ES2860937T3 - Pyrimidine-2,4-diamine derivatives for treating cancer - Google Patents

Abstract

A compound of formula I, ** (See formula) ** or a pharmaceutically acceptable salt thereof, wherein: R1 represents heteroaryl selected from benzofuran-3-yl, benzothiophene-3-yl, dihydrobenzofuran-7-yl, indole- 3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl, whose heteroaryl is connected to the pyrimidine of formula I through a heteroaryl ring carbon atom, and which heteroaryl is optionally substituted with one or more substituents selected from Y1 or -C 1-6 alkyl optionally substituted with one or more Y2; or aryl represented by ** (See formula) ** E3 and E4 represent hydrogen; and E1 represents -F and E2 represents -F, -CI, -CH3 or -CF3; or E1 represents -Cl and E2 represents -F, -CI, -CH3 or -CF3; or E1 represents -CH3 and E2 represents -F, -CI, -CH3, -CF3 or -CN; R2 represents hydrogen; R3 represents -C2-6 alkyl substituted with Z1; each Y1 independently represents halogen, -CN, -C (O) Ra, -C (O) N (Rb) Rc, -C (O) ORd, -N (Re) Rf, -N (Rg) C (O) Rh, -N (Ri) C (O) ORj, -N (Rk) C (O) N (Rl) Rm, -NO2, -N (Rn) S (O) 2Ro, -ORp, -OC (O) Rq, -OS (O) 2Rr, -S (O) mRs, -S (O) 2N (Rt) Ru, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6-14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; each Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rk, Rl, Rm, Rn, Rp, Rq, Rs, Rt and Ru independently represents hydrogen, - C1-6 alkyl optionally substituted with one or more substituents selected from W1, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or either of two Rb and Rc, Re and Rf, Rl and Rm and / or Rt and Ru are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring contains optionally one or two additional heteroatoms and whose ring is optionally substituted with one or more substituents selected from W2, C1-3 alkyl optionally substituted with one or more substituents selected from W1 and = O; each Rf, Rj, Ro and Rr independently represent -C 1-6 alkyl optionally substituted with one or more substituents selected from W1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more 0 substituents selected from W2, 6- to 14-membered aryl optionally substituted with one or more substituents selected from W3 or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; each Y2 independently represents halogen, -CN, -C (O) Rb1, -C (O) N (Rc1) Rd1, -C (O) ORe1, -N (Rf1) Rg1, -5 N (Rh1) C (O ) Ri1, -N (Rj1) C (O) ORk1, -N (Rl1) C (O) N (Rm1) Rn1, -N (Ro1) S (O) 2Rp1, -ORq1, -OC (O) Rr1, -OS (O) 2Rs1, -S (O) mRt1, -S (O) 2N (Ru1) Rv1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W1, optionally substituted 6- to 14-membered aryl with one or more substituents selected from W2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W2; each Rb1, Rc1, Rd1, Re1, Rf1, Rh1, Ri1, Rj1, Rl1, Rm1, Rn1, Ro1, Rq1, Rr1, Rt1, Ru1 and Rv1 independently represents hydrogen, C1-6 alkyl optionally substituted by one or more selected substituents of W1, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or any of two Rc1 and Rd1, Rf1 and Rg1, Rm1 and Rn1 and / or Ru1 and Rv1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, whose ring optionally contains one or two additional heteroatoms and whose ring is optionally substituted with one or more substituents selected from W2, C1-3 alkyl optionally substituted with one or more substituents selected from W1 and = O; each Rg1, Rk1, Rp1 and Rs1 independently represent C1-6 alkyl optionally substituted with one or more substituents selected from W1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, optionally substituted 6- to 14-membered aryl with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; Z1 represents -C (O) N (Rc2) Rd2, -N (Rf2) Rg2, -N (Rh2) C (O) Ri2, -N (Rl2) C (O) N (Rm2) Rn2, -N (Ro2 ) S (O) 2Rp2, -ORq2, -S (O) mRt2, - S (O) 2N (Ru2) Rv2, or aryl represented by ** (See formula) ** Rc2, Rf2, Rh2, Rl2, Rm2, Ro2, and Ru2 represent hydrogen; and Rd2, Rg2, Ri2, Rn2 Rp2, Rq2, Rt2 and Rv2 represent 6 to 14 membered aryl optionally substituted with one or more substituents selected from W6, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W6; each W1 independently represents halogen, -CN, -N (Rf3) Rg3, -N (Rh3) C (O) Ri3, -N (Rj3) C (O) ORk3, - N (Rl3) C (O) N (Rm3 ) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, -OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, heterocycloalkyl 3 to 12 membered optionally substituted with one or more substituents selected from G1, 6 to 14 membered aryl optionally substituted with one or more substituents selected from G2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2, o = O; each W2, W3, and W6 independently represents halogen, -Ra3, -CN, -C (O) Rb3 -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C (O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, - OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, aryl from 6 to 14 membered optionally substituted with one or more substituents selected from G2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2, o = O ; W7 and W11 represent hydrogen; each W8 and W10 independently represent halogen, -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3 ) C (O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, -OC ( O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, 6 to aryl 14 membered optionally substituted with one or more substituents selected from G2, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2; W9 represents halogen, -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C (O ) Ri3, - N (Rj3) C (O) ORk3, -N (R13) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3x, -OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, optionally substituted 6- to 14-membered aryl with one or more substituents selected from G2, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2; each Ra3, Rb3, Rc3, Rd3, Re3, Rf3, Rh3, Ri3, Rj3, Rl3, Rm3, Rn3, Ro3, Rq3, Rr3, Rt3, Ru3 and Rv3 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more G3; or either of two Rc3 and Rd3, Rf3 and Rg3, Rm3 and Rn3 and / or Ru3 and Rv3 are linked together to form, together with the nitrogen atom to which they are attached, a 4 to 6 membered ring, the ring of which contains optionally one or more heteroatoms and whose ring is optionally substituted with one or more G2; each Rg3, Rk3, Rp3, and Rs3 independently represent C1-6 alkyl optionally substituted with one or more G3; Rq3x represents C2-6 alkyl optionally substituted with one or more G3; each G1 and G2 independently represent halogen, -Ra4, -CN, -C (O) Rb4, -C (O) N (Rc4) Rd4, -C (O) ORe4, -N (Rf4) Rg4, -N (Rh4 ) C (O) Ri4, -N (Rj4) C (O) ORk4, -N (Rl4) C (O) N (Rm4) Rn4, -N (Ro4) S (O) 2Rp4, -ORq4, -OC ( O) Rr4, -OS (O) 2Rs4, -S (O) mRt4, -S (O) 2N (Ru4) Rv4, o = O; G3 represents halogen, -CN, -C (O) Rb4, -C (O) N (Rc4) Rd4, -C (O) ORe4, -N (Rf4) Rg4, -N (Rh4) C (O) Ri4, -N (Rj4) C (O) ORk4, - N (Rl4) C (O) N (Rm4) Rn4, -N (Ro4) S (O) 2Rp4, -ORq4, -OC (O) Rr4, -OS ( O) 2Rs4, -S (O) mRt4, -S (O) 2N (Ru4) Rv4, o = O; each Ra4, Rb4, Rc4, Rd4, Re4, Rf4, Rh4, Ri4, Rj4, Rl4, Rm4, Rn4, Ro4, Rq4, Rr4, Rt4, Ru4 and Rv4 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more -F; or either of two Rc4 and Rd4, Rf4 and Rg4, Rm4 and Rn4 and / or Ru4 and Rv4 are linked together to form, together with the nitrogen atom to which they are attached, a 3 to 6 membered ring, the ring of which is optionally substituted by one or more -F, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CF3 or = O; each Rg4, Rk4, Rp4 and Rs4 independently represents C1-6 alkyl optionally substituted with one or more -F; and each m independently represents 0, 1 or 2.

