot (C7):

Step 1. C7 was prepared in a manner simitar to that described in for making C3 in Step 3 of Example 1 except that 4-aminobenzyf alcohol (2.4g, 19mmol) was used instead of C2. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, dried over MgSO₄, and concentrated. The resultant tan solid was triterated with ether and a small amount of EtOAc, filtered and concentrated to provide C7 as a tan solid. Yield: 2.98g, 50%. MS⁺304.1. ’H NMR {500 MHz. d₆-DMSO) δ: 10.61 <s, 1H), 8.76 (s, 1H), 7.59 {d,

2H). 7.26 (d, 2H), 5.10 (bs, 1H). 4.43 (s, 2H).

Step 2. Compound 6 was prepared in a manner similar to that described for making compound 1 in Step 4 of Example 1, except that C7 {2.5g, 8.2mmol) was used instead C3. When the reaction was complete the reaction mixture was concentrated and dissolved in EtOA. The resultant solution was washed with water, brine, and dried over MgSO₄, and concentrated. The resultant solid was triterated with hot EtOAc, and the mixture was cooled to 0°C and filtered to provide 6 as a white solid. Yield: 2.94g, 74%. MS⁺ 483.4. ¹H NMR {500 MHz, d₅-DMSO) δ: 9.50 (s, 1H), 8.41 (d, 1H), 8.22 (s.

-1162016201820 23 Mar 2016

1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36 (m, 3H), 6.99 (d. 2H). 4.98 (t, 1H), 4.76 (d, 2H), 4.32 (d, 2H), 3.13 (s, 3H). 3.11 (s, 3H). FAK IC₅₀: <0.000595 μΜ (Table 1, Example 319)

Example 7

Preparation of N-(3-((2-(4-(chloromethyl)phenylamino)-5(trif!uoromeihyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (7)

A suspension of 6 (800mg, 1,66mmo!) in DCM (5mL) was cooled to 0°C and treated with a solution of thionyl chloride (0.266ml, 3.65mmol) in DCM (2.0 mL). The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 20 hours. The reaction mixture was then treated with DCM and washed with water (2x). The aqueous layer was collected and washed with DCM, The combined organic layers were then dried over MgSCU, filtered and concentrated to provide 7 as a white solid. Yield:

668mg, 80%. ¹H NMR (500 MHz, de-DMSO) δ: 6.68 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.64 (m, 2H), 7.42 (m, 3H), 7.14 (d, 2H), 4.82 (d, 2H), 4.66 (s, 2H), 3.17 (s, 3H), 3.15 (s, 3H). FAK ICm: 0.00155 μΜ (Table 1, Example 348)

Example 8

Preparation of N-(3-((2-(4-((1,3-dihydroxypropan-2~yiamino)metbyl)phenylamino)5-(trifluoromethyl)pyrimidin-4-yiamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide (8)

.OH

-117 2016201820 23 Mar 2016

A mixture of 7 (100mg, 0.200mmol), 2-amino-1,3-propanedioi (90.9mg, 0.998mmol), sodium hydroxide (7.98mg, 0.200mmol) and 2-propanol <0.5mL) was heated to reflux. After 30 minutes the mixture was cooled, treated with DCM, and washed with water. The organic phase was dried over MgSO_4l filtered and concentrated. The resultant residue was then purified by column chromatography -(silica gel; eluting with 6% MeOH/DCM with NH₄OH), and the eluents containing the product were combined and concentrated to provide 8 as a white solid. Yield; 60.9mg, 55%. MS* 556.2. ¹H NMR (500 MHz, d_e-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t, 2H), 3.58 (s, 2H), 3.34 (m,

4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m, 1H). FAK IC_S0: <0.000595 μΜ (Table 1,

Example 389)

Example 9

Preparation of terl-butyl 3-({4-[({2-[methyl(methylsulfonyI)amino]pyridin-315 yl}methyl)amino]-5-(trifIuoromethyi)pyrimidin-2-yl}amino)benzoate (9)

Step 1. Preparation of tert-butyl 3-{{4-chloro-5-(trifluoromethyl)pyrimidin-2yl}amino)benzoate (C8)

A solution of pyrimidine (24.8 g, 115 mmol) in tert-butanot (150 mL) and DCE (150 ml) was treated with ZnBr₂ (25.8 g, 115 mmol), and the resultant mixture was stirred at 25^BC until ail the ZnBr₂ dissolved. The resultant solution was cooled to 0° C and treated drop-wise with aniline (22.13 g, 115 mmol). The resultant brown mixture was then treated drop-wise with DIEA (40.1 mL, 230 mmol). The mixture was allowed

2016201820 23 Mar 2016

-118 to warm to 25°C and stirred for 16 hours under N₂ atmosphere. The mixture was concentrated, and the resultant residue was suspended in MeOH. The resultant white solids were collected to provide C8 as a white solid. Yield: 22.7 grams, 53%. APCI m/z 371.8/373.8 (M‘); ¹H NMR (d₆-DMSO) δ: 10.84 (bs, 1 H), 8.85 (s, 1 h), 8.37 (bs, 1 H),

7.92 (d, J = 7.8Hz., 1 h), 7.62 (d, J = 7.8 Hz., 1 H), 7.48 (t, J = 7.8 Hz., 1 H), 1.56(s, 9

H) ppm.

Step 2. A solution of tert-butanol (20.0 mL), DCE (20.0 mL) and DIEA (3.13 ml, 18.0 mmol) was treated with C8 (5.60 g, 15.0 mmol) and B5 (5.02 g, 15.0 mmol), and the resulting mixture was stirred at 80° C under an atmosphere of nitrogen for 16 hours.

The mixture was cooled to 25’C and concentrated. The resultant residue was partitioned between EtOAc and 1 N sodium hydroxide, and the organic phase was collected. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over MgSOi and filtered. The resultant filtrate was concentrated under reduced pressure, and the resultant residue was triturated with hot EtOAc to provide 9 as a white solid. Yield: 7.83 grams, 95%. LC/MS (standard) 25° = 3.0 min., m/z 553.6 (MH⁺). HPLC (FAK1) 25° = 8.14 min. ¹H NMR (d₆-DMSO) §: 9.75 (bs, 1 H), 8.44 (d, J = 5.2 Hz., 1 H), 8.29 (s, 1 H), 8.05 (bs, 1 H), 7.82 (d, J = 7.8 Hz., 1 H), 7.60 (t,

J = 5.7 Hz., 1 H), 7.44 - 7.40 (m, 2 H). 7.17 (t, J = 5.7 Hz, 1 H), 4.82 (d, J = 5.7 Hz., 2 H), 3.16 (s, 3 H), 3.13 (s, 3 H), 1.51 (s, 9 H) ppm. FAK IC₅o: 0.0006 μΜ

Example 10

Preparation of 3-{{4-[({2-[methyl(methylsuIfonyl)amino]pyridin-3-yl}methyl)amino]5-(trifluoromethyI)pyrimidin-2-yl}amino)benzoic acid trifluoroacetic acid salt (10)

A solution of 9 (7.83g, 14.1 mmol) in DCE (3Q.0mL) was cooled to 0°C and treated slowly with TFA (45.0mL). The resultant orange-brown solution was allowed to slowly warm to 25°C under an N₂ atmosphere and stirred for 4 hours. The mixture was then concentrated, and the resultant residue was treated wilh EtOAc. The resultant white solids were collected by filtration and washed with EtOAc to provide the trifluoroacetate

2016201820 23 Mar 2016

-119 salt form of 10. Yield: 7,24grams, 84%. APCI m/z 496.8 (MH*), HPLC (FAK1) 25° = 5.29 min., ¹H NMR (d₆-DMSO) δ: 9.82 (bs, 1 H), 8.44 (d, J = 5.2 Hz., 1 H), 8.29 (s, 1 H), 8.08 (bs, 1 H), 7.79 (d, J =7.8 Hz., 1 H), 7.60 - 7.38 (m, 4 H), 7.17 (t, J = 5,7 Hz, 1 H), 4.82 (d, J = 5.7 Hz., 2 H), 3.16 (s, 3 H), 3.13 (s, 3 H) ppm. FAK IC₅₀: 0.0006 pM

Example 11

Preparation of N-cyclopropy!-3-({4-[({2-[methyl(methylsu!fonyl)amino]pyridin-3yi)methyi)amino]-5-{trifluoromethyl)pyrimidin-2-yl)amino)benzamide (11)

A polymer supported carbodiimide (PS-CDI) (0.326mmol) was allowed to swell in acetonitrile (volume of 500pL). The resultant suspension was treated with 10 (100mg, 0.164mrriol) and DIEA (29pL, 0.164mmol). The resultant solution was then treated with cyclopropylamine (19pL, 0.164mmol). The resultant suspension was then mixed on a shaker plate for 16 hours. The mixture was then filtered, and the solids washed with 10% MeOH in chloroform. The combined filtrates were concentrated under reduced pressure, and the resultant residue was purified over silica (99:1:0,1

CHCI₃:CH₃OH:NH₄OH) to provide 11 as a white foam. Yield: 14.3mg, 16%. LC Ret.

Time (standard) = 2.1 min., m/z 536.2 (MH*); ¹H NMR (CD₃OD) $: 8.42 (d, J = 7.8 Hz., 1 H). 8.20 (s, 1 h), 7.97 (t, J = 7.8 Hz., 1 H), 7.81 (d, J = 7.8 Hz., 1 H), 1.68 (d, J = 7,8 Hz., 1 H). 7.39 - 7.34 (m, 2 H), 7.26 (t, J = 7.8 Hz., 1 H), 4.94 (s, 2 H), 3.23 (s, 3 H), 3.14 (S, 3 H), 2.82 (m, 1 H), 0.79 (m, 2 h), 0.60 (m, 2 H) ppm. FAK iC₅₀: 0.00186 pM

Example 12

Preparation of N-(3-((2-(4-(1-hydroxyethyl)phenylamino)-5(irifluoromethyl)pyrimidin-4-ylani!no)meihyl)pyridin-2-yl)-N-methylmethanesulfonamide (12)

-1202016201820 23 Mar 2016

Step 1. N-(3-((2-chloro-5-(trifIuoromethyl)pyrimidin-4-ylamino)methyl)pyndin-2yl)-N-methylmethanesulfonamide (C9)

A solution of B5 and trifluoroetiianol (120mL) was treated with triethylamine (TEA) (16.6mL) and stirred at 25°C for 1 hour. In a separate reaction flask, a solution of 2,4-dichloro-5-trifiuoromethylpyrimidine (13.2g, OO.Smmol) and trifluoroethanol (120mL) was cooled to -45°C. The cold 2,4-dichloro-5-trifluoromethylpyrimidine solution was then treated drop-wise with the solution containing B5 and stirred at -45°C for 2 hours. The mixture was allowed to warm to 25°C, and it was stirred at 25^eC for about 20 hours.

The reaction mixture was then concentrated and cooled to 0C. The resultant white mixture was diluted with EtOAc (15ml), and the solids collected by filtration. The white solids were then washed with water and EtOAc to provide C9. Yield; 0.7g, 45%. ¹H NMR (400 MHz, d₆-DMSO) §: 3.07 (s, 3H), 3.29{s, 3H), 4.68 (d, 2H), 7.39 (m, 1H), 7.72 (d, 1H), 8.40 (s, 1H), 8.50 (t, 1H); ESI-MS: 396.0 (MH*).

Step 2. A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treated with 1-{4-aminophenyl)ethanol (0.277 mmol) followed by potassium phosphate dibasic (0.746mmol). The mixture was stirred at 10Q°C for 1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (O.583mmol). The mixture was stirred at 100“C for

15 hours and concentrated. The resultant residue was purified first by column chromatography (silica gel; 10% (NH^OH/MeOHJ/CHiCla) followed by preparatory thin layer chromatography developed in 5% MeOH/CH2CI2 to provide 12. Yield: 13.6 mg.

2016201820 23 Mar 2016

-121 10.8%. Ή NMR(CD₃OD}5: 8.39(d, 1H), 8.13(s, 1H), 7.73(d, 1H), 7.33(m_s 3H), 7.14(d, 2H), 4.87(5, 2H), 4.72(q, 1H), 3.17(s, 3H>, 3.10(8, 3H), 1.37{d, 3H). MS: m/z497(MH⁺).

Example 13

Preparation of 2-fluoro-4-({4-i({2-[methyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amtno)benzamide formic acid salt (13)

A mixture of 4-amino-2-fiuorobenzamide (1.5 eq., 189 μΜ) in 2-propanol (1.0 mL) was treated with C9 (1 equiv., 130uM) followed by trifluoroacetic acid (2.7 equiv.,

341 μΜ) and stirred in a seated vial at 100°C for about 20 hours. The mixture was then cooled to 25°C, treated with DMSO, filtered, and purified on a Shimadzu using a reverse phase Symmetry C-8 column and eluting with 20-80%B for 10min at 40ml/min (A:0.1% formic acid in water, B: 0.1% formic acid in acetonitrile to provide the formic acid salt of 13 as a cream colored solid. Yield: 17.5mg, 27%. LC-MS M+1 = 514. NMR (d₆DMSO) §: 3.13 (6H, s), 4.81 (2H, s), 7.30-7.40 (6H, m), 7.41-7.73 (2H, m), 8.3 (1H, s), 8.41 (1H, s), 9.96 {1H, s). FAKIC₅₀: <0.000595 μΜ (Table 1, Example 320)

- 1222016201820 23 Mar 2016

Exampie 14

Preparation of 3-fluoro-4-({4-[({2-[methyl(methyisutfonyl)arnino]pyridin-3yl}methyl)amino]-5-(trifiuoromethyl)pyrimidin-2-yi}amino)benzamide formic acid salt (14)

Compound 14 was prepared in a manner similar to that described Example 13 for the preparation of 13 except that 4-amino-3-fluorobenzamrde (1.5 equ/189pM) was used instead of 4-amino-2-fluorobenzamide to provide the formic acid salt of 14 as a cream colored solid. Yield: 26mg, 37%. LC-MS M+1 = 514. NMR (d₆-DMSO) §: 2.98 (3H, s),

3.09 (3H, s), 4.65 (2H. s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s),

9.19 (i H, s). FAK IC₅₀: <0.000595 μΜ (Table 1, Example 322)

Example 15

Preparation of 4-(4-{[(3-methanesulfonyl-methyl-amino)-pyrazin-2-ylmethyi]15 amino}-5-(trifIuoromethyl)-pyrimidin-2-ylamino)-N-methyl-benzamide (15)

Step 1. A suspension of B20 (0,3 mmol), B2 (0.3 mmol), and diisopropylethyl amine (0.9 mmol) in 1:1 (v:v) DCE/tBuOH was mixed at 80°C for 9 hours. The mixture was allowed to cool to 25°C, and it was mixed at 25°C for 20 hours. The mixture was then treated with 9:1 (v:v) ether/ethanoi, The solids were collected and washed with water to provide 15. Yield: 0.23 mmol, 78%. HPLC (KDC 10_9Q) 3.526 min. ¹H NMR (500 MHz, de-DMSO) δ ppm 9.83 (s, 1 H), 8.69 (d. 7=2.59 Hz, 1 H), 8.58 (d, 7=2.59 Hz, 1 H), 8.31 (s, 1 H), 8.20 (d, 7=4.67 Hz, 1 H), 7.58 - 7.70 (m, 3 H), 7.41 (t, 7=5.18 Hz, 1

-1232016201820 23 Mar 2016

H), 5.00 (d, 7=5.18 Hz, 2 H), 3.23 (s. 3 H), 3.20 (s, 3 H), 2.75 (d, 7=4.15 Hz, 3 H). FAK ]C₅₀: <0.000595 μΜ (Table 1, Example 317)

Example 15A

Preparation of 4-{4-{[{3-methanesulfonyI-methyl-amino)-pyrazin-2-ylmethyl]amino}-5-(trif!uoromethyl)-pyrimidin-2-yfamino)-N-methyl-benzamide hydrochloride salt (15A)

Step 1. A suspension of B20 (26.3 mmol), B2 (28.9 mmol) and diisopropylethyl amine (105 mmol) was mixed in 1:1 DCE:tBuOH (80 mL) and heated to 88 °C in a sealed flask for 1.5 hour. The mixture turned green and a solid precipitated. The suspension was diluted with Et2O/EtOH (10:1) and filtered to obtain 10.1 g of a white solid (75%), 8 g of this product was slurried in 400 mL of MeOH and to the mixture was added 18mL 4.0M HCI in dioxane. This was stirred at room temperature for 1 hour, then it was filtered to obtain 15A as an off-white solid HCI salt (-quant yield). 1H NMR ¢400 MHz, DMSO-d₆) δ ppm 2.75 (d, 7=3.74 Hz, 3 H), 3.18 (m, 6 H), 5.01 (d, 7=4.98 Hz, 2 H), 7.52 (d, 2 H), 7.67 (d, 7=8.72 Hz, 2 H), 7.98 (br. s., 1 H), 8.29 <d,

7=4.15 Hz, 1 H), 8.42 (s, 1 H), 8.59 (d, 1 H), 8.68 (d, 1 H), 10.38 (s, 1 H). ESI-MS: 511.1 (MH⁺), 509.2 (M-H)\ FAK IC₅₀: 0.00179 μΜ (Table 1, Example 318)

Examples 16-415

Compounds 16-415 in Examples 16-415 (see Table 1) were prepared by the methods described above in the Detailed Description of the Invention and as described in Examples 1-15A. The amines used in these reactions were obtained commercially and used as received, prepared as described above for compounds B1-B20 or in Examples 1-15A above, or prepared by common synthetic methods for amines known to those skilled tn the art. Unless otherwise noted, compounds having chiral centers were prepared as racemic mixtures.

-1242016201820 23 Mar 2016

Table 1 also contains biological kinase inhibition (IC50 values) for compounds 16-415.

The present invention is not to be limited in scope by the specific embodiments 5 described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within Ihe scope of the appended claims,

Table 1. IC50 values against FAK kinase.__

Ex.	Structure	Compound Name	FAK IC50, μΜ
16	Φ ϋ 0	4-((4-(((2- [methyI(methylsulfonyl}amino3pyridin-3yf)methyl)amino]-5(triflu oromethy l)py rim idi n-2y))amino)benzenesulfon-amide (16)	0.00409
17	X&- o	4-((4-(((6- methyl-2- imethyl(methylsulfonyl)aminoIpyridin-3y!)meihyl)amino]-5(trifluoromethyf)pyrimidin-2yi}amino)benzene-sulfonamide (17)	0.00126
18	tAiAw o Φ SZ O	4-{I4-fl3-(methylsulfonyi)benzyl]amino}-5(trifiuoromethyl)pyrimidin-2yl]amino}benzene-sulfonamide (18)	0.0132
19	ό Si	4-((4-(((2- [methyl{metbylsuifonyl)amrno]pyridin-3yi)methyl)amino3-5(trifluoromethy()pyrimidin-2yl)amino)benzamide (19)	0.0034

-1252016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
20	joiy- ό ΐ?	4-((4-(((2- [methyt(methylsulfonyl)amino]pyridin-3- yf}meihyl)amrn0]-5- (triflu oromethy l)py rimid in-2- yQannino)benzamide (20), hydrochloride salt	0.0006
21	,ΛΛ„ ό Sir	4-({4-[({6-methy!-2- [methy!(methylsulfonyl)amirtoJpyridin-3yl}methyl)amino)-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (21)	0.001
22	frAAr. 0 ό	4-((4-(i3-(methylsulfonyl)benzyijamino}-5* (trifluoromethyl)pyrimidin-2yl)amino)benzamide (22)	0.00356
23	o Z V Q ^o-x	N-methyl-N-f3-({[2-{(6- (methylsulfonyl)pyridin-3-ylJamino}-5(trifluoromethyt)pyrimidin-4yl] aminojmethy I)py rid i n-2yljmethanesulfonamide (23)	0.0686
24	iZ’V^r ΛΛτ, j ό V··	N-4-[3-(methy Isu Ifony l)be nzy l]-N-2-[6(methy(suifonyl)pyridin-3-yf]-5(trif1uoromethyl)-pyrimidine-2.4-diamine (24)	0.337
25	,AA< --.,,--¾ ό Sa 'ey	N-methyt-N-|6-methyi-3-(([2-{[6(methylsutfQnyl)pyridin-3-yl]amino}-5trifluorometbyl)pyrimidin-4yi]amino)methyl)pyridin-2yljmethanesulfonamide (25)	0.0129
25	M , ό >>	N-methyi-N-[3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino)-5!) rifluoromethy l)pyrimidin-4yljamino)methyl)phenyijmethanesulfonam ide (26)	0.154

-1262016201820 23 Mar 2016

Ex,	Structure	Compound Name	FAK IC50, pM
27	it AX Φ Oi	N-[3-({[2-{i4-(1,Tdioxidofsothiazolidin-2yl)phenyl]amino}-5(trifluoromethyI)pyrimidin-4yl)amino}nnethyl)pyridin-2-ylJ-Nmethylmethane-sulfonamide ¢27)	0.00138
28	ό A 1 a	N-[3-({[2-{[4-(1,1 -dioxtdo isothiazol idi n^- yQphenylJaminoy-S- (trifl uoromethyl) py rimi d in-4- yl]amino}methy!)-6-methylpyridin-2-ylj-N- methylmethanesulfonamide (28)	0.00201
29	AX, 0 ό v- ύ<	N~2—[4-( 1,1 -d ioxidoisothiazo!idin-2- y!)phenyij-N~4~-(3- {methylsulfonyi)benzyl]-5- (trifluoromethyl)pyrimidine-2,4-diamine (29)	0.00209
30	rr-4- ό A 1 O±s3®s0 1 '	N-methyl-N-{3-[({2-{(4- {[(methy!sulfonyf)amino]methyl}phenyl)am ino]-5-(trifIuoromethyi)pyrimidin-4- yl}amino)methyl3pyridin-2- yljmethanesulfonamide (30)	0,00072
31	^AA, -sz -co Y? 0	N-[3-({[2-{{3- [(aminosulfonyl)methyi]phenyl}amino)-5(triftuoromethyt)pyrimidin-4yl]amino}methyl)pyridin-2-yl]-Nmethylmethane-sulfonamide (31)	0.00222
32	aXL?5- -μυ0 Ύί) 0	N-methyl-N-{3-[({2-[(3- {[(methy Is u Ifonyl) amino]methyl}pheny l)am inoJ-5-(trifiuoromethyl)pyrimidin~4- yl}amino)methyi]pyridin-2- yt)methanesuifonamide (32)
33	Λ&- -κύ 0	N-metbyl-N-{3-[{{2-[(3- {[(methylsulfonyl)amino]fnethyl}phenyl)am ino]*5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yljmethanesulfonamide (33), hydrochloride salt	0.00133

-1272016201820 23 Mar 2016

Cu LX.	Structure	Compound Name	FAKIC50, pM
34	AA, , φ Hax 0	4-{[5-bromo-4-({3- [methyl(methylsulfonyl)amino]benzyi}ami no)pyrimidin~2- yl]amino}benzenesulfonamide (34)	0.0156
35	AX , φ ΌΤ· «rtf*e o	4-{(5-bromo-4-{f3- (methylsulfony I) be nzy I] a mino}py rimidi n-2yi)amino]benzene-sutfonamide (35)	0.0176
36	v° A k\j / ties/	N-methyl-N-[3-({(2-{[1- (methylsulfony I) pi pe rid tn-4-y 11 a m ino}-5(trifluoromethyl)pyrimidin~4yl]amino}methyl)pyridin-2yljmethanesulfonamide (36)	0.188
37	\r° N—*v \_A_L jr %	N-methyl-N-[3-({(2-{i1(methylsutfonyl)piper!din-4-yl]amino)-5(trifluoromethyl)pyrimidin-4yl]amirso}methyl)pyridin-2ylimelhanesulfonamide (37), trifluoroacetic acid salt
38	oXcb<	N-[3-({[2-(cyclobutylamino)-5(trifluoromethyl)pyrimidin~4' y!]amino}methyl)pyridin-2-yl]-Nmethylmethane-sulfonamide (38)	0.497
39	*aa ~8χάχ	N-[3-({{2-{[(3R)-1-acetylpyrrolidin-3yl]amino}-5-(trifluoromethyl)pyrimidin-4yliamino}methy))pyridin-2-yl]-Nmethylmethane-sulfonamide (39)	1
40	F I JXo	methyl 4-({4-[({2- (methyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yi}amino)benzoate (40)	0.00059

-1282016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
41	,Λ,Λν ''‘k-'&o φ A	4-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3yQmelhyl)am!no3-5(trifluorome(hyl)py ri midin -2yl)amino)benzoic acid (41)
42	X' 1 ό X	4-((4-(((2- (rrtethyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzoic acid (42). sodium salt	0.188
43	ΖΖκ 'ΤΤ'^Ο ό A? cr^o	4-((4-(((2- [methyl(methylsulfonyl)amino)pyridin-3yl}methyl)aminoJ-5(trifluoromethyl)pyrimidin-2yljamino)benzoic acid (43), trifluoroacetic acid salt	0.0006
44	F F /-/K 0 AA, vr- ό /	N-methyl-N-[3-({[2-(piperidin-4-yIamino)5-(trifluoromethyl)pyrimidin-4y IJ a minojmethy l)pyrid i n-2yljmethanesulfonamlde ¢44)	0.188
45	F p AA \Ar 0 0Λχ	N-(3-(({2-((1-acetylpiperidirt-4-yl)amino]-5(trifluoromethyi)pyrimidin-4yl)amino)methyl]pyridin-2-yl}-Nmethylmethane-sulfonamide (45)	0.188
46	F uvA l/^/Al ο o ό	N-4-(3-(methy!sulfonyi)benzyl)-N-2phenyl-5-(trifluoromethyl)pyrtmidine-2,4diamine (46)	0.00102
47	F . AtAw ο o A Her tAx	3-methoxy-4-{(4-{(3(methylsulfonyl)benzyl]amino}-5(trifluoromethyl)pyrimidin-2yl]amino)benzamide (47)	0.00059

-12S2016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAKIC50, μΜ
48	F . ,Μ-,Μή '',Μ-	3-methoxy-4-({4-[{{2- [methyl(methyisulfonyl)annino]pyridin-3yl)melhyl)amino)-5(trifl uoromethy))pyrimidin-2yl}amino)benzamide (48)	0.00059
49	, ΧΪα i) <A-«	3-methoxy-4-((4-[({6-methyt-2- |methyl(methylsulfony!)-amino]pyridin-3- yl)methyl)amino]-5- (trif!uoromethyl)pyrimidin-2- yl)amino)benzamide (49)	0.00059
50	f jOCn i ό Vb	N-[3-(([2-anilino-5 {tri fluorom et h yl) py ri midin-4yl]amino}methyl)pyridin-2-yl]-Nmethylmethane-sulfonamide (50)	0.00059
51	Χίχ ό 'ύ-	N-[3-(([2-anilino-5- (t rifluorom ethy l)py rimidin-4yl]amino)methyl)-S-metbylpyridin-2-yt]-Nmethylmethanesulfonamide (51)	0.00059
52	χά .. I I **<- ό V Λ	N-methy[-4-{{4-{[3(methylsutfonyl)benzylJamino}-5(trifluoromethyl)pyrimidin-2yl]amino}benzamide (52)	0.00195
53	F Jd/F 1° ,ΟΟγο» -η'Ά ό X,” cr>i 1	N-methyl-4-({4-({{2- [methyl(methylsuifonyl)amrno]pyridin-3yl}methyl)3mino]-5(triftuoromethyl) py ri midin-2yl)amino)benzamide (53)	0.00059
54	AXkx ό Si ’ι	N-methy I-4-{{4-[({6-m ethy l-2- [methy ((methylsulfonyl) a min o]py ridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (54)	0.00059

-1302016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
55	F ? 0 (AA ό A <Aj °s.	N-[3-({[2-([1-(nriethoxyacetyl)piperidin-4- y (Jam i no}- 5-(trifl uorometh y l)pyrimid in-4yljaminojmethyl)pyridin-2-yij-Nmethylmethane-sulfonamide (55)	0.188
56	AA vV ό A A «γθ	N-{2-[4-{{4-(({2- [methyl(methylsulfonyi)amino]pyridin-3yt}methyl)aminoj-5· (triftuoromethy!)pyrimidin-2yl)a mino)piperidirt-1 -yl)-2oxoethyljacetamide (56)	0.188
57	F f 0 ,.Α.Α, fbc ό ύ cAw	4-((4-(((2- [methyt(methytsuifonyl)amino]pyridin-3yl)methyI)aminoJ-5(trifluoromethyl)pyrimidin-2yl}amino)piperidine-1-carboxamide (57)	0.188
58	«^γ^τ ο ΰ,Α \αγ ό A A	N-methy l-N-[3-({(5-(trifl uoromethy 1)-2-(( 1 - (3,3.3-trifluoropropanoyl)piperidin-4- yl]amino}pyrimtdin-4- yljamino)methyi)pyridin-2y!]methanesu!fonamide (58)	0.165
59	F αΑλ ή A fr^o	6-((4-(((2- [methy ((methylsulfo ny I)a mi n o] py ridi n- 3yl}methyl)amino]-5{trifluoromethyl)pyrimidin-2yl)amino)nicotinamide (59)	0.00893
60	Axcu A	ethyl cis-4-((4-[({2- [metbyi(methylsulFonyl)amino]pyridin-3yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)cyclohexanecarboxylate (60)	0.188
61	wSA °, >/£ A, -s?*- ό Yti· eA o	4-((4-(((2- [methyl(methyisulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trif)uoromethyl)pyrimidin-2-yl}amino)-Npyridin-2-yibenzenesuifonamide (61)	0.00102

2016201820 23 Mar 2016

-131 -

Ex.	Structure	Compound Name	FAK IC50. μΜ
62	ό ©L	N-[2-({I2-artilino-5(trifluoromethyljpyri midin-4yl]amino}methyl)-5- methylphenyl] methanesulfonamide (62)	0.0103
63	o X'F	N-[3-({(2-anilino-5(trifluoromefhyi)pyrimidin~4yiJamino}methyl)-4-methyiphenyl]-Nmethylmethanesulfonamlde (63)	0.0006
64	F I AA v-V ό	N-l2-({[2-anilino-5(trifluoromethyl)pyrimidin-4yl]amino}methyi)-6-methylpnenyl]-Nmethylmethanesulfonamide (64)	0.0006
65	f iTyV AA '-«'V ό Xl	N-[2-({{2-anilino-5(trifluorom ethyl) py rimidin-4yl]amino}methyl)“5-meihylphenylJ-Nmethylmethanesulfonamide (65)	0,0006
66	F 1 A A, 'nf-t0 ό	N-[2-({(2-aniIino-5(triflu oromethy l)py rim idin -4yl]amino)methyl)-4-methyiphenyl]-Nmethylmethanesulfonamide (66)	0.0006
67	F fVVf ( ό 2?	N-(2-({(2-anilino-5(trifiuoromethy IJpyrtmidi n-4y0amino}methyi)-3-methylphenytJ-Nmethylmelhanesulfonamide (67)	0.0006
68	f ίΓΎ^ ! ό ©	N-(2-((f2-anilino-5- - (trifluoromethy ί} py rim id in -4yi]amino)mefhyl)phenyl]methanesulfonam ide (68)	0.00059
69	F 1 tr^UV'f , Aa A° ό X	N-[2-({(2-anilino-5(trifluoromethy 1) pyrimid in-4 yt)amino)metbyl)-3- metfiyiphenyijmethane-sutfonamide (69)	0.0006

-1322016201820 23 Mar 2016

) Ex.	Structure	Compound Name	FAK IC50, pM
70	xchx ό	N-(3-(((2-anilino-5- (trifluoromethyi)pyrimidin-4yl3amino}methyl)-5-methylpyridin-2-ylJ-Nmethylmethanesuifonamide (70)	0.0006
71	P ryV v ό ύ	4-((4-(((3- [methyl(methylsuifonyl)amino]pyrazin-2yl}methyi)amino]-5(trifluoromethyl)pyrimidin-2yt}amino)benzamide (71)	0.0006
72	f xX° ό X“	4-((4-(((3- [methyl(methylsulfonyl)amino]pyrazin-2yI}methyl)amino]-5(trifluoromethy I) py ri mid in-2yl)amino)benzamide (72), hydrochloride salt
73	xckx 0 VS OX	4-((4-(((3- [methyl(methylsulfonyl)amino]pyridin-2yl}methyl)aminol-5(trifluoromethyl)pyrimidin-2yl}amirto)benzamide (73)	0,0006
74	XX ό v^ Or''»	4-((4-(((3- [methyl(methylsu)fonyl)amino]pyridin-2yl}methyl)amino]-5(trifluoro methy I) pyr im id i n-2yl}amino)benzamide ¢74), hydrochloride salt
75	xkx ό	N-(3-(([2-anilino-5- (tri flu orometbyl)py ri midin-4ytjamino}methyl)pyrazin-2-yiJ-Nmethylmethane-sulfonamide (75)	0.0006
76	χάχ ό ό	N-[2-(((2-anilino-5(trifiuoromethy!)pyrimidin-4yijamino}methyI)pyridin-3-yl]-Nmethylmethane-sulfonamide (76)	0.093

-1332016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
77	F hAAh o o ό X	N-e!hyl-4-{(4-{(3(roethylsulforiyl)benzyl]amino}-5(trifluoromethyl)pyrimidin-2yl)amino}benzamide (77)	0.0006
78	xXx o X	N-[3-({[2-anilino-5(trif!uoromethyl)pyrimidin-4yl]amino}methyi)-4-methylpyridin-2-yl]-Nmethylmethanesulfonamide (78)	0.0006
79	F xxhx ό X	N-[5-({I2-anilino-5(trinuoromelhyl)pyrimidin-4yl]amino}methy})-2-methylpyrimldin-4-ylJN-methylmelhanesulfonamide (79)	0.00262
80	ό X	N-[5-(((2-anilino-5- (triflu oromethyl) py rimidi n-4- y IJa mino}methy l)-2-methy I py rid in-4-y I]-N- methylmelhanesutfonamide (80)	0.00059
81	V	N-methyl-N-[3-({£5-(trifluoromethyi)-2-{[6(trifluoromethyl)pyridin-3y IJamirtoJpyrim idin-4 yl]amino}methyl)pyridin-2yljmeihanesulfonamide (81)	0.0158
82	f AA '-«'K ό CrN	4-((4 -[({5-methyl-2- [methyl(methylsulfonyI)aminojpyridi'n-3yl}methyl)amino)-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (82)	0.0006
83	f ryV v ό X αΆ	4-({4-[({4-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3yi)methyl)amino]-5(trifiuoromethyi)pyrimidin-2yl}arnino)benzamide (83)	0.0006