Description

DESCRIPTION

Pyrimidine-2,4-diamine derivatives for treating cancer

Field of the invention

The invention relates to new compounds, compositions and methods for the treatment of cancer. In particular, the invention relates to new compounds, compositions and methods for treating cancers by inhibiting MTH1.

Background of the invention

The listing or discussion of an apparently previously published document in this specification should not necessarily be taken as an acknowledgment that the document is part of the state of the art or is of common general knowledge.

Background

Dysfunctional reduction-oxidation regulation of cell signaling and increased ROS (reactive oxygen species) tension have been shown to play a crucial role in cancer etiology, progression, and metastasis (Zhang et al., Antioxid Redox Signal 15 ( 11) 2011: 2876-2908). ROS are mediators of tumor-promoting characteristics such as, for example, rampant proliferation, survival signaling, increased migration, angiogenesis. ROS are generated during cell metabolism and are highly reactive with macromolecules such as DNA, proteins, and lipids. Exposure of nucleic acids to ROS can create more than 20 oxidatively modified nucleotides, of which 8-oxo-7,8-dihydroxyguanine (8-oxodG) is the most abundant. 8-oxo-dG plays a fundamental role in mutagenesis (Sekiguchi and Tsuzuki., Oncogene 21 (58) 2002: 8895-906). To protect themselves from carcinogenic effects, mammalian cells are armed with a suite of repair enzymes to remove oxidized nucleotides and maintain the integrity of the genome. One of these protective enzymes is MTH1 (MutT 1,8-oxo-dGTPase homolog, NUDT1). Interestingly, MTH1 is upregulated in various forms of cancer, suggesting that the cancer cell depends on the function of MTH1 to survive increased DNA damage (Human Proteinatlas, Koketsu et al., Hepatogastroenterology, 51 (57) 2004: 638 -41). Suppression of the level and activity of MTH1 through the use of RNAi technology leads to reduced survival of cancer cells, premature senescence and DNA strand breaks (Rai et al, PNAS, 106 (1) 2009 : 169-174), Helleday et al, unpublished data). Interestingly, lung cancers that form spontaneously in OGG - / - mice do not form in crosses with MTH1 - / - mice, suggesting that MTH1 is necessary for lung cancer cells to survive (Sakumi et al., Cancer Res 63, 2003: 902). We have observed that down-regulation of MTH1 protein levels in human colon cancer tumors in xenograft mouse models reduced tumor growth and significantly reduced tumor (Helleday et al, unpublished data). In tumor cells, reducing the ability to remove oxidized dNTPs by inhibiting MTH1 activity will reduce cancer cell survival and therefore will be a promising new cancer therapy, either as monotherapy in forms of cancer with high levels of oxidative stress and / or in combination with radiation therapy and chemotherapy drugs.

Deficiencies and complications with current treatment

Current cancer treatment is not effective for all patients with diagnosed disease, including also a large proportion of patients who experience adverse effects from existing therapies or where resistance to ongoing therapy develops over time.