-1342016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAKIC50, μΜ
84	0 ©Λ	4-<{4-[({2-methyl-4- (methyl(methyfsulfonyl)amino]pyrimidin-5yi)methyl)amino]-5(trifluoromethyi)pyrimidin-2yQaminoJbenzamide (84)	0.00171
85	,X4'X ό 'Δ.	4-({4-[({6-methyl-4- (methyi(methylsulfonyl)amino3pyridin-3yl)methyl)amino]-5(trifIuoromethyi)pyrimidin-2yl}amino)benzamide (85)	0.00084
86	F K'vSt ''rr'i'O ψό © ©	N-methyl-3-({4-({{2- [methyl(methylsulfonyl)aminolpyridin-3yl)methyi)amino]-5(trifluoromethyI)pyrimidin-2yl)amino)benzamide (86)	0.00161
87	t Χ&Λ. . fb A Ar	3-((4-(((2- (methyl(methylsuIfonyl)aminojpyridin-3- yl)methyi)amino]-5- (trifluo ro methyi)py ri midin-2-y I) ami no)-N[3-(triffuoromethyi)pbenyl]benz8mide (87)
88	rrV t fASrS Si'FQ ., ψύ Ά Ay	3-((4-(((2- [mefhyi(methylsulfonyl)amino]pyridin-3- yi)methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N(3-(trifIuoromethyi)pheny[]benzamide (88), hydrochloride salt	0.0215
89	xxKa° ί Ά.	N-ethyl-4-((4-(((6-methy!-2- methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino}-5- lrifluoromethyl)pyrimidin-2yl)amino)benzamide (89)	0.0006
90	χά-Λ νό ©	N-[3-((E2-((3-[(3-hydroxyazetidrn-1yl)csrbonyl]phenyl}amino}-5(trifluoromethyI)pyrimidin-4yl]amino)methyl)pyridin-2-yi]-Nmethylmethane-sulfonamide (90)	0.00072

-1352016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
91	t	N-(3-[({2-[(1-elhyl-1H-pyrazo!-5-yl)amino]5-(trifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl}-Nmethylmethane-sutfonamide (91)	0.188
92		N-(3-[({2-[(2-chtoropyrtdin-4-yl)amino)-5(trifiuoromethyl)pyrimidin-4yl)a mino)methy l]pyrtdin-2-y l}-Nmethylmethane-sulfonamide (92)	0.00192
93	©	N-(3-[({2-[(2-meth oxypy ridi n-4-y IJamtn oj5-(trifluoromethyl)pyrimidin-4yl}amino)mefriyl]pyridin-2-yl}-Nmethylmethane-sulfonamide (93)	0.0006
94	F 9uct*x ''ό'	N-methyI-N-{3-[({2-i(3-methy!pyridin-4- yl)amino]-5-(trifluoromethyl)pyrinnidin-4y I} aminojmethyljpyrid in-2yQmethanesulfonamide (94)	0.00801
95	©	N-{3-[({2-[(4-cyanophenyl)amino]-5(trifluoromethyl)pyrimidin-4yl}amino)rrtethyl]pyridin-2-yl)-Nmethylmethane-sulfonamide (95)	0.0006
96	F fjf'v 1 $ 1	N-methyl-4-{[4-({2- imethyl{methylsulfonyl)amino]benzy!)ami no)-5-(trifluoromethyi)pyrimidin-2yl]amino)benzamide (96)	0.00059
97	0 ©I k	N-ethy 1-4-((4-[((3- [methyI(methyisulfonyl)amino)pyridin-2yl)methyt)amino]-5(trifluoromethy))pyrimidin-2yl)amino)benzamide (97)	0.00059
98	ό © Ί	ethyl [4-((4-(((2- [methyl(methyfsulfonyI)amino]pyridin-3yl}methyi)amino)-5(trifluoromethyl)pyrimidin-2yl)ainino)phenyi]acetate (98)	0.00059

-1362016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
99	r Λλ' , ό VT·	4-((4-((3- (methyi(methylsulfonyl)amino]benzyi)amr no)-5-(trifluoromethyl)pyrimidin-2yl]amino}benzamide (99)	0.00038
100	F j φ Vri	4-((4-((3- [rnethyi(methylsulfonyl)amino]benzyi}ami no)-5-(trifluoromethyl)pyrimidin-2yl]amino}benzamide (100), hydrochloride salt
101	r $ I	N-methyl-4-{[4-({3- [methyl{methylsulfo ny !)am i no) benzyija mi no)-5-(trifluoromethyl)pyrimidin-2yl]amino}benzamide (101)	0.00059
102	\i·	N-(5-({4-[({2- (methyi(methytsulfonyl)amino]pyridin-3y ijmethy l)am ino]-5(irifluoromethyl)pyrimidin-2y[)amino)pyridin-2-yl)acetamide (102)	0,00233
103	Xd’-X ό I	N-methyl-4-({4-[({6-m ethy i-4- Imethyl(methylsulfonyl)amlno)pyridin-3- yl)methy!)amino]-5- (trifluoromethyl)pyrimidin-2yljamino) benz amide (103)	0.00059
104	,^5<<F o AAv* ό V	N-{3-({[24(4-(arninomethyl)phenyl]arnino}5-(trifiuoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2-yl]-Nmethylmethane-sutfonamide (104)	0.00059
105	iV^ ,Λ,A« -sr ό y	[4-((4-(((2- [me(hy[(methylsu!fonyl)aminoJpyridin-3yl}methy!)amino]-5(irifluoromethy IJpyrim i di n-2 yl}amino)phenyl]acetic acid (105) .....	0.00094

- 1372016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50. pM
106	A , ό	4-{[4-({2-methy!-5- (methyl(methylsulfonyl)amino]benzyl)ami no)-5-(trifluoromethyl)pyrimidin-2yljaminojbenzamide (106)	0.00096
107	F , AA„ ό A crS	4-fl4-({2-methyi-6- [methyl(methylsu[fonyl)amino]benzyt)ami no)-5-(trifluoromethyl)py rimid i n-2yljamtnojbenzamide (107)	0.00059
106	F $	4-{f4-({3-methyI-2- [methyt(methylsulfonyl)amino]benzyi)ami no)-5-(trifluoromethyl)pyrimidin-2yl]amino)benzamide (108)	0.0006
109	r 1 ΛΑ -«'V ό A	4-{[4-({4-methyl-2- [methyl(melhylsuifonyl)amino]benzyl}ami no)-5-(trifluoromethyl)pyrimidin-2yf]amino}benzamide (109)	0.0006
110	r ΐΠτΑ ι $. Y	4-fi4-({5-methyl-2- [methyl(methylsulfony!)amino]benzyl)ami no)-5-(triflu oromethy l)pyrimid in-2yijaminojbenzamide (110)	0.0006
111	ArV f ΛΑ ,r-t° ό A ςτΆ	4-((4-((2- [(methylsulfonyl)amirto]benzyl}amino)-5(trifluoromethyl)pyrlmidIn-2yljaminojbenzamide (111)	0.0006
112	F ΐΓΎΑ 1 ,AA„ ό A Cr^M	4-£[4-({4-methyl-2- [(methylsu!fonyl)amino]benzyl)amino)-5(trifiuoromethyl)pynmidin-2yljamino} benzamide (112)	0.0006

-1382016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
113	F ό /5°	4-{(4-({2-methyl-6- ((methylsulfonyl)amino]benzyl)amino)-5(trifluoromelhyl)pyrimidin-2y[)amino}benzamide (113)	0.0006
114	Χ©Α· 0	N-(2-hydroxyethyi)-N-methyl-3-{{4-(((2- (methyl(methylsuifonyI)aminoJpyridin-3y])methyl)amino)-5(trifluoromethyl)pyrimidin-2yi)amino)benzamide (114)
115	X©,A° ό o	N-(2-hydroxyethyI)-N-mGthyl-3-({4-[{{2- (methyl(methyIsuIfonyl)amino]pyridin-3- yl)methyi)amino]-5- (iiifluorometbyl)pyrimidin-2y!)amlno)benzamide (115), trifluoroacetic acid salt	0.00088
116	MS cu/j ©· a	3-((4-(((2- (methyf(methylsulfonyl)amino]pyridin-3- yi}methyl)amino]-5- (frifluoromethyl)pyrimidin-2-yl}amino)-N[(2R)-tetrahyd rofijra n-2ylmethyijbenzamide (116)
117	<Χγ0 U	3-((4-(((2- [methyl{methylsu!fonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluorometbyl)pyrimidin-2-yl}arnino)-N[(2R)-tetrahydrofuran-2ylmethyl]benzamide (117), trifluoroacetic acid salt	0.00147
118	Χ0Α cr©	3-((4-(((2- [methyl(metbylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yi}amino)-N- (tetrahydro-2H-pyran-3-yl)benzamide (118)
119	ηύ j,” ./\Λ. 'w-K ςτΖ	3-((4-(((2- (metbyl(methylsulfonyl)amino]pyridin-3yljmetby I )amin oJ-5- (trifluoromethyi)pyrimidin-2-yl}amino)-N(tetrahydro-2H-pyran-3-yi)benzamide (119), trifluoroacetic acid salt	0.00114

- 1392016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
120	xxAa ,,-,-0 V	3-({4-I({2- fmethyJ(methylsulfonyl)amino]pyridin-3- y|)methyl)aminoJ-5- (trifluoramethyl)pyrimidin-2-yl}amino)-N- (tetrahydro-2H-pyran~4-yl)benzamide (120)
121	jrd'A0 ,,,0 O	3-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3- yl)methyl)aminoJ-5- (trif]uoromethyl)pyrimidin-2-yl}amino)-N(tetrahydro-2H-pyran-4-yl)benzamide (121), trifluoroacetic acid salt	0.00094
122	χύ-Χ a/) to? 0	N-metbyl-N-(3-({E2-{(3-(morpholin-4ylcarbonyl)phenyl]amino}-5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridrn-2yljmethanesulfonamide (122)
123	χύΤ 'j,O to A	N-methyl-N-[3-(((2-([3-(rnorph oli n-4ylcarbonyl)phenyl]a min o}-5(trifluoromethyl)pyrimidin-4yl]amino)methyl)pyridin-2yljmethanesulfonamide (123), trifluoroacetic acid salt	0.00215
124	Xxhx: cfri) fy o	N-(3-({[24(3-(azetidin-1- ylcarbony!)phenylJamino}-5(trifluoromethyl)pyrimidin-4yl]amino)methyt)pyridin-2-yl)-Nmethylmethane-sulfonamide (124)
125	xxV· Ογό Ab 0	N-[3-(([2-([3-(azetidin-1- ylcarbonyl)phenylJamino)-5((rifluoromethyl)pyrimidin-4yl]amino)methy))pyridin-2-yi]-Nmethylmethanesulfon-amide (125), trifluoroacetic acid salt	0.00127
126	4<k F >K>\ 0 JL/ > OA_, TV v,./	N-[(1-hydroxycyc(obutyl)methyl]-3-({4- t((2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)aminoj-5- (trifluorometbyl)pyrimidin-2yl)amlno)benzamide (126)
127	_	N-[(1-hydroxycyclobutyl)methyl]-3-({4- [({2-(methy!(methylsulfonyl)amino]pyridin- 3-yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yljaminojbenzamide (127), trifluoroacetic acid salt	0.00211

-1402016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
128	. Atv Λ/> fr o	N,N-bis(2-hydroxyethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino)pyridin-3- yl}methyl)aminoj-5- (trifiuoromethyl)pyrimidin-2yl}amlno)benzamlde (128)
129	. xAa· AZ) Ti? c	N,N-bis(2-hydroxyethyl)-3-({4-[({2[methy I (methyls u I fony l)a minojpy rid in-3yf}methyl)amino]-5- {trifluoromethyI)pyrimidin-2yl}amino)benzamide (129), trifluoroacetic acid salt	0.00076
130	f pA* ?.· ΛΑ '•(.-'‘-s σΎ0	N-cyclopentyl-N-m ethyl-3-((4-(((2(methyl(methylsulfonyl)amino]pyridin-3y IJmethyl) a mino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (130)
131	T 7/'·, -A σψό y>-	N-cyclopentyl-N-methyl-3-({4-[({2- [methyl(methylsuifonyl)amino]pyridin-3- yI)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (131), trifluoroacetic acid salt	0.0108
132	F . xA Άό A o	N-(2-(dimethylamino)-2-oxoethyi)-3-((4- ({{2-[methyt(methylsulfonyl)amino]pyridln- 3-yl}methyl)amlno]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (132)
133	. χΑλ’ Άό V 0	N-[2-(dimethylamino)-2-oxoethyl]-3-({4- [({2-(methyl(methy1sulfonyl)amino]pyridin- 3-y!)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (133), trifluoroacetic acid salt	0.00195
134	zA Μ Tb ΰ	N-[3-(((2-({3-((3-hydroxy-3methylpyrro!idin-1yl)carbonyljpheny!}amino)-5(trifluoromethyl)pyrimidin-4y l]a m in o}methy l)py ridin-2-y I)- Nmethylmethane-sulfonamide (134)
135	„ χΑχ Τψό ν 0	N-E3-((E2-((3-[{3-hydroxy-3methylpyrrolidin-1yl)carbonyi]phenyl}amlno)-5(trifl uoromethyl)pyrimidin-4y I] am in ojmethy I) py ridin-2-yl]-Nmethylmethane-sulfonamide ¢135), trifluoroacetic acid salt	0.00333

-1412016201820 23 Mar 2016

( Ex.	Structure	Compound Name	FAK IC50, μΜ
136	xfoU· fo I o	N-[2-(dimethylamino)ethy|J-N-methyl-3- ((4-(((2- [methy l(methy Isulfony l)a m in o] pyridin-3yl}methyl)amino]-5(trifluorome1hyl)pyrimidin-2yl}amtno)benzamide (136)
137	fo 1 0	N-[2-{dimethylamirto)ethyl]-N-rnetbyl-3- ¢(4-(((2- (methyl(methylsulfonyl)amino]pyridin-3yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (137), trifluoroacetic acid salt	0,00433
138	χύ-Λ 0..,0 fo o	3-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (trifiuo romethy l)py rimidin-2-yI}ami n o)-N(pyridin-2-y!methyl)benzamide (138)
139	fofoo· Cofo) fo β	3-((4-(((2- [meEhyl(methylsulfonyl)annino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyi)pyrimidin-2-yl}amino)-N(pyridin-2-ylmethyl)benzamide (139), trifluoroacetic acid salt	0.00191
140	xfoo cpfo fo- Q	3-((4-(((2- (methyl(melhylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluo romethy IJpyrimid in-2-yl} am ino)-N[(3-methy loxeta n- 3-y I) methy IJbenzamide (140)
141	xfofo.· cpfo fo β	3-((4-(((2- imethyl(methylsulfonyl)aminoJpyridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N{(3-me(hyIoxetan-3-yl)methyl]benzamide (141), trifluoroacetic acid salt	0.00084
142	tes Xfo/A· φψό fo	N-methyl-N-{3-(({2-({3-{((3S)-3- methyImorpholin-4- yl]carbonyl)phenyl)amino]-5- (trifIuoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yljmethanesulfonamide (142)
143	>63 xfox· fofo fo	N-methyl-N-(3-((i2-{(34i(3S)-3- methylmorpholin-4yl]carbonyl}phenyl)amino]-5(trifiuoromethyl)pyrimidin-4yl}amino)methyl)pyridin-2yljmethanesulfonamide (143), 'rifluoroacetic acid salt	0.0024

- 1422016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
144	..!__A A	N-t3-(dimethylamino)propyi]-3-({4-[({2- [methyl(methylsutfonyl)amino)pyridin-3yl)methyl)amino)-5(tr ifluoromethy l)pyri midi n-2yl}amino)benzamide (144)
145	A ί>	N-[3-(dimethyiamino)propyl]-3-((4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl)methyi)amino]-5' (trifluoromethyl) pyrimidin-2yi)amino)benzamide (145), trifluoroacetic acid salt	0.00254
146	AAA	N43-E({2-[(3-(i2- (hydroxymethyl)pyrrotidin-l- yi]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (146)
147	f Ρ?4 ίζο (fff) A	N-(3-E({2-[(3-{{2(hydroxymethyl)pyrrolidin-l y)]carbonyl}phenyl)amino]-5(frifluoromethyi)pyrimidin-4y (}a min o)methy IJ pyridi n-2-y l}-Nmethylmethane-sulfonamide (147). trifluoroacetic acid salt	0.00474
148	.. .ΎΟ A o	N-(3-methoxypropyl)-3-({4-[({2- [methyl(methy[sulfonyt)-aminoJpyridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2y))amirto)benzamide (148)
149	( , oe ΛΛ- mA A g	N-(3-methoxy pro py I)-3 - ({4- [({2[methyi(methy Isulfony I)amino] py rid in-3y!)methyl)amino)-5- (trrfluoromethyf)pyrimidin-2yt}amino)benzamide (149). trifluoroacetic acid salt	0.00151
150	άΛ 1 v/5	N-{ 1 -cyclopropylethyl)-3-({4-[({2- [methyi(methylsulfony!)-amino]pyridin-3yl}methy!)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (150)
151	zsA „ aaa vP A I ό	N-(1-cyc(opropyiethyl)-3-({4-(({2- (methyl(methylsu!fonyl)-amino]pyridin-3- yi}methyt)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (151), trifluoroacetic acid salt	0.00524