Previous technique

Engelhardt, H. et al. Journal of Medicinal Chemistry (2013), 56 (11), 4264-4276 and US patent application US 2010/0016344 disclose certain 6-aryl-2,4-diaminopyrimidines that have an additional pyrimidine appendage as receptor modulators. of histamine H4. The compounds are claimed to be useful for various diseases including cancer pain, but their use in the treatment of cancer as such is not disclosed or suggested. International patent application WO 2013/066839 discloses 6- (3-pyridyl) - (2,4-diaminopyrimidines as HDAC inhibitors. However, the substituent on the 4-amino group contains a prerequisite 5-trifluoromethyl-1 group, 2,4-Oxadiazol-3-yl. In the international patent application WO 2010/059658 2,4-diaminopyrimidines substituted in position 6 with 3-aminoindazoles have been described. Although indazoles without the amino groups are also mentioned, it is made It is evident from the examples that the 3-amino substituent on indazole is necessary for activity. The same document also describes 2,4-diaminopyrimidines substituted at the 6-position by a 3-cyano-2-fluorophenyl group. However, these compounds they are simply precursors of the 3-aminoindazoles mentioned above and there is no disclosure or suggestion in the document that they possess any anticancer activity.

International patent application WO 2006/078886 describes 2,4-diaminopyrimidines substituted in position 6 by an aryl group as modulators of Wnt. The 4-aryl group is devoid of substituents or must be substituted at the 3-position with methoxy. The document does not disclose or suggest compounds with any other pattern of substituents, nor does it mention or suggest the use of such compounds in the treatment of cancer. Furthermore, in all examples, the 4-amino group of pyrimidine is substituted by 1,3-benzodioxol-5-ylmethyl or by 4-hydroxy-phenethyl. Several scientific publications describe the use of one of the compounds (N4- (1,3-benzodioxol-5-ylmethyl) -6- (3-methoxyphenyl) -2,4-pyrimidinediamine) as a tool to investigate the Wnt pathway. International patent application WO 86/04583 describes aziridinyl substituted antineoplastic compounds. There is only one compound that has a 6-aryl substituent and a 4-N-alkyl group attached to the 2-aminopyrimidine nucleus. The compound has in addition to the aziridinyl group a fluorine at the 5-position of the pyrimidine ring. Both aziridinyl and fluorine are assumed to be important for activity and there is nothing to suggest that antineoplastic activity can be obtained without at least one of these substituents. British patent application GB 681712 describes 2,4-diaminopyrimidines substituted at position 6 by an aryl group for use in treating cancer, but in only one example the aryl is phenyl and the 4-amino group is substituted by a I rent. In this compound, the phenyl is unsubstituted and the alkyl is methyl. There is no disclosure in these documents of compounds in which the 6-phenyl may be substituted by groups other than chloro or nitro in the para position, that the 6-phenyl may contain more than one substituent, or that the 4-alkylamino group is larger than methyl or may carry substituents.

Two publications of the group of H. Junjappa (Indian Journal Chemistry (1985), 24B 466; Synthesis (1980), 748) describe the synthesis of certain 2-amino-4- (N-alkylamino) -6-arylpyrimidines. The publications do not mention or suggest the use of the synthesized compounds in the treatment of cancer.

There are numerous 2-amino-4- (N-alkylamino) -6-arylpyrimidines that are, or have at one time been said to be, commercially available but have no ascribed pharmaceutical use, or other use, attributed to them. .

Inhibitors of MTH1 have been described in Streib, M. et al. Angewandte Chemie, Int. Ed. (2013), vol. 52. The compounds are organometallic and are not 2-amino-4- (N-alkylamino) -6-arylpyrimidines.

Summary of the invention

Although the finding of oncogenes and the development of new cancer treatments and diagnoses have improved the life span of cancer patients, there is still a great medical need to find more effective and less toxic treatments for, for example, cancer of the breast, leukemia, colon or lung cancer. Our preliminary data suggest that MTH1 inhibitors have the potential to be very effective against forms of cancer with dysfunctional reduction-oxidation state, with minimal overall toxic effects. Inhibition of MTH1 may also be a suitable adjuvant therapy to be used in conjunction with radiotherapies or other chemotherapeutic methodologies.

The present invention aims to provide new cancer treatments that can be achieved by inhibiting MTH1.

Brief description of the drawings

Figure 1. Effect on cell survival after depletion of MTH1 siRNA in various normal human and cancer cell lines.

Figure 2. MTH1 inhibitor reduces cell survival in various cancer cell lines, with less effect on normal immortalized cells (VH10 and BJ hTERT)

Detailed description of the invention

In one embodiment of the invention a compound of formula I is provided,

or a pharmaceutically acceptable salt thereof, wherein:

R1 represents heteroaryl selected from benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3 -yl, pyridin-4-yl, pyrrol-2-yl, and quinolin-5-yl, the heteroaryl of which is connected to the pyrimidine of formula I through a heteroaryl ring carbon atom, and which heteroaryl is optionally substituted with one or more substituents selected from Y1 or C1-6 alkyl optionally substituted with one or more Y2; or aryl represented by

E3 and E4 represent hydrogen; and

E1 represents -F and E2 represents -F, -Cl, -CH3 or -CF3; or

E1 represents -Cl and E2 represents -F, -Cl, -CH3 or -CF3; or

E1 represents -CH3 and E2 represents -F, -Cl, -CH3, -CF3 or -CN;