-1432016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
152	IM xZa· 'ό ο	N-{34<£2-[(3-i[(3R,4R)-3,4diftuoropyrrolidin-1yl]carbonyl)phenyl)amino]-5(trifluoromethyl)py rimidi rs-4y l)a mino)methy l]py ridin-2-y I}- Nmethylmethane-suifonamide (152)
153	MU , χΖλ σ	N-{3-(({2-[(3-{[{3R,4R)-3,4difluoropyrrolidin-T ylJcarbonyl}phenyi)aminoj-5(trifiuoromethyl)pyrimidin-4y l)amino)methy I] pyridin-2-y l}-Nmethylmethane-sulfonamide (153), (rifluoroacetic acid sail	0.00335
154	aXSA 9γό υ	N-methyl-N-[3-({[2-({3-[(2- methyipyrrolidin-1' yl)carbonyl]pheny!)amino)-5(trifluoromethyl)pyrimidin-4ylJamino}metliyl)pyridin-2yljmethanesulfonamide (154)	I
155	φψύ υ	N-methyl-N-[3-({[2-({3-[{2* methylpyrrolidin-1- yl)carbonylJphenyi}amino)-5- (trifluoromethyi)pyrimidin-4- yl]amino}methyl)pyridin-2- yijmethanesulfonamide (155), (rifluoroacetic acid salt	0.00975
156	MS χΖα· ~Όψ0 Ζ 0	N-{3-[({2-[(3-{{(3S)-3-hyd roxy py rroii d i n-1 yl]carbonyi}pfienyl)aminol-5(trifluoromethyi)pyrimidifi-4yl) amin o)methyl Jpy rid in-2-y l}-Nmethylmethane-sulfonamide (156)
157	Α£5 •Εγ^’ β, «Χ,Ζ» ''Ζ. -<\ώ Ζ Β	N-{3-[({2-((3-{[{3S)-3-hydroxypyrrolidin-1yiJcarbonyl}phenyl)amino]-5(trifiuoromethyt)pyrimidin~4y l}amino)methy I Jpy rid in-2-yl}- Nmethylmelhane-sulfonamide (157), trifiuoroacetic acid salt	0.00424
158	*££. ρΐ'· ι* K-'S/'-H 'ή'1'·' χχό Ζ 0	N-(3-[({2-[(3-([(3S)-3-hydroxypiperidin-1yl]carbonyl)phenyl)amino]-5(trifluoromethyl)pyrimidin-4y l)am ino)methyl]pyridi n-2-yi}-Nmetbylmeihane-sulfonamide (158)

- 1442016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
159	aAa· χψό X 6	N43-[({2-[(3-{[(3S)-3-hydroxypiperidin-1yl]carbonyl)phenyl)amino]-5(trifluoromethyl)pyrimidin-4yl)amino)me!hyl]pyridin-2-yl}-Nmethylmethane-sutfonamide (159), trifluoroacetic acid salt	0.00614
160		N-[(1R)-1-(hydroxymethyl)-2- methylpropylj-3-({4-(({2- [methyl(methylsulfonyl)aminoJpyridin-3yl)methyt)aminoJ-5(trifluoromethyl)pynmidin-2yl}amino)benzamide (1S0)
161	Aid	N-(( 1R)-1 -(h ydroxy methy 1)-2- methyipropyi]-3-({4-(({2- [methyt(methyisulfonyl)amino]pyridin-3- yf}methyl)amino]-5- (trifl uoromethy l)py rimidin-2- yl}amino)benzamide (161), trifluoroacetic acid salt	0.00374
162	ΛΧΪ7Α οΆ	N-cyclopentyl-3-((4-i({2- (methyl(me{hylsulfonyl)amino]pyridin-3yl} methy l)am in o]-5(trifluoromethyl)py ri midin-2yl)amino)benzamide (162)
163	aAa- σΑ	N-cyciopentyl-3-({4-(((2- [methyl(methy(sulfonyl)amino]pyfidsn-3yl)methyl)amino)-5(trifiu oromethy I) py rim idin-2yl}amho)bertzamide (163), trifluoroacetic acid salt	0.0051
164	λΑα· χό χ· Q	N-{3-[((2-[(3-{[3-(dimethylamino)azetidin1 -y IJcarbony Qpheny I) a rnino j-5(trifluoromethyl)pyrimidin-4yl}amino)melhyl]pyridin-2-y|}-Nmethylmethane-sulfonamide (164)
165	Κ\ό X-	N-{3-i({2-((3-{[3-(dimethylamino)azetidin1-ylJcarbonyl}phenyi)amino]-5(trifluoromethy l)py rim id i n-4yl)amino)methyl]pyridin-2-yl)-Nmethytmethane-sulfonamide (165), trifluoroacetic acid salt	0.00493

-1452016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50. pM
166	xAa· A 0	N-(2-(acetylamino)etbyl]-3-({4-(({2- [methyi(methylsulfonyl)aminoJpyridin-3- yi)methyl)amino]-5- (tnfiuoromethyt)pyrimidin-2yl}amino)benzamide (166)
167	x/x Α^ψό Hi c	N-[2-(acetylamino)ethyl]-3-({4-[({2- [methyl(methylsutfonyl)amino)pyridin-3- yl)methyl)aminoJ-5- (trifluorometbyi)pyrimidin-2yi}amino)benzamide (167), trifluoroacetic acid salt	0.00344
168	aAa° y/ό v	N-[( 1 R)-1-(hydroxymethy l)propylJ-3-({4- |({2-[methyl(methylsulfonyl)aminojpyridin- 3-yl)methyl)amino)-5- (trifluoromethyl)pyrimidin-2yljaminojbenzamide (168)
169	A££ xAa° Ζγό A	N-f(1 R)-1 -(hydroxymethyl)propyl]-3-({4[({2-[me!hyl(methyls u lfonyl)am inojpyridin3-yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2y(}amino)benzamide (169), trifluoroacetic acid salt	0.00247
170	χΑχ 0./ A· o	N-methy!-N-[3-({[2-([3-<piperidin-1 ylcarbonyl)phenyl]amino}-5(trifluoromettiyl)pyrimidin-4ylJamino}rrtethyl)pyridin-2yljmethanesulfonamide (170)
171	0/ 0	N-methyi-N-[3-({(2-{[3-(piperidin-1- ylcarbonyl)phenyl]amino}-5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2yljmethanesulfonamide ¢171), trifluoroacetic acid salt	0.00791
172	x/θ A- AT i	3-((4-(((2- [methyi(methylsulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl)amirto)-N(1-methylpiperidin-4-yl)benzamide (172)
173	x/x χ>·	3-((4-(((2- Emethyi(methyisulfonyl)amino]pyridin-3- yi)methyl)amino]-5- [trifluoromethyl)pyrimidin-2-yl}amino)-N;i-methylpiperidin-4-yl)benzamide (173), irfluoroacetic acid salt (	0.00096

-1462016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
174	-€ψ0 V 0	N-{3-[({2-[(3-{[{3R,-3-hydroxypyrfoiidin-1 y IJcarbonylJphe nyl)ami n o]-5(trifluoromethyi)pyrimidin-4yl}amino)methyl]pyridin-2-yIpNmethylmethane-sulfonamide (174)
175	ΛΪ3 «ΆΛ- γΑ -Οψό	N-{3-[({2-[(3-{[(3R)-3-hydroxypyrroIidin-1yl]carbonyl}pheny!)amino]-5(trifiuoromethyl) pyrimtdin-4yl}amino)rnethyi]pyridin-2-yl}-N-methylmethanesulfonamide (175), trifiuoroacetic acid salt	0.00408
176	χί-Λ· Χ?γ0 'xb	N-[3-{{[2-{{3-E(3,3-dif1uoropyno!idin-1yl)carbonyi]phenyl}amino)-5(trifluoromethyl)pyrimidin-4yljaminoJmethyi)pyridin-2-yi]-Nmethylmethane-sulfonamide (176)
177	4?Α· χ\ό Ά' ο	N-[3-({[2-({3-((3,3-d ifluoro py rrolid in-1 y l)carbony IJpheny l}a m ino)-5(trifluoromethy!) pyrimidin-4-yl]amino} methyl)pyridin-2-yl]-N-methylmethanesutfonamide (177), trifiuoroacetic acid salt	0.00593
178	ΑΕ4 χ0α· Λ,ψό / °	N-[( 1S)-1 - (hydroxymethy l)-2- methylpropyl}-3-({4-[({2- (methyl(methylsulfonyi)amino]pyridin-3- yi}methyl)amino]-5- (trifiuoromethyi)pyrimidin-2- yl}amino)benzamide (178)
179	«ε r «''V'k'* ο„ χνό *ύ > °	N-[(1 S)-1 -(hydroxy methyl)-2- methylpropyl]-3-({4-[({2- [methyi(methylsulfonyl)amino]pyridin-3- yl}melhyl)amino3-5- (trifiuoromethyl)pyrimidin-2- yi)amino)benzamide (179), trifiuoroacetic acid sait	0.00109
180	ο	N-(3-methoxypropyl)-N-methyl-3-{{4-[({2- [methyi(methylsulfonyl)amino]pyridin-3- yi}methyl)aminoJ-5- (tr ifluoro metbyl)pyrimid in-2yl}amino)benzamide (180)

-1472016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
181	xA A o	N-(3-methoxypropyI)-N-methyl-3-({4-[{{2- (methyt(methylsu!fonyl)amino]pyridin-3yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (181), trifluoroacetic acid salt	0.00918
182	xcA _A A	N-[{1S)-1 -(hyd roxy melhy l)pro pyl]-3-({4- [({2-[methyJ{methylsulfonyl)amino}pyridin3-y!}methyI)amino]-5(trifluoromethyl)pyrimidln-2y[)amino)benzamide (182)
183	xA A	N-(( 1 S)-1-(hydroxymethyl)propyl]-3-({4[({2-tmethyl(methy Is ulfony l)am in o]py ridin3-yl)methyl)aminoJ-5- (trifluoroir>ethyl)pyrimidin-2yl)amino)benzamide (183), trifluoroacetic acid salt	0.00196
184	xA czA	N-cyclobutyl-3-({4-[({2- (m ethyl(methy Isuf fony l)amin o]py rid in-S- ylJmethyiJaminoJ-S- (trifluoromethyl)pyrimidin-2yl)amino)benzamlde ¢184)
185	xrA A a	N-cyclobutyi-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (185), trifluoroacetic acid salt	0.00217
186	Ο>γ·Λ A-V Ά' 1	N-cyclohexyJ-3-{{4-[((2- [methyl(mettiylsulfonyl)amino)pyridin'3' yl}methyl)amino]-5- (trifluoromelhy!)pyrimidin-2yl}amino)benzamide ¢186)
187	Οαλ -/Ά• AjA *	N-cyclohexyl-3-({4-[({2[methyl(methylsulfony I) am i n o]pyridin-3yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (187), trifluoroacetic acid salt	0.00584
188	xA A A J 0	N-isopropyl-3-({4-[({2- trr>ethyi(methylsulfony!)aminojpyridin-3- yl)methyl)aminoJ-5- (trifIuoromethyi)pyrimidin-2yl}amino)benzamide (188)

-1432016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
189	χύ-Λ· Ύψό 'Ό ’ ο	N-isopropy 1-3-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3- yI}methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (189), trifluoroacetic acid salt	0.0043
190	χΕα· ,ψό Ν- 0'	N-benzyl-3-({4-[({2- (methyl(methylsulfonyl)aminoJpyridin-3yl}methyl)amino]-5(trifluoromethy!)pyrimidin-2yl}amino)benzamide (190)
191	rr^ ό	N-benzyl-3-({4-(({2- [methyl(methylsulfonyl)amino]pyridin-3yl}methyt)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (191), trifluoroacetic acid salt	0.0055
192	, χΑα· AJ0 kb _ϊ	N-(2-hydroxyetbyl)-3-({4-[({2- (methyi(methylsulionyl)amino]pyridin-3- yl}methyl)amino)-5- (trifl u orometh y i)pyrimid in-2-y l}a min o)-Npropylbenzamide (192)
193	Λ0	N-(2-hydroxyethyl)-3-({4-[({2- (methyl(methylsulfonyi)amino]pyridin-3- yi}methyl)amino]-5- (trifiuoromethyl)pyrimidin-2-yl}amino)-Npropylbenzamide (193), trifluoroacetic acid salt	0.0011
194	αχΑα· Γ..ρ kb· ο	N-ethyl-N-(2-methoxyethyl)-3-({4-(({2- (methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifiuoromethyl)pyrimidin-2yl}amino)benzamide (194)
195	^?νό kb 0	N-ethyl-N-(2-methoxyethyl)-3-({4-(({2- (methyl(methylsulfonyl)aminoJpyridin-3- yl}methyl)amino]-5- (trifluoromethy l)pyri mid in-2yl)amino)benzamide (195), trifluoroacetic acid salt	0.00681
195	χΕα· Όψ0 Ά 0	N-methyl-N-[3-(((2~((3-[(4-methylpiperidin1-yl)carbonyi]phenyl}amino)-5(trifluoromethyl)pyrimidin-4ylja mino}methyl)pyridin-2yljmetbanesulfonamide (196)

- 1492016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
197	aAa τ?γό fy· o	N-methyl-N-[3-(([2-{{3-[(4-methylpiperidin1-yl)carbonyl]phenyl)amino)-5(trifluoromethyl)pyrimidin-4y I] a m lno)m ethy l)py ridin-2yljmethanesulfonamide ¢197), trifluoroacetic acid salt	0.00447
198	χύχ Όψό %· α	N-methyl-N-[3-({(2-({3-[(4- methylpiperazin-1- yl)carbonyl]phenyl)amino)-5- (trifluoromethyi)pyrimidin-4- yl)amino)methyl)pyridin-2- yljmethanesulfonamide (198)
199	/Ax.' Όψό fy 0	N-methyl-N-I3-{{(2-({3-[(4methyipiperazin-1yl)carbonyl]phenyl}amino)-5(triflu orom el hy I) pyri mid in-4 yl]amino}methyl)pyridin-2yljmethanesulfonamide ¢199), trifluoroacetic acid salt	0.00256
200 1	χχΑ ο	N-(2-hydroxy-1,1 -dimethylethyl)-3-({4- f({2-fmethyl(methylsulfonyl)amino]pyridin- 3-yl)methyl)amino)-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (200)
201	χάχ 0	N-(2-hydroxy-1,1 -drmethylethyl)-3-({4- {{{2-|methyl(methyIsuifonyl)amino]pyridin- 3-yl}methyi)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (201), trifluoroacetic acid salt	0.00164
202	χάχ ^.ψό % X 0	N-[ 1 - (hydroxy methy l)propyQ-3- ({4-(((2- (methyl(methylsu!fonyl)aminoJpyridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (202)
203	χάχ	N -(1 -(hydroxy methy I) pro py I (-3-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (trifluoromefhyl)pyrimidin-2yl}amino)benzamide (203), trifluoroacetic acid salt	0.00113
204	Γχ* Λ· % 1 0	N-[2Tdimethylamino)ethyl]-3-({4-(({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyI)amino]-5- (trifiuoromethyl)pyrimidln-2yl}amino)benzamide (204)

-1502016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
205	xAv	N-[2-(dimethylamino)ethyl]-3-((4-[({2- [methyl(mGthylsulfonyl)amino)pyridin-3- yl)methyl)amino)-5- (trinuoromethy I) pyrim id in-2yl)amirto)benzamide (205), trifluoroacetic acid salt	0.0032
206	xdx- Ουό V I S	N-methyl-N-{3-(((2-[(3-{[(3R)-3- me(hytmorphoiin-4- ytJcarbony!)phenyl)aminoJ-5- (trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2- yljmethanesulfonamide (206)
207	A£3 X· O,.O ® ’ D	N-methyi-N-(3-[((2-[(3-{[(3R)-3- methylmorpholin-4- yl]carbonyl)phenyl)amino)-5- (trif)uoromethyi)pyrimidin-4- yl)amino)meihyl]pyridin-2- yljmethanesulfonamide (207), trifluoroacetic acid salt	0.00278
208	Χ®Λ· '-γγό Ά	3-((4-(((2- [methyl(methyisulfonyl)afnfrroJpyridin-3- yl}methyl)amino3-5- (trifluorometbyl)pyrimidin-2-yl)amino)-N(l-propylcyclopropyl)benzamide (208)
209	Η---Ζί. ''Ζ'·	3-((4-(((2- (methyl(methylsulfonyl)amino]pyridin-3- yl}methyi)amsno)-5- (trifluorometbyl)pyrimidin-2-yl}amino)-N(1-propylcyclopropyl)benzamide (209), trifluoroacetic acid salt	0.00368
210	χΑ ~γό Ά	N-[(1sj-2-hydfoxy-1-rnethylethyl3-3-({4- [((2-{methyl(methylsulfonyl)amino]pyridin3-yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yi}amino)benzamide (210)
211	«Β χΑ ^γό A Ζ ·	N-[( 1 S)-2-hydroxy-1 -methylethy)J-3-({4- f({2-[methyl(meihylsulfonyl)amino]pyrid!n- 3-yl)nethyl)amino(-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (211), trifluoroacetic acid salt	0.00106
212	χόχ Χψ£> ο	N-methyl-N-[3-(((2-((3-[(3-oxopiperazin-1yl)carbonyl]phenyl)amino)-5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2yljmethanesulfonamide (212)