R2 represents hydrogen;

R3 represents C2-6 alkyl substituted with Z1;

each Y1 independently represents halogen, -CN, -C (O) R8, -C (O) N (Rb) Rc, -C (O) ORd, -N (Re) Rf, -N (Rg) C (O) Rh, -N (Ri) C (O) ORj, -N (Rk) C (O) N (Rl) Rm, -NO2, -N (Rn) S (O) 2Ro, -ORp, -OC (O) Rq, -OS (O) 2Rr, -S (O) mRs, -S (O) 2N (R ') Ru, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6-14 aryl members optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3;

each Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rk, R1, Rm, Rn, Rp, Rq, Rs, R * and Ru independently represents hydrogen, C1-6 alkyl optionally substituted with one or more substituents selected from W1, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or

either of two Rb and Rc, Re and Rf, R1 and Rm and / or R * and Ru join to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, whose ring optionally contains one or two additional heteroatoms and whose ring is optionally substituted with one or more substituents selected from W2, C1-3 alkyl optionally substituted with one or more substituents selected from W1 and = O;

each Rf, Rj, Ro and Rr independently represent C1-6 alkyl optionally substituted with one or more substituents selected from W1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, optionally substituted 6- to 14-membered aryl with one or more substituents selected from W3 or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3;

each Y2 independently represents halogen, -CN, -C (O) Rb1, -C (O) N (Rc1) Rd1, -C (O) ORe1, -N (Rf1) Rg1, -N (Rh1) C (O) Ri1, -N (Rj1) C (O) ORk1, -N (Rl1) C (O) N (Rm1) Rn1, -N (Ro1) S (O) 2Rp1, -ORq1, -OC (O) Rr1, - OS (O) 2Rs1, -S (O) mRt1, -S (O) 2N (Ru1) Rv1, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W1, 6-14 membered aryl optionally substituted with one or more substituents selected from W2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W2;

each Rb1, Rc1, Rd1, Re1, Rf1, Rh1, Ri1, Rj1, Rh, Rm1, Rn1, Ro1, Rq1, Rr1, R * 1, hydrogen, C1-6 alkyl optionally substituted by one or more substituents selected from W1, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen , nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or

either of two Rc1 and Rd1, Rf1 and Rg1, Rm1 and Rn1 and / or Ru1 and Rv1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, the which optionally contains one or two additional heteroatoms and whose ring is optionally substituted with one or more substituents selected from W ² , C ^1-3 alkyl optionally substituted with one or more substituents selected from W ¹ and = O;

each R ^g1 , R ^k1 , R ^p1 and R ^s1 independently represent C ^1-6 alkyl optionally substituted with one or more substituents selected from W ¹ , 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W ² , aryl 6 to 14 membered optionally substituted with one or more substituents selected from W ³ , or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W ³ ;

Z ¹ represents -C (O) N (R ^c2 ) R ^d2 , -N (R ^f2 ) R ^g2 , -N (R ^h2 ) C (O) R ⁱ² , -N (R ^l2 ) C (O) N ( R ^m2 ) R ⁿ² , -N (R ^o2 ) S (O) ² R ^p2 , -OR ^q2 , -S (O) ^m R ^t2 , -S (O) ² N (R ^u2 ) R ^v2 , or represented aryl by

R ^c2 , R ^f2 , R ^h2 , R ¹² , R ^m2 , R ^o2 , and R ^u2 represent hydrogen; and

R ^d2 , R ^g2 , R ⁱ² , R ⁿ² R ^p2 , R ^q2 , R ^t2 and R ^v2 represent 6 to 14 membered aryl optionally substituted with one or more substituents selected from W ⁶ , or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W ⁶ ;

each W ¹ independently represents halogen, -CN, -N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3 , -OC (O) R ^r3 , -OS (O) ² R ^s3 , -S ( O) ^m R ^t3 , -S (O) ² N (R ^u3 ) R ^v3 , 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , 6 to 14-membered aryl optionally substituted with one or more substituents selected from G ² , 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G ² , o = O;

each W ² , W ³ and W ⁶ independently represents halogen, -R ^a3 , -CN, -C (O) R ^b3 , -C (O) N (R ^c3 ) R ^d3 , -C (O) OR ^e3 , - N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 , -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3 , -OC (O) R ^r3 , -OS (O) ² R ^s3 , -S (O) ^m R ^t3 , -S (O ) ² N (R ^u3 ) R ^v3 , 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , 6 to 14 membered aryl optionally substituted with one or more substituents selected from G ² , 5 to heteroaryl 10 members containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G ² , or = O;

W ⁷ and W ¹¹ represent hydrogen;

each W ⁸ and W ¹⁰ independently represent halogen, -R ^a3 , -CN, -C (O) R ^b3 , -C (O) N (R ^c3 ) R ^d3 -C (O) OR ^e3 , -N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 , -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3 , -OC (O) R ^r3 , -OS (O) ² R ^s3 , -S (O) ^m R ^t3 , -S (O) ² N ( R ^u3 ) R ^v3 , 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , 6 to 14 membered aryl optionally substituted with one or more substituents selected from G ² , or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G ² ;