- 151 2016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
213	Χψό A 0	N-methyl-N-[3-({[2-({3-((3-oxopiperazin-1yl)carbony!]phenyl)amino)-5(trifluoromethy!)pyrimidin-4yl]amino)methyi)pyridtrt-2yljmethanesulfonamide (213), trifluoroacetic acid salt	0.00288
214	© © H	N-[3-({(2-((3-(aminomethyl)phenyl]aminoF 5-(trif1uoromethyl)pyrimidin-4yl)amino)methyi)pyridin-2-yl]-Nmethylmethane-sulfonamide (214)	0.0007
215	r , ΛλΆ 0»^ z >- O	N~2~-acetyf-N-[4-({4-(({2- (methyl(methy!sulfonyl)amino]pyridin'3“ yi)methyl)aminoJ-5- (trifl uoromethy I )py ri midin-2yl}amino)benzyl)g!ycinamide (215)	0.0006
216	λΛ^- ό © «=( N	N-(3-[({2-[(4-{f(a m in ocarbony l)a minojmethyl)phenyl)amino]-5(trifiuorometliyl)pyrimidin-4yl)amino)methyl]pyridin-2-y!}-Nmethylmethane-sulfortamide (216)	0.0006
217	Λλ© ό ©	N-cycl opropy 1-2-(4-((4-[({2- [methyl(methylsulfonyl)aminoJpyridin-3- yi}methyl)amino]-5- (trifIuoromethyl)pyrimidin-2yl)amino)phenyljacetamide (217)	0.0006
218	/) © N	N-[3-({4-[({2- [methy!(methylsulfonyl)amino]pyridin-3yi}methyl)amino]-5(trifiuoromethy i) py ri midin-2y!)amino)benzyl]acetamide (218)	0.0006
219	ά Αχν*	tert-butyl 4-((4-(((2- (methyi(methylsulfonyl)amino]pyridin-3y l)m ethyl)amin o]-5(trifluoromethyl)pyrimidin-2yl)amino)benzoate (219)	0.0006

-1522016201820 23 Mar 2016

Ex.	Structure | Compound Name	FAK IC50, pM
220	y	N-{3-i({2-t(5-cyano-2- methylphenyl)amino]-5(trifiuoromethyJ)pyrimidin-4yl}amino)methylJpyridin-2-yl)-Nmethylmethane-sulfonamide {220)	0.0006
221	F joxAx A	N-methy l-N-(3-[({2-[(2-methy Ipy rid iπ-4yl)aminoJ-5-(tπfiuoromethyl)pyΓίmidtn-4yl}amino)methyl]pyridin-2yljmethanesulfonamide (221)	0.188
222	>00/) Ά M ^CS20 N	N-(3-[{(2-[(3~{[{aminocarbonyl)amino]methyl)phenyl)amino]-5(tr!fluoromethyl)pyrimidin-4yl}amino)methyl)pyridin-2-yl}-Nmetbylmethanesulfonamide (222)	O.OOOS
223	Λίγά ! J'®	N-2-acetyl-N-[3-({4-(({2- [mefhyl(methylsuifonyl)aminojpyridin-3yl)methyl)aminoJ-5(trifluoromethyl)pyrimtdin-2yl)amtno)benzyi]glycinamide (223)	0,0006
224	F ό (A-w' ι	Ν,Ν-di methyl-4-{[4-({2- [methyl(methylsulfonyi)amino]benzyl)ami no)-5-(trifIuoromethyt}pyrimidin-2yljamino}benzamide (224)	0.0006
225	.aA «V $ I	N,N-dimethyl-4-{[4-({2- [(methylsulfony|)aminojbenzyl}amino)-5(trifluoromethyl)pyrimidin-2yljamino)benzamide (225)	0.00098
226	i I	N,N-dimethyl-4-{[4-{{4-methyl-2[{methy Isu Ifonyt) am ino] benzy !}a m i n oJ-SitrifluoromethyOpyrimidin^yl]amino}benzamide (226)	0.00292

-1532016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
227	0 cA-m'' I	N,N-dimethyl-4-([4-({2-methyl-6(<methylsulfonyl)amino]benzyl}amino)-5(trifluo romethy i)pyri midi n-2yl]amino}benzamide (227)	0.00343
228	-Οφ ,. ό Ηχτ Λ/ I	N. N-dimethyi-4-{[4-({3[nriethyl(rnethylsiiifonyl)amino]berizyl}ami no)-5-( trifluoromethyl Jpyrimid i n-2yljaminojbenzamide (228)	0.00219
229	f Λ $ 7 \Λο ζΓ I °	N,N-dimethyl-4-((4-((3(methylsulfonyl)benzylJamino}-5(trifluoromethy I) py rimid in-2yi]amino)benzamide (229)	0.00493
230	F rrV v AA ''«A ό ''jAo	N,N-dimethyl-4-({4-[{{2- (methyl(methylsulfonyl)amino]pyridin-3yl)meibyl)amino)-5(tri(1uoromethyl)pyrimidin-2yl)amirto)benzamide (230)	0.00233
231	f O 0 AsAx sA<- ό ίι Άβ I	N, N -dime! hy l-4-((4-{((6-methy I-2- [methyl(methylsulfonyl)amino]pyridin-3- yl)methyi)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (231)	0.0006
232	>fS AA, --,ζϊ'Ό ό ,.pA	N-(3-t({2-((4-{[(3Rl4R)-3.4diftuoropyrrolidin-1yl]carbonyl}phenyl)amino]-5(trifluo romethy I )py rim i din-4y0amino)methyJJpyridin-2-yJ)-Nmethytmethane-sulfonamide (232)	0.00262

-1542016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50. pM
233	, Αλ» 1-0 i °	N-(3-(dimethylamino)propyl]-4-({4-[({2- [methyt{methylsulfonyl)amino]pyridin-3yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (233)	0.00133
234	ό X”	N-(2-hydroxyethyf)-N-methyl-4-({4~[({2- [methyl(methyisulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (trifliioromethyl)pyrimidirt-2yl}amino)benzamide (234)	0.00232
235	xxhx ό	N-(3-(ff2-((4-((3-fluoropyrrolidin-1yl)carbonyl]phenyl)amino)-5(trifluoromethyl)pyrimidin-4yl]a minojmethy I) py r(din-2-y I]- N~ methylmethane-sulfonamide (236)	0.0006
j 236	rV1, ι .Z-A'-'u SZ>0 ό X	N-(3-[({2-[(4-{((3S)-3-f!uoropyrroiidin-1yl]carbonyl}phenyl)amino]-5(trifluoromethyl)pyrimidin-4yi}amino)melhyl]pyridin-2-yl)-Nmethylmethane-sulfonamide (236)	0.00141
	-ΟΛ
237	X' , .ΑΆ-» Srlf'o Φ xr qA.	N-methy I-N-[3-({[2-([4-(py rrolidin- Ϊ - y lea rbony I) ph en y l)amino}-5(triftuoromethyl)pyrimidin-4yl]amino)methyl)pyridin-2yljmethanesulfonamide (237)	0.00205
238	ASS xiu. ό	4-({4-(({2- [methy1(methy !su Ifony I) a m i no] py ridi n-3yl}methyl)amino]-5- (trifiuoromethyl)pyrimidin-2-yl}amino)-N[{2R)-tetrabydrofuran-2ylmethyl]benzamide (238)	0.00125
239	, Af\ 'v^o ό X AT’	N-[3-({[2-({4-[{4-hydroxypiperidin-1yf)earborty!]phertyl}amtno)-5(trifluoromethy!)pyrimidin-4y IJaminojmethy I) py rid in-2-y l)-Nmethylmethane-sulfonamide (239)	0.0006

-1552016201820 23 Mar 2016

EX.	Structure	Compound Name	FAK IC50, pM
240	ΛΑ χ,^0	N-cyclobutyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trifluoramethyl)pyrimidin-2yl)amtno)benzamide (240)	0.00069
241		N-[1-(hydroxymethyl)-2-methylpropyi)-4- ({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trif)uoromethyl)pyrimidin-2yl)amino)benzamide (241)	0.0006
242	xCa Λ Ά AA	N-rsopropyl-4-({4-[{{2- [methy ((methyl sutfony IJamino] pyrid in-3yl)methyl)aminol-5(trifluoromethyl)pyrimidin-2yl)amino)bsnzamide (242)	0.001
243	'F -V I Ars vl>o ό ^A,	N-(cyclopropylmethyl)-N-methyl-4-({4- [({2-[methyl(methylsuifonyl)amino]pyridin- 3-yl)methyl)amino]-5- (tritluoromethy l)py ri mtdin-2- yl}amino)benzamide (243)	0.0021
244	V', ηΆΑχι	N-(2-hydroxyethy!)-4-({4-[{{2- [methyi(methylsulfonyt)amino]pyridin-3- yl)methyl)amino)-5- (1rifluoromethyl)pyrimidin-2yl)amino)benzamide (244)	0.00111
245	Jfi/' I ΛΑ, χ«-ί·0 ό \y 0	N-[2-{acetylamino)ethyl]-4-({4-(({2- [methyl(methylsuifonyl)amino]pyridin-3- yl)methyl)amino]-5- (lrifluoromethyl)pyrimidin-2yl)amino)benzamide (245)	0.00262
246	kAA„ \A ό A‘ ^>Λ.	N-[(1-hydroxycyc!obulyl)methyll-4-({4- [({2-|methyl(methyisulfonyl)amino]pyridin- 3-yl)methyl)amino)-5- (trifl uoromethyl)py ri midi n-2- yl}amino)benzamide (246)	0.0006

-156 2016201820 23 Mar 2016

Εκ.	Structure	Compound Name	FAK IC50, μΜ
247	ό Ά·	N-[3-(((2-((4-((3-hydroxy piperidin-1 - yl)carbonyl]phenyl}amino}-5(trifl u oromethy i)pyrimidin-4~ yi)amino}methyl)pyridin-2-yl]-Nmethylmethane-sulfonamide (247)	0.00063
248	ΛΑ ο ίΑ	4-((4-(((2- (methyl(m ethy I sulfony l)am i nojpyrid i n-3yl}methy!)amino]-5- (trifiuoromethyl)pyrimidin-2-yl}amino)-N{pyridin-2-ylmethyl)benzamide (248)	0.00935
249	APS xdA ό X' Aj 6	N-(3-[({2-i(4-{((3R)-3-hydroxypyrrolidin-1ylJcarbonyl)phenyl)aminoJ-5(tnfluoromethyl)pyrimidin-4yi}amino)methyl]pyridin-2-yl}-Nmethytmethane-sulfonamide (249)	0.00191
250	Xf A UA	4-((4-(((2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)aminoJ-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N(1-methylpiperidin~4-yi)benzamide (250)	0.00069
251	Az^» X	N-[2-(dimethylamtno)ethylJ-4-({4-[({2- (methyl(methylsulfonyl)amino3pyridin-3- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amirto)benzamide (251)	0.00121
252	fF AA« ’'•«'S) ό A-	N-(cyclopropy I methyl)-4-({4 -(((2- (methyl(melhy!sulfonyi)amino]pyridin-3- yt}methyt)amino]-5- {trifluoromethyl)pyrimidin-2y!}amino)benzamide (252)	0.00148
253	χΛ 1 Λη. ό X’ CA	N-(3-(([2-([4-(azetidin-1yicarbonyl)phenyl]amino}-5(trifluorome1hyf)pyrimidin-4yl]amino}methyt)pyridin-2-ytj-Nmethytmethane-sulfonamide (253)	0.0006

-1572016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK iC50, μΜ
254	K xCv 0 A “V'-rA'o	N-methy i-N-(3-({[2-({4-({3-oxo pi peraz in-1 - y|)carbonyl]phenyl}amino)-5(trifJuoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2yljmethanesulfonamide (254)	0.00133
255	xAa. ό ©	N-(3-hydroxypropy1)-4-({4-[({2- [methyl(methy!sulfony!)aminoJpyridin-3- yl}methyl)amino]-5- (trifluoromethyi)pyrimidin-2yl}amrno)benzamide (255)	0.00082
256	Ά ί Χά-'τ, ''m'S’o ό	N-(3-hydroxy-2,2-dimethytpr opy 1)-4-((4- [({2-[methyi(methylsuifony!)aminoJpyridin- 3-yl}methyl)amino)-5- (trifluorometbyl)pyrimldin-2yl)amino)benzamide (256)	0.00157
257	MS f» mt'-x*. A	N-(( 1R)-1 -(hydroxymethyl)butyl]~4-({4- [({2-[methyl(methylsulfonyi)amino]pyridin- 3-yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (257)	0.0058
258	j /VS '•«4*» 0 A' oA	N-melhyl-N-[3-({[2-{[4-(piperidtn-1ylcarbonyl)phenyl]amino)-5(trifluoromethy!)pyrimidin-4y l]ami no) methy 1) py rid in-2yljmethanesulfonannide (258)	0.00179
259	rA , «•'Si'*1''» ''rf'^s , ί 0	N-[2-(dimethylamino)-2-oxoethyl]-4-({4- [({2-(methyl(metbylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5- (trif]uoromethyl)pyrimidin-2yl}amino)benzamide (259)	0.00157
260	«6 XCa 0 A cU	N-(3-[({2-[(4-{[(3S)-3-hydroxypiperidin-1yljcarbonyl}phenyl)amino]-5(trifluorornethyl)pyrimidin-4y I}am ino)methy Qpyrid in-2-y I}-Nmethylmethanesulfonamide (260)	0.0023

-1582016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
261	xdv, ό Ab- t La	N-methyl-N-(3-[({2-[{4-{[(3S)-3- methylmorpholin-4yl]carbonyi}phenyl)amino]-5(trifluorometbyl)pyrimidin-4y)}amino)metby I jpy rid tn-2yljmethanesulfonamide (261)	0.00113
262	if ρΛ' . X * I	N-cyclopenty[-N-methyl-4-({4-[({2- [methyl(nrtethyfsu!fony!)amino]pyridin-3- yI)methyl)amino]-5- (trifluoromethyi)pyrimidin-2yl}amino)benzamide (262)	0,0058
263	AXitk o$	4-({4-[({2- [methyl(methyisulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yt}amino)-N(ietrahydro-2H-py ran-3-yl )benza mide (263)	0.00081
264	ρΛ I ,ό Ab;	N-[2-hydroxy-1 -(hyd roxym ethyl)ethyl)-4({4-(((2- [m ethyl(methy Isulfony I) a m inoJpyridin-SytJmethylJaminoJ-S(trifluoromethyj)pyrimidin-2yl}amino)benzamide (264)	0.0046
265	ΑΧΪΑλ, δ Ab Aj ·	N-methyl-N-I3-({[2-({4-[(4-methylpiperidin1 -yl)carbonylJphenyl}amino)-5(trifluoromethyi)pyrimidin-4yl]amino)methyl)pyridin-2yl]methanesulfonamide (265)	0.0006
266	XCa δ Ab xf·-	N-[3-({[2-([4-i(3,3-djfluoropyrrolidin-1yi)carbonyljphenyl}amino)-5(trifiuoromethyOpyrimidin-4y (Jam inojm ethy l)py ridin-2-yiJ- Nmethylmethane-sulfonamide (266)	0.0006
267	tei VsA« ό Ab <p	N-(3-(({2-[{4-{[(3S)-3-hydroxypyrrolidin-1yiJcarbonyl}pbenyt)amino]-5(trifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl}-Nmethylmethane-sulfonamide (267)	0.00115