W ⁹ represents halogen, -R ^a3 , -CN, -C (O) R ^b3 , -C (O) N (R ^c3 ) R ^d3 , -C (O) OR ^e3 , -N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 , -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3x , -OC (O) R ^r3 , -OS (O) ² R ^s3 , -S (O) ^m R ^t3 , -S (O) ² N (R ^u3 ) R ^v3 , 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , 6 to 14 membered aryl optionally substituted with one or more substituents selected from G ² , or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G ² ;

each R ^a3 R ^b3 R ^c3 R ^d3 R ^e3 R ^f3 R ^h3 R ⁱ³ R ^j3 R ^l3 R ^m3 R ⁿ³ r ^o3 R ^q3 R ^r3 R ^t3 Ru3 and Rv3 independently represents hydrogen or C ^1-6 alkyl optionally substituted by one or plus G ³ ; or

either of two Rc3 and Rd3, Rf3 and Rg3, Rm3 and Rn3 and / or Ru3 and Rv3 are linked together to form, together with the nitrogen atom to which they are attached, a 4 to 6 membered ring, which ring optionally contains one more heteroatom and whose ring is optionally substituted with one or more G2;

each Rg3, Rk3, Rp3, and Rs3 independently represent C1-6 alkyl optionally substituted with one or more G3; R ^q3x represents C ^2-6 alkyl optionally substituted with one or more G ³ ;

each G ¹ and G ² independently represent halogen, -R ^a4 , -CN, -C (O) R ^b4 , -C (O) N (R ^c4 ) R ^d4 , -C (O) OR ^e4 , -N (R ^f4 ) R ^g4 , -N (R ^h4 ) C (O) R ⁱ⁴ , -N (R ^j4 ) C (O) OR ^k4 , -N (R ^l4 ) C (O) N (R ^m4 ) R ⁿ⁴ , - N (R ^o4 ) S (O) ² R ^p4 , -OR ^q4 , -OC (O) R ^r4 , -OS (O) ² R ^s4 , -S (O) ^m R ^t4 , -S (O) ² N (R ^u4 ) R ^v4 , o = O;

G ³ represents halogen, -CN, -C (O) R ^b4 , -C (O) N (R ^c4 ) R ^d4 , -C (O) OR ^e4 , -N (R ^f4 ) R ^g4 , -N (R ^h4 ) C (O) R ⁱ⁴ , -N (R ^j4 ) C (O) OR ^k4 , -N (R ^l4 ) C (O) N (R ^m4 ) R ⁿ⁴ , -N (R ^o4 ) S (O) ² R ^p4 , -OR ^q4 , -OC (O) R ^r4 , -OS (O) ² R ^s4 , -S (O) ^m R ^t4 , -S (O) ² N (R ^u4 ) R ^v4 , o = OR;

each Ra4, Rb4, Rc4, Rd4, Re4, Rf4, Rh4, Ri4, Rj4, Rl4, Rm4, Rn4, Ro4, Rq4, Rr4, Rt4, Ru4 and Rv4 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more -F; or

any of two R ^c4 and R ^d4 , R ^f4 and R ^g4 , R ^m4 and R ⁿ⁴ and / or R ^u4 and R ^v4 are linked together to form, together with the nitrogen atom to which they are attached, a ring of 3 to 6 members, the ring of which is optionally substituted by one or more -F, -CH ³ , -CH ² CH ³ , -CHF ² , -CF ³ , -CH ² CF ³ , or = O;

each R ^g4 , R ^k4 , R ^p4 and R ^s4 independently represents C ^1-6 alkyl optionally substituted with one or more -F; and each m independently represents 0, 1 or 2;

which compounds may be referred to herein as "the compounds of the invention".

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Said salts may be formed by conventional means, for example, by reacting a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (eg, in vacuo, by lyophilization or by filtration). Salts can also be prepared by exchanging a counter ion of a compound of the invention in salt form with another counter ion, for example, using a suitable ion exchange resin. For the avoidance of doubt, solvates are also included within the scope of the invention.

The compounds of the invention may contain double bonds and therefore may exist as geometric E (entgegen) and Z (zusammen) isomers around each individual double bond. All of these isomers and mixtures of these are included within the scope of the invention.

The compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and, therefore, may exhibit optical and / or diastereoisomerism. Diastereoisomers can be separated using conventional techniques, for example, chromatography or fractional crystallization. The various stereoisomers can be isolated by separating a racemic or other mixture of the compounds using conventional techniques, eg, fractional crystallization or HPLC. Alternatively, the desired optical isomers can be obtained by reacting the appropriate optically active starting materials under conditions that will not cause racemization or epimerization (i.e., a "chiral grouping 'method), by reacting the appropriate starting material with an' auxiliary. chiral 'which can subsequently be removed in a suitable step, by derivatization (i.e. resolution, including dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst, all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

Unless otherwise specified, the C ^{1 -q} alkyl groups (where q is the upper limit of the range) defined here can be straight chain or, when there are a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched chain and / or cyclic (thus forming a C ^{3 -q} cycloalkyl group). When there are a sufficient number (ie a minimum of four) of carbon atoms, these groups can also be partially cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, an alkenyl group C ^2-q or alkynyl C ^2-q) .

Unless otherwise specified, C ^{1 -q} alkylene groups (where q is the upper limit of the range) defined here may (similarly to the definition of C ^{1 -q} alkyl) be straight chain or, where there is a sufficient number (ie a minimum of two or three, as appropriate) of carbon atoms, either branched chain and / or cyclic (thus forming a C ^3-q cycloalkylene group). When there are a sufficient number (ie a minimum of four) of carbon atoms, these groups can also be partially cyclic. Such alkylene groups can also be saturated or, when there are a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, an alkenylene group or C ^2-q alkynylene C ^2-q). Particular alkylene groups that may be mentioned include those that are straight chain and saturated.

The term "halo", when used herein, includes fluorine, chlorine, bromine, and iodine (eg, fluorine and chlorine).

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may have an additional bridge) in which at least one (for example, one to four) of the ring system atoms is other than carbon ( i.e., one heteroatom), and wherein the total number of atoms in the ring system is between three and twelve (eg, between five and ten, and more preferably between three and eight, eg, a heterocycloalkyl group 5 or 6 members). Furthermore, said heterocycloalkyl groups can be saturated or unsaturated and contain one or more double and / or triple bonds, forming, for example, a C ^2-q (for example, C ^4-q ) heterocycloalkenyl (where q is the upper limit of the range) or a C ^{7 -q} heterocycloalkynyl group. ^{Mentioned C 2 -q} heterocycloalkyl groups include 7-azabicyclo- [2.2.1] heptanyl, 6-azabicyclo [3.1.1] heptanyl, 6-azabicyclo [3.2.1] -octanyl, 8-azabicyclo [3.2. 1] octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl ( including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, 7-oxabicyclo [2.2.1] heptanyl, 6-oxabicyclo [3.2.1] -octanyl, oxethanyl, oxiranyl, piperazinyl, piperidinyl , pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thiethanyl, thiranyl thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl, and the like. Substituents on heterocycloalkyl groups can, where appropriate, be located on any atom of the ring system, including a hetero atom. Furthermore, in the case where the substituent is another cyclic compound, then the cyclic compound can be attached through a single atom in the heterocycloalkyl group, forming a compound called "spiro". The point of attachment of the heterocycloalkyl groups can be through any atom in the ring system including (where appropriate) a hetero atom (such as a nitrogen atom), or an atom in any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups can also be in the N- or S-oxidized form. At each occurrence, when mentioned herein, a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (eg, a 5- or 6-membered heterocycloalkyl group).

The term "aryl", when used herein, includes C ^to-14 aromatic groups (eg, C ^6-10 ). Said groups can be monocyclic or bicyclic and, when they are bicyclic, be totally or partially aromatic. ^{C to-10} aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (eg, phenyl, naphthyl, and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups can be through any carbon atom in the ring system.

The term "heteroaryl" (or heteroaromatic), when used herein, includes 5 to 10 membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur. Said heteroaryl group can comprise one or two rings, of which at least one is aromatic. Substituents on heteroaryl / heteroaromatic groups can, where appropriate, be located on any atom of the ring system, including a hetero atom. The point of attachment of heteroaryl / heteroaromatic groups can be through any atom in the ring system that includes (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may comprise a benzene ring fused to one or more additional aromatic or non-aromatic heterocyclic rings, in which cases, the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be through any ring that includes the ring. of benzene or the heteroaryl / heteroaromatic or heterocycloalkyl ring. Examples of heteroaryl / heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrazolimidyl, pyrazolinyl, pyrazolimidyl, pyrazolynyl, aindinyl, pyrolimidyl , pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzotriazolyl. Heteroaryl / heteroaromatic group oxides are also included within the scope of the invention (eg, the N-oxide). As noted above, heteroaryl includes polycyclic (eg, bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Thus, other heteroaryl groups that may be mentioned include, for example, benzo [1,3] dioxolyl, benzo [1,4] dioxinyl, indolinyl, 5H, 6H, 7H-pyrrolo [1,2-b] pyrimidinyl, 1,2 , 3,4-tetrahydroquinolinyl, and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boron, and preferably oxygen, nitrogen, and sulfur.

For the avoidance of doubt, in cases where the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are in no way interdependent.

For the avoidance of doubt, when R ¹ is defined as

is connected to the rest of formula I by the bond interrupted by the wavy line, and formula I can thus be represented by

Likewise, when R3 is C2-6 alkyl substituted by Z1, and Z1 is represented by

then if for example R3 is C2 alkyl, then formula I can be represented by

The present invention also encompasses isotopically-labeled compounds of the present invention that are identical to those listed here, but by 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 generally found in nature (or the most abundant found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Thus, the compounds of the invention also include deuterated compounds, that is, in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

All individual characteristics (eg, preferred characteristics) mentioned here can be taken in isolation or in combination with any other characteristics (including preferred characteristics) mentioned here (therefore, preferred characteristics can be taken together with other preferred characteristics, or regardless of them).

The skilled person will appreciate that the compounds of the invention that are the subject of this invention include those that are stable. That is, the compounds of the invention include those that are robust enough to survive isolation from, for example, a reaction mixture to a useful degree of purity. Compounds of formula I where R ¹ represents heteroaryl are those where R ¹ represents benzofuran-3-yl, benzothiophene-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5- yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl, and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include those in which R ¹ represents indol-3-yl, indol-4-yl or indol-5-yl, where indolyl is optionally substituted on the nitrogen with -S ( O) ² Ar ^x , where Ar ^x is aryl or heteroaryl, preferably optionally substituted phenyl, eg, unsubstituted phenyl or phenyl substituted at the 4-position with -F, -CI, -CH ³ or -CF ³ .

Preferred compounds of formula I that may be mentioned include those in which R ¹ is represented by

where:

E ³ and E ⁴ represent hydrogen; and

E ¹ represents -F and E ² represents -F, -CI, -CH ³ or -CF ³ ; or

E ¹ represents -Cl and E ² represents -F, -CI, -CH ³ or -CF ³ ; or

E ¹ represents -CH ³ and E ² represents -F, -CI, -CH ³ , -CF ³ or -CN.