-1592016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
268	t 1 * ί ό A Α·	N-(3-({[2-({4-((3-hydroxy-3- methylpyrrolidin-1yI)carbonyl]phenyl}amino)-5(trifluoromethyl)pyrimidin-4ylJamlno)methyl)pyridin-2-yl)-Nmethylmethane-sulfonamide (268)	0.00262
269	,οΑ. ό Η5 νζ-^,Λ, Η	N-(2-hydroxyethyl)-4-({4-[({2- (m ethy l{methy Isuifo rsy I)ami no] py ridi n-3yl}methyl)amino]-5- (trrfluoromethyl)pyrimidirs-2-yi}amino)-Npropy (benzamide (269)	0.00869
270	/7. ό Si	N-(5-hyd roxy penty 1)-4-((4-(((2- [methyl(methylsulfonyl)aminojpyridin-3- yl)melhyl)aminoj-5- {lrifluoromethyl)pyrimtdin-2yl)amino)benzamide (270)	0,00099
271	αΧ^Α ό ςρΑ	N-benzyl-4-({4-(({2- [melbyl(methylsuSfonyI)amino]pyridin-3yI}methyl)amino)-5(triftuoromethyl)pyrimidin-2yl)amino)benzamide (271)	0.00114
272	Α% ''.r'i'ti Λ <α,° Ο ι> A^°	N-(3-(((2-((4-((3-fluoroazetidin-1yl)carbonylJphenyl)amino)-5(tri fluoromethyl) py ri midi n-4y I] am ino)methyl)pyridin-2-yl]-Nmethylmelhane-sulfonamide (272)	0.00264
273	ASS Axii^c ό ϋ;	N-{((1R,2R)-2- (hy d roxy methyl) cy clop ropy l]methy 1)-4-((4[({2-[methyl(methylsulfonyl)amino)pyridin3-yl)melhyl)amino]-5- (trifluoromethyl)pyrimidin-2yl)amino)benzamide (273)	0.00269
274	Ff A ( AA« ''κ'ϊ’-Β , ό A 1	N-(2-(dimethylamino)ethyl]-N-methyl-4- ({4-(((2- [methyl(methylsulfonyl)amino]pyridin-3yl}methyl)aminoJ-5(trifluoramethyl)pyrimidin-2yl}amino)benzamide (274)	0.00466

-1602016201820 23 Mar 2016

I Ex,	Structure	Compound Name	j FAK iC50, μΜ
275	Vi»o ό fo	N-{3-(((2-((4-{[(3R}-3-hydroxypiperidin-1yl]carbonyl}phenyl)amino]-5(trifluoromeihyl)pyrimidln-4y IJamino) methy I] py ridirt-2-yl}- Nmethylmethane-sulfonamide (275)	0.00236
276	xxfo.. fo	N-(2-methoxy ethy 1)-4-((4-(((2- [methyl(methyisutfonyl)aminoIpyridin-3- yl}methyl)amino]-5- (trifluoromethyi)pyrimidin-2yl}amino)benzamide (276)	0.0006
277	xCa. ό fo	N-(3-methoxypropyi)-N-methyl-4-{{4-[({2- (methyl(methyisulfonyl)amino]pyridin-3yl)methyl)amino]-5(trifIuoromethyl)pyrimidin-2y|)amino)benzamide (277)	0.00236
278	j£$ .Axfo ^„a.o ό fo ΟΛ	N-methyl-N-{3-[({2-[{44((3R)-3- methylmorpholin-4- y]Jcarborsyl}phenyl)amino)-5- (trifluoromethy))pyrimidin-4- yt}amino)methyllpyridin-2- yljmethanesulfonamide (278)	0.00664
279	σ' a 1	N-{3-[({2-[(4-{(3-(dimethylamino)azetidin1 -yi] carbony l}ph eny!) ami noJ-SftrifiuoromethyOpyrimrdirMyl}amino)methyi]pyridin-2-yl}-Nmethylmethane-sulfonamide (279)	0.00397
280	Γ jf2ifoF t- ,ΡΑγ-ή Φ V Α°	N-{3-[({2-[(4-methoxyphenyl)amino]-5(trifluoromethyl)pyrimidin-4y l}amin o)methy IJpyri din-2-y I}- N methylmeihane-sulfonamide ¢280)	0.0006
281	F I rf^xSf $ »Α.λι 'νΑο fo) fo	N-{3-[({2-((3-methoxyphenyl)amino|-5(triftuoromethyl)pyrimidin-4y I) amino) methy i]pyridin-2-yl)-Nmethylmethane-sulfonamide (281)	0.0006

-161 2016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, yM
282	F ά. ό J '	N-{3-(({2-K3,4-dimethoxyphenyi)amino3-5- (tri{luoromethyl)pyrimidin-4- yl}amino)methyt]pyridin-2-yl}-Nmethytmethane-sulfonamide (282)	0.0006
283	•aA-A A) A	Ν-[3-({(2-{[3- (hydroxymethyl)phenyi]amino}-5(trifiuoromethyl)pyrfmidin-4yl]amino)methyl)pyridin-2-ylJ-Nmethylmeihane-sulfonamide (283)	0.0006
284	Axkx” φ A r	N-methyl-N-[3-({[2-(i4- (trifiuoromethoxy)phenyl]amino}-5(trifluoromethyl)pynmidin-4yi)amino}methyl)pyridrn-2yljmethanesulfonamide (284)	0.00183
285	Γ xchx ό	N-me!hyI-N-(3-({[2-(pyridin-4-ylamino)-5(trifluoromethyf)pyrimidin-4yljamino}methyl)pyridin-2yljmethanesulfonamide (285)	0.00127
286	*# qjXa Si-	N-(3-(({2-[(3-cyanophenyl)aminoJ-5(tri fl u oromethyl) py rimidin-4yi)amino)methyl]pyridin-2-yl)-Nmethylmethanesutfonamide (286)	0.00164
287	%AC?A A	N-[3-methyi-2-({l2-([4-( 1 H-tetrazoI-5yl)phenyi]amtno}-5(trifluoromeibyl)pyrimidin-4yl]amino}methyl)phenyl]methanesulfonam ide (287)	0.00195
288	AcAa. A	N-metbyi-N-{3-[({2-[(3-methylisoxazol-5yl)amino]-5-(trifluoromethyl)pyrimidin-4ylja mtno) methy IJpy ridin-2yljmethanesulfonamide (288)

-1622016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
289	ZaXZ. sS	N-methyl-N-{3-[({2-[(3-methylisoxazo!-5' yl)amino]-5-(trifluorornelhyl)pyrimidin-4yl}amino)metbyl)pyridin-2yljmethanesulfonamide (289), formic acid salt	0.0182
290	A-A ? UAAA z	N-methyl-N-{3-(({2-[(4-morphoIin-4- ylphenyl)amino]-5(trifluoromethyl)pyrimidin~4yl)amino)methyljpyridin-2yljmethanesulfonamide (290)
291	kx-vAAi,'-tA’ z	N-methy l-N-{3-(((2-((4-mo rpholi rMylphenyOaminoJ-S(trifiuoromethyI)pyrimidin-4yl)a mino) methy IJpyridi n-2yl)methanesulfonamide (291), hydrochloride sail	<0.000595
292	A	N-(3-t({2-[(6-cyanopyridin-3-yl)amino]-5(trifluoromethyl) pyrim idi n-4yl}amino)methy!Jpyridin-2-yl)-Nmethylmethane-sulfonamide (292), trifiuoroacetic acid salt	0.0233
293	A f zY^r ? XA A A.. ’•.A® z	N-methyl-N-{3-(({2-((5-morphoIin-4y lpyridin-2-y I) a mino]-5(trifluorofnethyi)pyrimidin-4yl)amino)methylJpyridin-2yl}methanesulfonamide (293), trifiuoroacetic acid salt	<0.000595 (n=2)
294	F Mx^St<y'F ο o Η.,Ζ,λ,,, C0& 0	3-((4-( ({6-methyi-2- (methyt(methylsuIfonyi)aminoJpyridin-3yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (294)	<0.000595
295	F ο o « I F *'* Kr^ir'^ai Οψη^ o	3-((4-(((3- fmethyl(melhyisulfonyl)aminoJpyridin-2yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (295)	0.00133
296	f fY/T °.° wAA« nA- όψΛ 0	3-({4-[({2-methyi-4- [methyl(methylsu!fonyl)amino]pyrimidin-5yl}methyl)aminoJ-5~ (irifluoromethyl)pyrimidin-2yl)amino)benzamide (296)	0.00389

-1632016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
297	F CA w AtA-wi Nr*-· όγΧ o	3-((4-(((3- [methy 1 (methylsul fony 1) amino]pyrazin-2yl}methyl)amino]-5(trifluoramethyl)pyrimidin-2yl}amino)benzamide ¢297)	0.00226
298		N-(3-[((2-({4-aminopyrimtdin-2-yS)amino]5-(trifluoromeihy!)pyrimidin-4y l}a mino)methy i] pyrid i n-2-y l}-Nmethylmethane-sulfonamide (298)	0.0328
299	f) y	N-(3-[({2-[{2-aminopyrimidin-4-yl)amino]5-(trifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl}-Nmethylmethane-sulfonamide (299)	>0.188
300	AGS 1 Vt ό f*T*O ό I	4-{((7R)-8-cyclopentyl-7-ethyl-5-methyl-6oxo-5,6,7,8-tetrahydropteridin-2yl]amino}-3-methoxy-N-(1methylpiperidin-4-yl)benzamide (300)	0.121
301	F rA k yO V	N-[3-({[2-([3-(1hydroxyethyl)phenyl(amino}-5(trifluoromethyi)pyrimidin-4yl]amino}methyl)pyridin-2-yl]-Nmelfiytmethane-sulfonamide (301)	<0.000595
302 .	X&- J A ι 'V°	1,1,1-trifluoro-N-[4-({4-(({2- [methyl{methy!sulfonyl)amino]pyridin-3- yl)meihyl)aminoJ-5- (trifluoromethyl)pyrimidin-2- yl}amlno)benzyl]rrtethanesulfonamide (302)	6.00100

2016201820 23 Mar 2016

- 164-

Ex.	Structure	Compound Name	FAK IC50, pM
303	,χόϊ'·- o hH X	1,1.1 -tri fl uoro-N-[3-{{4-(({2- [methyl(methyisulfonyl)amino]pyridin-3- yl}methyl)amino]-5- (trifiuoromethyl)pyrimidirt-2- yl}amino)benzyl]methanesLilfonamide (303)	0.000727
304	f ύγ,ύ o	4-methoxy-3-({4-[({2- [m ethy !(m ethy lsulfonyl)a mino]py ridi n-3yl)methyl)amino]-5(trifluorom ethyl) pyrimid in-2yl)amino)benzamide (304)	0.000777
305	f χά o	4-methoxy~3-({4-(({6-methyl-2- fmethyl(melhylsulfony!)-amirio]pyridin-3- yf)methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (305)	0.000646
306	, Λ σ	4-melhoxy-3-({4-[({3- (methyI(methylsulfonyl)amino]pyridin-2yl}methyi)amino]-5(trif!uoromethyl)pyrimiciin-2yl)amino)benzamide (306)	0.000696
307	F ο o , «ΛΑ,,Χ χχ· Ρ	4-methoxy-3-({4-[({3- (methyl(methylsulfonyl)amirtojpyrazin-2yl)methyl)amino]-5(trifIuoromethyl)pyrimidin-2yl)amino)benzamide (307)	0.00111
308	F . , *ΛΑι« χχ 0	4- methoxy-3-({4-[({2-methy Ρ4[methyl(methylsulfonyl)-amino]pyrimidin- 5- yl)methy[)amino]-5- (trifluoromethyl)py rtmid i n-2yl}amino)benzamtde (308)	0.00350

-1652016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK iCSO, μΜ
309	t 0	4-methyl-3-({4-[({3- (methyl(methylsulfonyl)amino]pyrazin-2yi)methyl)amino]-5<trifJuorometbyl)pyrimidin-2yl}amtno)benzamide (309)	0.00351
310		4-methyI-3-({4-[((2-methyl-4- [methyi(methylsuifonyl)amino]pyrimidin-5- yl)methyl)amino]-5- (trif1uoromethyl)pyrimidin-2yijamino)benzamide (310)	0.00504
311		N-{3-[({2-[{4-acetylphenyl)aniino]-5- (trifluoromethyl)pyrimidin-4yl}amino)methyllpyridin-2-yl)-Nmethylmethane-sulfonamide (311)	0.00100
312	>AaA\a	N-{3-(({2-[(3-acetyiphenyl)amirto]-5(trifluoromethyOpyrimidirMyl}amino)metbyl]pyridin-2-yl)-Nmethyfmethane-sulfonamide (312)	0.00126
313		N-methyl-N-{3-[({2-[(3-mofpholin-4yfpheny!)amino)-5(trifluoromethy l)py ri mid in-4yi)amino)methyl]pyridin-2yljmethanesulfonamide (313)	0.00202
314	^-c6a	N-methyl-N-|3-({[2-{[4-( 1 H-tetrazol-5yl)pheny ija mino}-5(trifluorometbyl)pyrimidin-4yl]amino)methyl)pyridin-2yljmethanesulfonamide (314)	<0.000595
315	x£vV ,u0 'xtr Ci	N-i3-({(2-{[3-(4,5-dihydro-1,3-oxazol-2- yl)phenyl3amino}-5(trifluoromethy!)pyrimidin-4y))amino}methyl)pyridin-2-yl]-Nmethylmethane-suifonamide (315)	0.000914

-1662016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
316	X©X ό X ί	N-methyl-4-({4-[({3- jmethyl(methylsulfonyl)amino]pyridin-2yl)methy!)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (316)	0.000965
317	Χδχ ό V (Α'τΛ Η	N-methyl-4-{{4-[({3- (methyl(metbylsulfonyl)amino]pyrazin-2yl}methyi)amino]-5(trifiuoromethyl)pyrimidin-2yl)amino)benzamide (317)	<0.000595
318	χάχ ό X Η	N-methyl-4-({4-[({3- (methyi(methylsulfonyI)amino)pyrazin-2yl}methyl)aminoj-5(trifluoromethyl)pyrimidiri-2yl)amino)benzamide (318), hydrochloride salt	0.00179
319	H^r'Sr^w δ ^CH	N-[3-({I2-{E4- (hydroxymethyi)phenyl]amino)-5(trif1uoromethyt)pyrimidin-4yl)amino}methyl)pyridin-2-yl]-Nmethylmethane-suifonamide (319)	<0.000595
320	Η Η Μ	2-fluoro-4-({4-[({2- (methyl(methyisuifonyl)amino)pyridin-3yl)methyl)amino]-5(trifluoromefhyl)pyrimidin-2yl}amino)benzamide (320), formic acid salt	<0,000595
321	Ρ «Λδδ 'γ ό Vv Γ	4-{{4-({3-f(difluoromethyl)(methylsulfonyl)amino]benzyl)amino)-5(trifluoromethyl)pyrimidin-2yljaminojbenzoate (321)	0.119 (0.0159-0.883 n=2)

-1672016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
322	xdA I	3-fluoro-4-({4-[({2- [methyl(methyIsulfonyl)amino]pyridin-3yl}metbyl)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (322), formic acid salt	<0.000595
323	j? ό A	N-[3-({[2-{[4- (1 -hydroxy-1 melhy lethy I) ph eny I] amino}-5(tritluoromethyi)pyrimldin-4yl]amino}methyl)pyridin-2-ylJ-Nmethylmethane-sulfonamide (323)	0.00150
324	AA«, ! Q	N-[3-({[ 2-{[4-{ 1 -hydroxy-1 methyiethyl)phenyl]amino}-5(trifluoromethyl}pyrimidin-4y Ijami n o}methy I) pheny t J-N methytmethanesulfonamide (324)	0.00187
325	aX^x ό Ά	N -12-({ [2 -{[4-(1 -hydroxy-1 meihyiethyl)phenyI]amino}-5(trifluoromethyf)pyrimidin-4y!]amino}methyl)pyridin-3-y!]-Nmethylmethane-sulfonamide (325)	0,00266
326	ό A Ά(3ι	N-[3-((I2-{(4-(1-hydroxy-1methy!eihy!)phenyl]amino}-5(trifluorom et hy l)pyrimidin-4ylJamino]methyt)pyrazin-2-yl]-Nmethylmethane-sulfonamide (326)	0.00162
327	ΜγΑγ< F 1 Hi w· M	2-fluoro-4-({4-[({3- imethyl(methylsulfonyl)am!no3pyrazin-2yt)methyt)amino]-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (327), formic acid salt	0.00169

-1682016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
328	rA ,,Λ'χ/'Χη ( £	N-[3-({(2-{[4-(1- hydroxyethy l)pheny I] a min o}-5- (triftuoromethyI)pyrimidin-4- yl]amino}methyl)phenyl]-N- methylmethanesulfonamide (328)	0.000619
329	ό A	N-M2-{i4-(1- hydroxy ethyl)pheny IJami no}-5- (trifiuoromethyl)pyrimidin-4- yl)amino)methyi)pyridin-3-yIl-N- methylmethane-sulfonamide (329)	0.000914
330	ό V	N-[3-({[2-{{4-(1- hydroxyethyi)phenyl]amino}-5- . (trifluoromethyl)pyrimidin-4yl]amino}methyl)pyrazin-2-yi]-Nmethylmethane-sulfonamide (330)	0.000750
331	AA A >cc An A*	2-fluoro-4-({4-[({3- [methyi(methylsulfonyi)amino]pyridin-2y))methyl)amino)-5(trifiuoromethyl)pyrimidin-2yl)amino)benzamide (331), hydrochloride salt	0.00177
332	/Λ < A- Λ A	2-fluoro-4-({4-[({3- [methyi(methylsulfonyl)amino)pyridin-2yl}methyl)amino)-5(trifluoromethyl)pyrimtdin-2yl)amino)benzamide (332), formic acid salt	0.000863
333	Γ'ΥΆ Λ	2-fluoro-4-{[4-({3- (methyl(methylsulfony()amino]benzy!}arrti n o)-5-(trifl u oromethy l)pyri midin-2yl]amino)benzamide (333)	0.00214
334	joAu ά. A Am	2-methyl-4-«4-[({2- [methyl(methy!sulfonyl)amino]pyridin-3y(}methyl)amino]-5(trifluoromethyi)pyrimidin-2yl)amino)benzamide (334)	<0.000595 (n=2)

-1692016201820 23 Mar 2016

Ex,	Structure	Compound Name	FAK IC50, μΜ
335	X&A A A	2-methyl-4-{{4-[({2- [methyl(methylsulfonyl)amsno]pyridin-3yl}methyl)amino]-5(trifiuoromethyl)pyrimidin-2yl)amino)benzamide (335), hydrochloride salt	<0.000595 (n=2)
336	XCAu A v A	2-methyl-4-({4-[({3- [methyl(methy!sulfonyl)amino]pyridin-2yl)methyl)amino]-5(triiluoromethyl)pyrimidin-2yl)amino)benzamide (336)	<0.000595
337	..0 AA A	2-methyl-4-({4-(({3- [methyl(methylsulfonyl)amino]pyridin-2yl]methyl)amino]-5(trifluoromelhyl)pyrimidin-2yl)amino)benzamide (337), hydrochloride salt	<0.000595
338	XOsA0k Ό	2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (338)	<0.000595
339	jO0k?!Ok A	2-methyl-4-{{4-[({3- [methyl(methylsulfony!)amino]pyrazin-2yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amrno)benzamide (339), hydrochloride salt	<0.000595
340	A KiA/Sti . Λ Vf	2-methyl~4-{[4-({3- [methyl{methylsulfonyl)amino]benzyl}ami no)-5-(trifluoromethyl)pyrimidin-2yl]amino}benzamide (340)	<0.000595

- 1702016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
341	ATxA & A“	3-methyl-4-({4-(({2- tmethyl(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trifluofOmethyl)pyrimidin-2yl}amino)benzamide (341)	<0.000595
342	dr A /A	3-methyl-4-({4-t({2- [methyl(methylsulfonyl)amino]pyridln-3yl}methyl)amino3-5(trifluoromethyl)pyrimidin-2yljaminojberszamide (342), hydrochloride salt	0.00103
343	„aAA& A <Α-η	3-metbyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2yl}methyl)amino]-5(trifluo romethy t)py rim id in-2yl}amino)benzamide (343)	0.000993
344	«λλ. sA dr A oAjq,	3-methyl~4-({4-[({3- [methyl(methy!suIfonyl)amino]pyrazin-2yl)methyl)aminoj-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (344)	0.000900
345	xdA- & A-,,,,	3-methyl-4-({4-(({3- [methyl(methylsulFonyl)amino]pyrazin-2yl)meihyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)benzamide (34S), hydrochloride salt	0.000981
346	Χ'γΑ iw^ftSw j & Vf	3-methyl-4-{{4-({3- [methyl(methylsulfonyl)amino]benzyl)ami no)-5-(trifIuoromethyl)pyrimidin-2yljaminojbenzamide (348)	0.000886

- 171 2016201820 23 Mar 2016

Ex.	j Structure	Compound Name	FAK 1C50, pM
347	ό AS	N-[3-{{[2-{[4- (isopropoxy melhy l)pheny I] am ino}-5(trifluoromethyl)pyrimidin-4y I] a mino}methyl) py rid in-2-ylj- Nmethyimethane-sulfonamide (347)	0.00215
	k A
348	f O ΑΑ.-Λ ό \S	N-[3-(([2-(i4-{chloromelhy!)phenyl]amino}5-(trifluoromethyl)pyrimidin-4yl]amino)methyl)pyrtdin-2-yf]-Nmethylmethane-sulfonamide ¢348)	0.00155
349	ο/ίόζ 0 Xr	N-nrtethyl-N-[3-({[2-(E4-(morpholin-4yImethyl)phenyl]amino}-5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2yljmethanesulfonamide (349)	<0.000595
	X
350	F ό S6 cA-rw,	4-((4-(((2- [melhyl(meihyfsulfonyl)amino]pyridin-3yl}melhy!)amino]-5(trifluoromethyt)pyrimidin-2y!}oxy)benzamide (350)	0.0637
351	fSS f Xkx ό S0 /¼	N-[3-(((2-((4-[(1R)-1- aminoethyljphenyl)amino)-5(trifluoromethyl)pyrimidin-4y(]amino}methyl)pyrazin-2-yl]-Nmethylmethane-sulfonamide (351). hydrochloride salt	0.000616
352	4QS xkx ό X	N-[2-(((2-((4-[(1R)-1- aminoethyl]phenyl)amino)-5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridtn-3-yl]-Nmethylmethane-sulfonamide (352), hydrochloride sail	<0.000595

-1722016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK 1C50, μΜ
353	A® ΑΛ» i ό	N-[3-({(2-({4-[(1R)-1- aminoethy!Jphenyl}amino)-5(trifluoromethyl)pyrimidin-4yllamino}methyl)phenyl]'Nmethylmethanesulfonamide (353), hydrochloride salt	<0.000595
354	ASS X6x 0 A /	N-[3-(([2-((4-f(lR)-1aminoethyllphertyl}amino)-5(triflu oromethy I) py rimid in-4yl]amino)methyl)pyridfn-2-yt]-Nmethylmethane-sulfonamide (354), hydrochloride salt	<0.000595
355	ASS F & „aA„ ό A Z\«,	N-(3-(([2-({4-[(1S)-1amin oethy l]p he nyljam i noJ-StlrifiuorometliylJpyfimidin-ly I] a mlno)methy I) py raz i π-2-y l]-Nmethylmethane-sulfonamide (355), hydrochloride salt	<0.000595
356	AaS xdx ό A	N-[2-({[2-({4-[(1S)-1aminoethyllphenyl)amino)-5(trifluoromethyl)pyrimidin-4ylJamino)methylJpyridin-3-ylJ-Nmethylmethane-sulfonamide (356), hydrochloride salt	0.000593
357	χέ , ά. Α> cZA«<,	2-chloro-4-{[4-{{3- [methyl(methylsulfonyl)amino]benzyl)ami no)-5-(trifluoromethyl)pyrimidin-2yl]amino)benzamtde (357)	0.00147
358	F jfA y ά. A	2-chloro-4-({4-f{{2- methy!(methylsulfonyl)amino]pyridin-3yl}methyl)amino]-5(trifluoromelhyl)pyrimidin-2yl)amino)benzamide (358)	<0.000595

-1732016201820 23 Mar 2016

Ex,	Structure	Compound Name	FAK IC50, μΜ
359	kb	2-chloro-4-({4-[({3- [methyl(methyisulionyl)amino]pyridin-2yl}methyl)aminoJ-5(trifluoromettiy I) pyrimid in-2yi}amino)benzamide (359)	<0.000595
360	a kb	2-chloro-4-({4-(({3- [methyl(methylsulfonyl)amino]pyrazin-2yl}methyl)amirto]-5(trifluoromethyl)pyrimidin-2yljaminojbenzamide (360)	<0.000595
361	ac0sAo ’--A o	3-((4-(((2- [methyl(methylsuIfonyl)amino]pyridin-3- yi}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-Npiperidin-4-ylbenzamide (361), hydrochloride salt	0.00870
362	ΧΧγΥ $	N-[2-({(2-({4-((1R)-1- aminoethyl]phenyl}amino)-5(trifiuoromethyt)pyrimidin-4yl]amino}methyl)phenyf]-Nmethylmethanesulfonamide (362), hydrochloride salt	<0.000595
363	$	N-(2-{((2-({4-((1S)-1aminoethyl]phenyl}amino)-5(trif!uoromethyl)pyrimidin-4yl]amino}methyl)phenylj-Nmethylmethanesulfonamide (363), hydrochloride salt	<0.000595
364	_Xx\x ό X *»	N-[3-({(2-{{4-[(1S)-1aminoethylJphenyl}amino)-5(trifluoromethyl)pyrimidin-4yljamino}methyi)pyridin-2-yl]-Nmethylmethane-sulfonamide (364), hydrochloride salt	0.000644

-1742016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
365	ΛΒ5 «ΛΑ,. , ό Xrx An	N-[3-({(2-({4-[(1S)-1- ami noethy ijpheny !}a min o)-5- (trifluoromethyl)pyrimidin-4- ylJamino)methyl)phenyl]-N- methyfmethanesutfonamide (365), hydrochloride salt	0.000976
366	F hAAhVS OL V Ao	N-[3-({4-[({2- (methyl(methylsulfonyl)amino]pyridin-3yl)methyl)amino]-5(trifluo romethy I )pyrim idin-2yl)amino)phenyl]acetamide (366)	<0.000595
367	r „ΛΑ« v% όχΧ A? 0 \	N-rnethyl-N-[3-({[2-([3-(3-rnethyl-2~ oxoimidazolidin-1-yl)phenyi]amino}-5(trifluoromethyl)pyrimidin-4yi]amino}methyl)pyridin-2yljmethanesulfonamide (367)	0.00164
368	χόχ	3-fluoro-N-methyM-({4-[({3- [methyl(melhyisuffonyi)aminoJpyrazin-2- yl}methyl)amino]-5- (trifluoromethy])pyrimidin-2yl)amino)benzamide (368)	<0.000595
369	ΓΤ^Άτ ρ «AAh.w*” X X £jX« j	3-ftuoro-N-methyl-4-({4-[({3- [methyl(methylsuifonyl)amino]pyrazin-2- yl)meihyl)aminoJ-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (369), hydrochloride salt	0.00149
370	xcix X X 1	2-fluoro-h!-methyl-4-({4-[{{3- [methy[(methytsu]fonyl)amino]pyraz(n-2- yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2yl}amino)benzamide (370)	0.000600

-1752016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
371	jcAa A A	N-[3-((4-f({2~ (methyl(methylsulfonyl)aminojpyridin-3yl)methyl)amino]-5(trifluoromethyI)pyrimidin-2yl}amino)phenyl]propanamide (371)	0.00194
372	jA'a ό a a -tH,	5-((4-(((2- (methy I (methy isu!fonyi)amin o] py ridin- 3yl)methyl}aminoJ-5(trifluoromethyl)pyrimidin-2yl}amino)pyridine-2-carboxamide (372), formic acid salt	0.00400
373	xAx A 0	4-fluoro-3-({4-(({3- (methyJ(methy)sulfbnyl)amino}pyrazin-2yQmethyl)amino]-5(trifluoromethy!)pyrimidin-2yi)amino)benzamide (373)	0.00749
374	F *T^Tf Az W o	4-fluoro-3-{[4-({3- [methyl(methylsulfonyi)amino]benzyl}ami no)-5-(trlfluoromethyi)pyrimidin-2yl]amino}benzamide ¢374)	0.0155
375	Az A 0	4-fluoro-3-({4-[{{2- [methy!(melhy!sulfonyl)amino]pyridin-3- yl)methyl)amino]-5- (tr ifl uoromethy I) py rimidin -2- yi)amino)benzamide (375)	0.00629
376	F CrV » AA ό AA	5-((4-((3- [methyl(methylsulfonyl)amino]benzyl)ami no)-5- (trifluoromethyl)py rim id in-2yl]amino}pyridine-2-carboxamlde (376), formic acid salt	0.00615
377	xAa° ό A	5-((4-(((3- [metby I (methy isu Ifony l)a mino] py rid in -2yI}metbyl)amino]-5(trifiuoromethyl)pyrimidin-2yl)amino)pyridine-2-carboxamide (377), formic acid salt	0.0153

-1762016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
378	fex fer A o	4-fluoro-3-({4-(({3- (methyi(methylsulfonyl)amino]pyridin-2yl}methyl)amino]-5(trifltioromethyl)pyrimidin-2yl}amino)benzamide (378)	0.00194
379	χά , fe fe· O f	2-fluoro-54I4-({3- (methyl (methy Isuifony l)am in o]be nzy l}a mi no)-5-(trifluoromethyl)pyrimidin-2yl]amino}benzamide (379), hydrochloride salt	0.00478
380	f .AAA,, ''v'1'. fe Xf O F	2-fluoro-5-({4-[((2- [methyl(methylsu!fonyl)amino]pyridin-3- y(}methyl)aminoj-5- (t r ifiuoro methy Opyrim idin-2- yt}amino)benzamide (380), hydrochloride salt	0.00160
381	xfe<° fe Si <1 f	2-fluoro-5-({4-(((3- (methy!(methylsulfonyl)amino]pyridin-2yl)methyl)amino)-5(triiluoromethyl)pyrimidin-2yi}amino)ben2amide (381), hydrochloride salt	0.00455
382	r Xtx fe © o r	2-fluoro-5-((4-(((3- [methyl(methylsulfonyt)amino]pyrazin-2yl}me(hyl)aminoJ-5(trifluoromethyl)pyrimidin-2yl}amino)benzamide (382), hydrochloride salt	0.0107
383	s O-l	N-{3-[({2-((4-(((2- hydroxyethyl) a mi no] methy 1} phenyl) amino] -5-{irifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl}-Nmethylmethane-suifonamide ¢383)	<0.000595
384	F X. v\ ό Ό1	N-[3-({[2-({4- ((isopropylamino)methyl]phenyl}amino)-5(trifluoromethyl)pyrimidin-4yl]amino)methyl)pyridin-2-yl]-Nmethylmethane-sulfonamide (384)	<0.000595
	k, fe

-1772016201820 23 Mar 2016

£x.	Structure	Compound Name	FAK iC50, μΜ
385	F - fofo V	N-[3-«4-K{3- imethyl(methylsulfonyl)amirto]pyrazin-2yl}methyl)amino]-5(trifluoromethyl)pyrimidin-2yl)amino)phenyl]acetamide (385)	0.00144
386	1 αΛΧ&Α SA	N-[3-({4-|{{3- [methyl(methylsulfonyl)amino]pyridin-2yl}methyl)amino]-5(trifiuoromethyl)pyrimidin-2yl)amino)phenyljacetamide (386)	0.00165
387	AXvfo , W	N-(3-fl4-({3- [methyl(methylsulfonyl)amino]benzyl}ami rt o)-5-(tri fl u oromethy l)py rimidin-2yl]amino)phenyl)acetamide ¢387)	0.00295
388	c o fofo™ vC ό fo	N-{3-[({2-E(4-{((2- methoxyethyi)amino]metfiyl}phenyl)amino ]- 5- (trifl uoromethy l)py rimidin^yflaminoJmethyiJpyridin^-ylJ-Nmethylmethane-sulfonamide (388)	<0.000595
389	t ΑγΆ o .,ΛΛ,,, νζ” ό fo A fo'» CH Of	N-[3-({[2-{[4-(([2-hydroxy-1- (hydroxy methyl)ethy I ] a mino}methyl)pheny IJamino}-5-(trifluoromethyl)pyrimidin-4y!]amino}methyi)pyridin-2-yl]-Nmettiylmethane-sulfonamide (389)	<0.000595
390	f t V	N-(3-(({2-|{4-cyano-3hydroxyphenyi)amino]-5(trifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl}-Nmethylmethane-sulfonamide (390)	0.000746
391		N-{3-(({2-[(4-cyano-3hydroxyphertyl)amino]-5(trifluoromethyl) pyri mid i ri-4yl}amino)methyl]pyrazin-2-yl}-Nmethyimethane-sulfonarrtide (391), hydrochloride sail	0.00124
392	f F	N-{3-[((2-[(4-cyano-3hydroxyphenyl)amino]-5(trifluoromethyl)pyrimidin-4yl)amino)methylJphenyI}-Nmethylmethanesulfonamide (392)	0.00451

-1782016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK 1C50, pM
393		2-hydroxy-4-{[4 -{{3(methylsulfonyl)benzyl]amino}-5(trifiuoromethyi)py ri mid in-2yljamino)benzonitrile (393)	0.00741
394	•fOjC&f rt H B J	2-hydroxy-4-{{4-[({2- [methyl(methylsulfonyl)amino]pyridin-3ylJmethylJaminoj-S(lnfIuoromethyl)pyrimidin-2yl)amino)benzamide (394), formic acid salt	<0.000595
395	ΑουοΧό	2-hydroxy-4-({4-[{{3- Emetbyt(methyisulfony!)amino]pyrazin-2yi)methyI)amtno]-5(triftuoromethyl)pyrimidin-2yl}amino)benzamide (395), formic acid salt	0.000849
396		2-hydroxy~4-{[4-({3- (melhyl(meihylsulfonyl)amino]benzyl}ami no)-5-(trifluoromethy!)pyrimidin-2yl]amino}benzamide (396), formic acid salt	0.00313
397	t vjuoxAa. • ‘ A	N-2-acetyl-N-E3-({4-[({3- [methyi(metfiyisulfonyl)amino]pyrazln-2yl}meihyl)amino]-5(triftuoromethyI)pyrimidin-2yl}amino)phenyl]glycinamide (397)	0.00151
398	^ulXixAa, Ύ ' ' A	N~2~-acetyl-N-I3-({4-I({3- [methy ((methy isulfonyl )ami n o] pyridi n-2- y!}me(hyl)amino]-5- (trifluoromethy l)py ri m idin-2yi}amino)phenyl]giycinamide (398)	0.00218
399	Ycu0uA , Ύ ' ' AV	N-2-acetyl-N-<3-{[4-({3- [methyl(methylsu)fonyl)amino]benzyl}ami n o)-5-(tr ifl uo romethyl)pyrimid i n-2yi]amino}phenyl)glycinamide (399)	0.00557
400	«XX« a?®- 2) ί	N,2-dimethyl-4-({4-[{{3- [methyl(methylsulfonyl)amino3pyrazin-2- yl)methyl)amino]-5- (trifluoromethyi)pyrimidin-2- ytjamino) benzamide (400), hydrochloride salt	0.000660