Preferred compounds of formula I that may be mentioned are those in which Z ¹ represents -OR ^q2 and R ^q2 represents aryl optionally substituted with one or more substituents selected from W ⁶ , or heteroaryl optionally substituted with one or more substituents selected from W ⁶

The most preferred compounds of formula I that may be mentioned are those where Z ¹ represents -N (R ^f2 ) R ^g2 , R ^f2 represents hydrogen and R ^g2 represents aryl optionally substituted with one or more substituents selected from W ⁶ , or optionally heteroaryl substituted with one or more substituents selected from W ⁶

Other preferred compounds of formula I that may be mentioned are those in which Z ¹ represents -N (R ^o2 ) S (O) ² R ^p2 , R ^o2 represents hydrogen and R ^p2 represents aryl optionally substituted with one or more substituents selected from W ⁶ , or heteroaryl optionally substituted with one or more substituents selected from W ⁶

Preferred compounds of formula I where Z1 represents

that can be mentioned are those where:

(a) each W ⁸ and W ¹⁰ are independently selected from -F, -CI, -CH ³ , -CN, -CF ³ , or more preferably hydrogen and W ⁹ is selected from -R ^a3 , -CN, -C ( O) R ^b3 , -C (O) N (R ^c3 ) R ^d3 , -C (O) OR ^e3 , -N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 , -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3x , -OC ( O) R ^r3 , -OS (O) ² R ^s3 , -S (O) ^m R ^t3 , -S (O) ² N (R ^u3 ) R ^v3 , heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , aryl optionally substituted with one or more substituents selected from G ² or heteroaryl optionally substituted with one or more substituents selected from G ² ; and

(b) each W ⁹ and W ¹⁰ are independently selected from -F, -CI, -CH ³ , -CN, -CF ³ , or more preferably hydrogen and W ⁸ is selected from -R ^a3 , -CN, -C ( O) R ^b3 , -C (O) N (R ^c3 ) R ^d3 , -C (O) OR ^e3 , -N (R ^f3 ) R ^g3 , -N (R ^h3 ) C (O) R ⁱ³ , -N (R ^j3 ) C (O) OR ^k3 , -N (R ^l3 ) C (O) N (R ^m3 ) R ⁿ³ , -N (R ^o3 ) S (O) ² R ^p3 , -OR ^q3x , -OC ( O) R ^r3 , -OS (O) ² R ^s3 , -S (O) ^m R ^t3 , -S (O) ² N (R ^u3 ) R ^v3 , heterocycloalkyl optionally substituted with one or more substituents selected from G ¹ , aryl optionally substituted with one or more substituents selected from G ² , or heteroaryl optionally substituted with one or more substituents selected from G ² .

For example, particular compounds of formula I that may be mentioned include those in which W ⁸ and W ¹⁰ represent hydrogen and W ⁹ represents -F, -CI, -CH ³ , cyclopropyl, -CF ³ , -CN, -NH ² , -N (Ch ³ ) ² , -N (H) C (O) CH ³ , -N (H) C (O) OC (CH ³ ) ³ , -SO ² CH ³ , -SO ² NH ² , -S (O) ² N (CH ³ ) ² , -S (O) ² -4-morpholinyl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-ylmethyl or 1,2,3-thiadiazol-4- ilo; or W ⁹ and W ¹⁰ represent hydrogen and W ⁸ represents -F, -Cl, -CN, -CH ³ , -NMe ² , -S (O) ² NH ² or -S (O) ² NMe ² .

The most particularly preferred compounds of formula I which may be mentioned are those in which W ⁶ represents -F, -CI, -Br, -CH ³ , cyclopropyl, -CF ³ , -CN, -N (CH ³ ) ² , -SO ² CH ³ , -SO ² NH ² and -SO) ² N (CH ³ ) ² .

In one embodiment, the compound according to the invention is selected from the compounds of the Examples described herein.

As discussed hereinabove, the compounds of the invention are referred to as pharmaceuticals. In accordance with a further aspect of the invention, there is provided a compound of the invention, as defined hereinbefore, for use as a pharmaceutical.

In another aspect of the invention, there is provided the use of a compound of the invention, as defined hereinbefore, for the manufacture of a medicament for treating cancer.

Although the compounds of the invention may possess pharmacological activity as such, certain pharmaceutically acceptable (eg, "protected") derivatives of the compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally. and subsequently metabolized in the body to form compounds of the invention. Said compounds (which may possess some pharmacological activity, provided that said activity is appreciably less than that of the "active" compounds to which they are metabolized) can therefore be described as "prodrugs" of the compounds of the invention.

By "prodrug of a compound of the invention", we include compounds that form a compound of the invention, in an experimentally detectable amount, within a predetermined time, after enteral or parenteral administration (eg, oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention.

Furthermore, certain compounds of the invention may possess minimal or no pharmacological activity as such, but can be administered parenterally or orally, and then metabolized in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also include compounds that may possess some pharmacological activity, but that activity is appreciably less than that of the "active" compounds of the invention to which they are metabolized), can also be described as "prodrugs".

Thus, the compounds of the invention are useful in that they possess pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that possess pharmacological activity.