-1792016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
401	Ό A £	N,3-dimethyl-4-({4-I({3- (mef hyl(methyisulfo nyl)amin o]py razin-2yl)methyl)amino]-5(trifluoromethy l)py rimtd in-2yl}amino)benzamide (401), hydrochloride salt	0.00117
402	JO V A« I	N12-dimethyl-4-({4-(({2- (methyl(methylsuifonyi)amino]pyridin-3y0methyl)amino]-5(trifluoromethyl)pyrirr)idin-2yljamtno)benzamide (402), hydrochloride salt	<0.000595
403	jcA^- A A A I	N,3-dimethyI-4-({4-(({2- (m ethy l(methy Isulfony l)amin o]py rid i n-3yl)methyl)amino]-5(trifluoromethyl)pyrimidin-2yi)amino)benzamide (403), hydrochloride salt	0.00109
404	»ArA« , ό AY	4-((4-(((4- (methy l(meihyls ulfonyl) a mino]pyridin-2- yl)methyl)amino]-5- (trifl u oro meihy l)py rimidin-2 yl)amino)benzamide (404), formic acid salt	0.00207
405	✓Ά Αζγ , 30 V+· ctSh,	3-methyl-4-({4-[({4- (methyt(methylsulfonyl)amino]pyridin-2yl}methyl)amino]-5(trifIuoromethyI)pyrimidin-2yl)amino)benzamide (405), formic acid salt	0.0173
406	ο οΛ— A	2-methyl-4-({4-[({4- [methyl(methylsulfonyl)amino]pyridin-2yl)methyl)amino]-5(trifluoromethyi)pyrimidin-2yl}amino)benzamide (406), formic acid salt	0.000784
407	t 0 -AucQb	N’-hydroxy-4-({4-[({2- [methyI(methylsutfonyl)amino]pyridin-3yl)methyl)amino]-5{trifluoromethyl)pyriiDldin-2yl)amina)benzenecarboximidamide (407), formic acid salt	<0.000595

-1802016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, μΜ
408		N'-hydroxy-3-({4-[({2- [methyl(methy is ulfony l)amln o] pyrid! n-3yl}methyl)amino]-5(trifluoromethy l)pyri m idin-2yl)amino)benzenecarboximidamide (408), formic acid salt	0.00229
409	ό SrS 7	N-i3-({{2-{{4-(2,2-dimethyI-1,3-dioxolan-4- yl)phenylJamino}-5- (triflu oromethy I) py rimidin-4yi]amino}methyl)pyrazin-2-yl]-Nmethylmethane-sulfonamide (409)	0.00475
410	αϋΑ ό A	N-(3-({[2-{(4-(2,2-dimethyl-1,3-dioxolan-4yl)phenyljamino)~5(trifluoromethyl)pyrimidin-4yl]amino}methyl)pyridin-2-yl)-Nmethylmethane-sulfonamide (410)	0.00119
	ί
411	αΑα ό V -Λ κ>	N-[3-({(2-{(4-(1,2- dihydroxyethyl)phenyl]amino}-5(trifluoromethyl)pyrimidin-4yl)amino)methyl)pyrazin-2-yl]-Nmethylmethane-sulfonamide (411), hydrochloride salt	0.000941
412	rZ'V-'-'S ο Ο V HD	N-(3-{{[2-{[4-(1,2- dihy d roxyethyl)phenyl]a min o}-5(irifluoromethyl)pyrimidin-4yl]amino}nnethyl)pyridin-2-ylj-Nmethylmethane-sulfonamide (412), hydrochloride salt	<0.000595
413 .	„λΛ„ νζ ό A A O1	N-(3-[((2-((4-{((2-hydroxy-2- methylpropy))amino]methyl}phenyl)amino] -5-(trifluoromethyl)pyrimidin-4yl}amino)methyl]pyridin-2-yl)-Nmethyimethanesulfonamide (413)	<0.000595

-181 2016201820 23 Mar 2016

Ex.	Structure	Compound Name	FAK IC50, pM
414	•XCyV Λ X I	N-methyl-N-[3-({(2-({4- [(methylamino)methyl]phenyl}amino)-5(trifluoromethy i)py ri midin-4y IJaminoJmethyl) py ridi n-2yljmethanesulfonamide ¢414), hydrochloride salt	<0.000595
415	F ΑΑλΧ 1	N-methyl-N-[2-({[2-({4- [{methylamino)methyl]phenyi}amino}-5(trifluoromethyl)pyrimidin-4yl)amino)methyl)phenyl]methanesuifonam ide (415), hydrochloride salt	<0.000595

- 182 -

Claims (39)

1. Claims

   2016201820 04 Jul 2016

   We claim:

   5 1. A method of making a compound of Formula (I), the method comprising reacting a compound of Formula (II) (II) with a compound of Formula (III),

   0.

   R⁵ (III)

   A, /'

   R⁴—N h₂n-(CR²R³)„

   - 183 2016201820 04 Jul2016 thereby providing the compound of Formula (I); wherein A is phenyl;

   B is phenyl or a 5- to 6-membered heteroaryl;

   K is CH;

   5 each R¹ is independently selected from the group consisting of —H, halo, —CF₃, —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(=CR⁹), —CR⁷(NR⁷R⁸)(=NR⁷), — NR⁷C(NR⁷R⁸)(=NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)C(O)R⁹, — C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, — OC(O)OR¹⁰, — S(O)jR¹¹, —S(O)(=NR⁷)R⁸, —(C_r C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅10 Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(CiC₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆15 C_w)aryl and —(Ci-C₉)heteroaryl moieties of said R¹ is optionally independently substituted by one to three Regroups;

   R²and R³are each independently selected from the group consisting of —H, halo, —OR¹⁰, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆20 C_w)aryl and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, — (C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R²and R³is optionally substituted by one to three Regroups;

   R⁴and R⁵are each independently selected from the group consisting of —H, —

   25 NR⁷R⁸, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci30 C₉)heteroaryl moieties of said R⁴ and R⁵ is optionally substituted by one to three R¹² groups;

   R⁶ is —CF₃;

   R⁷and R⁸are each independently selected from the group consisting of —H, — OR¹⁰, — S(O)jR¹¹, —NO₂, — (Ci-C₆)alkyl, — (C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, — C₃- 184 2016201820 04 Jul2016

   Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, — (C₆-C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl,

   5 —(C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R⁷and R⁸is optionally substituted by one to three Regroups;

   each R⁹is independently selected from the group consisting of —H, -halo, — NR¹³R¹⁴, — (Ci-C₆)alkyl, — (C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, — (C₃-Ci₀)cycloalkyl, — (C₅10 Ci₀)cycloalkenyl, —(C₆-Ci ₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆15 Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R⁹ is optionally substituted by one to three Regroups;

   each R¹⁰is independently selected from the group consisting of —H, —(C₂C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄20 C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl — (C₆-Ci₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₆-Ci₀)cycloalkenyl, —(C₂C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R¹⁰is optionally substituted by one to three Regroups;

   25 R¹¹ each is independently selected from the group consisting of —H, —NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(Ci-C₆)alkenyl, —(C₂-C₆)alkynyl, — (C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Ci₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl; and wherein each of the

   30 foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ci₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-Ci₀)aryl and —(Ci-C₉)heteroaryl moieties of said R¹¹ is optionally substituted by one to three R¹² groups;

   each R¹²is independently selected from the group consisting of —H, —OR¹³, —

   35 C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, — C(O)NR¹³R¹⁴, —

   -1852016201820 04 Jul2016

   NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(=NR¹³), —NR¹³C(NR¹³R¹⁴)(=N— C(O)R¹³), —NR¹³C(O)R¹⁴, — NR¹³S(O)jR¹³, — S(O)jR¹³, —CF3, —CN, — (Ci-C6)alkenyl, —(C2-C6)alkynyl, —(C3-Ci0)cycloalkyl, —(C5-Ci0)cycloalkenyl, —(C6-Ci0)bicycloalkyl, — (C6-Ci0)bicycloalkenyl, —(C2-C9)heterocycloalkyl, —(C4-C9)heterocycloalkenyl, —(C65 C9)heterobicycloalkyl, —(C6-C9)heterobicycloalkenyl, —(C6-Ci0)aryl, and —(CiC9)heteroaryl; wherein each of the foregoing —(Ci-C6)alkyl, —(C2-C6)alkenyl, —(C2C6)alkynyl, —(C3-Ci0)cycloalkyl, —(C5-Ci0)cycloalkenyl, —(C6-Ci0)bicycloalkyl, —(C6Ci0)bicycloalkenyl, —(C2-C9)heterocycloalkyl, —(C4-C9)heterocycloalkenyl, —(C6C9)heterobicycloalkyl, —(C6-C9)heterobicycloalkenyl, —(C6-Ci0)aryl and —(Ci10 C9)heteroaryl of said R¹² is optionally independently substituted by one to three groups selected from the group consisting of -halo, —CF3, —CN, —NO₂, —OH, —O((CiC₆)alkyl), —C(O)R¹⁵, — C(O)NR¹⁵R¹⁶, —S(O)jR¹⁵, and — S(O)jNR¹⁵R¹⁶, — (C₃Ci₀)cycloalkyl, — (C₂-C₉)heterocycloalkyl, —SH, — S((Ci-C₆)alkyl), —NH₂, — NH((CiC₆)alkyl) and — N((Ci-C₆)alkyl)₂;

   15 R¹³ and R¹⁴ are each independently selected from the group consisting of —H, —NR¹⁵C(O)R¹⁶, —CF3, —CN, — S(O)jR¹⁵, — (Ci-C6)alkyl, — (C₂-C₆)alkenyl, — (C₂C₆)alkynyl, —C₃-Ci₀)cycloalkyl, —(C₅-Ci₀)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-Ci₀)aryl, and —(Ci20 C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, — (C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, — (C₆-Ci₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl and —(CiC₉)heteroaryl of said R¹³and R¹⁴is optionally independently substituted by one to three

   25 groups selected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH, —

   O((Ci-C₆)alkyl), —C(O)((Ci-C₆)alkyl), —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, — SH, — S((Ci-C₆)alkyl), —NH₂, — NH((Ci-C₆)alkyl) and — N((Ci-C₆)alkyl)₂;

   R¹⁵and R¹⁶are each independently selected from the group consisting of —H, —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅30 Ci₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(Ci-C₉)heteroaryl; and wherein each of the foregoing —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, — (C₅-Ci₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl, —(C₂35 C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, —(C₆C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl and —(Ci-C₉)heteroaryl of said R¹⁵and R¹⁶is

   -1862016201820 04 Jul2016 optionally independently substituted by one to three groups selected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH, —O((Ci-C₆)alkyl), —C(O)((Ci-C₆)alkyl), —(C₃-Ci₀)cycloalkyl, —(C2-C₉)heterocycloalkyl, —SH, —S((Ci-C₆)alkyl), —NH₂, — NH((Ci-C₆)alkyl) and — N((Ci-C₆)alkyl)₂;

   5 wherein one or two carbon ring atoms in each of the aforementioned —(CiC₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅Ciojcycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Cio)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and — (C₆-C₉)heterobicycloalkenyl in said R¹-R¹⁴groups may optionally and independently be

   10 replaced with —C(O)— or —C(S)—;

   wherein two groups attached to the same tetravalent carbon atom in each of the aforementioned —(Ci-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-Ci₀)cycloalkyl, —(C₅-Cio)cycloalkenyl, —(C₆-Ci₀)bicycloalkyl, —(C₆-Cio)bicycloalkenyl, —(C₂C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and —

   15 (C₆-C₉)heterobicycloalkenyl of said R¹ to R¹⁴ groups may optionally join to form a ring system selected from the group consisting of a —(C₃-Ci₀)cycloalkyl, —(C₅Ciojcycloalkenyl, —(C₂-C₉)heterocycloalkyl and —(C₄-C₉)heterocycloalkenyl; and wherein j is an integer from 0 to 2;

   20 n is an integer from 1 to 3; and m is an integer from 0 to 3.
2. 2. A method of making a compound of the Formula (IV), the method comprising reacting a compound of the Formula (V)

   -1872016201820 04 Jul2016 (V)

   H₂N so₂ch₃ with a compound of the Formula (VI) (VI) thereby providing a compound of the Formula (IV)

   5
3. 3. The method of claim 2, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed in the presence of a solvent.
4. 4. The method of claim 3, wherein the solvent comprises dichloroethane and tBuOH.
5. 5. The method of claim 4, wherein the ratio of dichloroethane to tBuOH is 1:1.

   10
6. 6. The method of claim 2, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed in the presence of a base.
7. 7. The method of claim 6, wherein the base is Hunig's base.
8. 8. The method of claim 2, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed in a sealed container.

   -1882016201820 04 Jul2016
9. 9. The method of claim 2, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed at elevated temperature.
10. 10. The method of claim 9, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed at 88° C.

    5
11. 11. The method of claim 2, wherein the reaction of the compound of Formula (V) and the compound of Formula (VI) is performed for 1.5 hour.
12. 12. The method of claim 2, further comprising isolating the compound of Formula (IV), wherein isolating the compound of Formula (IV) comprises precipitating the compound of Formula (IV) from the reaction mixture.

    10
13. 13. The method of claim 12, wherein isolating the compound of Formula (IV) comprises dilution of the reaction mixture with Et₂O/EtOH.
14. 14. The method of claim 13, wherein the ratio of Et₂O/EtOH is 10:1.
15. 15. The method of any one of claims 12 to 14, wherein the isolation of the compound of Formula (IV) further comprises filtration.

    15
16. 16. The method of any one of claims 2 to 15, wherein the compound of Formula (IV) is converted into a salt thereof.
17. 17. The method of claim 16, wherein the salt is an HCI salt of Formula (IV).
18. 18. The method of claim 17, wherein the HCI salt is formed by a reaction with 4M HCI in dioxane.
19. 20 19. The method of claim 18, wherein the reaction with 4M HCI is performed in a solvent.

    20. The method of claim 19, wherein the solvent is methanol.
20. 21. The method of any one of claims 18 to 20, wherein the reaction with 4M HCI is performed at ambient temperature.

    - 189 2016201820 04 Jul 2016
21. 22. The method of any one of claims 18 to 21, wherein the reaction with 4M HCI is performed for 1 hour.
22. 23. The method of any one of claims 17 to 22, wherein the isolation of the HCI salt of Formula (IV) comprises filtration.

    5
23. 24. The method of claim 2, wherein the compound of Formula (VI) is made by a method which comprises reacting a compound of Formula (VII) (VII) cXX

    H with a compound Formula (VIII) (VIII)

    10 thereby providing a compound of the Formula (VI).
24. 25. The method of claim 24, wherein the reaction of the compound of Formula (VII) and the compound of Formula (VIII) is performed in a solvent.
25. 26. The method of claim 25, wherein the solvent comprises dichloroethane and tBuOH.

    15
26. 27. The method of claim 26, wherein the ratio of dichloroethane to tBuOH is 1:1
27. 28. The method of claim 24, wherein the reaction of the compound of Formula (VII) and the compound of Formula (VIII) is performed in the presence of a zinc salt.

    2016201820 21 Feb 2018

    -190
28. 29. The method of claim 28, wherein the zinc salt is ZnBr2.
29. 30. The method of claim 24, wherein the reaction of the compound of Formula (VII) and the compound of Formula (VI11) is performed in the presence of a base.
30. 31. The method of claim 30, wherein the base is triethylamine.
31. 32. The method of claim 24, wherein the compound of Formula (VII) and the compound of Formula (VIII) is added to a reaction vessel at decreased temperature.
32. 33. The method of claim 32, wherein the temperature during addition of the compound of Formula (VII) and the compound of Formula (VI11) is 5° C.
33. 34. The method of claim 24, wherein the reaction of the compound of Formula (VII) and the compound of Formula (VIII) is performed at 25° C.
34. 35. The method of any one of claims 24 to 34, wherein the reaction of the compound of Formula (VII) and the compound of Formula (VIII) is performed for 20 hours.
35. 36. The method of any one of claims 24 to 35, wherein the compound of Formula (VI) is purified using column chromatography.
36. 37. The method of claim 36, wherein the compound of Formula (VI) is further purified by trituration with water.
37. 38. The method of isolating the compound of Formula (VI) in claim 37 by filtration.
38. 39. A compound of Formula (I) produced by the method of claim 1.
39. 40. A compound of Formula (IV) produced by the method of any one of claims 2 to 38.