It is stated herein that the compounds of the invention may be useful in treating cancer. For the purposes of this specification, and for the avoidance of doubt, the term "treatment" includes treatment per se, prevention, and prophylaxis.

In an alternative embodiment, the compounds of the invention may be useful in treating cancer.

Preferably, the cancer is selected from the group comprising: soft tissue cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine, (lymphoma, small intestine, (adenocarcinoma) carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, giant cell malignant tumor chordoma, osteochronphroma (osteocartilaginous exostosis), benign chondroma, chondroma, chondroblastoma, chondromixofibroma, osteoid osteoma, and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, retinoblastoma, schizophrenia congenital), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pretumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], thecal granulosa cell tumors, cell tumors Sertoli-Leydig, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood and bone marrow (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin : malignant melanoma, basal cell carcinoma, cell carcinoma squamous, Kaposi's sarcoma, dysplastic nevi moles, lipoma, angioma, dermatofibroma, keloids, psoriasis; neurofibromatosis and adrenal glands: neuroblastoma. The term "cancer cell" as provided herein includes a cell affected by any of the conditions identified above.

In certain embodiments of the present invention, the cancer is a solid tumor cancer.

In certain embodiments of the present invention, the cancer is selected from pancreatic cancer, ovarian cancer, and colorectal cancer.

In certain embodiments of the present invention, the cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, and glioma. In certain embodiments of the present invention, the cancer is selected from non-small cell lung cancer, ovarian cancer, metastatic breast cancer, pancreatic cancer, hepatobiliary cancer (including hepatocellular cancer, bile duct cancer, and cholangiocarcinoma) and gastric cancer.

In certain embodiments of the present invention, the cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer (including hepatocellular cancer, cancer bile duct and cholangiocarcinoma), gastric cancer, testicular cancer, and squamous cell carcinoma of the head and neck.

In certain embodiments of the present invention, the cancer is selected from leukemia (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia), lymphoma (including mantle cell lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma). Hodgkin) and prostate cancer. The compounds of the invention will normally be administered by oral, intravenous, subcutaneous, buccal, rectal, dermal, nasal, tracheal, bronchial, sublingual, intranasal, topical routes, by any other parenteral route or by inhalation, in a pharmaceutically acceptable dosage form.

The compounds of the invention can be administered alone, but are preferably administered by known pharmaceutical compositions / formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

The compounds of the invention (ie, compounds that inhibit MTH1) can be administered in the form of tablets or capsules, for example, extended release capsules that are taken orally. Alternatively, the compounds of the invention can be in liquid form and can be taken orally or by injection. The compounds of the invention can also be in the form of suppositories or creams, gels and foams, for example, which can be applied to the skin. In addition, they can be in the form of an inhalant that is applied through the nose.

Such compositions / formulations can be prepared in accordance with standard and / or accepted pharmaceutical practice.

According to a further aspect of the invention, there is thus provided a pharmaceutical composition / formulation that includes a compound of the invention, as defined hereinbefore, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. Such compositions / formulations may be useful in the treatment, prevention and / or prophylaxis of cancer and diseases that benefit from the inhibition of MTH1.

Depending on, for example, potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%). %, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (that is, the addition of adjuvant, diluent, and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least minus 50:50) by weight.

The invention further provides a process for the preparation of a pharmaceutical formulation, as defined hereinbefore, which process comprises associating a compound of the invention, as defined hereinbefore, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable adjuvant. , diluent or carrier.

Also disclosed herein are methods for treating cancer which comprise administering a therapeutically effective amount of a compound of the invention to a subject (eg, a patient) in need of such treatment.

"Patients" include mammalian patients (including humans).

The term "effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect can be objective (that is, measurable by some test or marker) or subjective (that is, the subject gives an indication or feels an effect).

The compounds of the invention can also be combined with other therapeutic agents that are useful in the treatment of cancer.

In accordance with another aspect of the invention, a combination product is provided comprising:

(A) a compound of the invention, as defined hereinbefore; and

(B) another therapeutic agent that is useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent and therefore may be presented as separate formulations, wherein at least one of those formulations comprises a compound of the invention and at least one it comprises the other therapeutic agent, or it may be presented (ie, formulated) as a combined preparation (ie, presented as a single formulation that includes a compound of the invention and the other therapeutic agent).

Therefore, it is additionally provided:

(1) a pharmaceutical formulation that includes a compound of the invention, as defined hereinbefore, another therapeutic agent that is useful in the treatment of cancer, and a pharmaceutically acceptable adjuvant, diluent, or carrier; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation that includes a compound of the invention, as defined hereinbefore, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier; and

(b) a pharmaceutical formulation that includes another therapeutic agent that is useful in treating cancer in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier, components (a) and (b) of which are each provided in a form that is suitable for administration together with the other.

The invention further provides a process for the preparation of a combination product as defined hereinbefore, which process comprises associating a compound of the invention, as defined hereinbefore, or a pharmaceutically acceptable salt thereof with the other therapeutic agent. which is useful in the treatment of cancer, and at least one pharmaceutically acceptable adjuvant, diluent or carrier.

By "associating", we mean that the two components become suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as defined herein above, by putting the two components "in association" with each other, we include that the two components of the kit of parts can be: (i) provided as separate formulations (ie, independently of each other), which are subsequently put together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

The compounds of the invention can be administered in varying doses. Oral, pulmonary, and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) can range from about 0.01 mg / kg of body weight per day (mg / kg / day) to about 100 mg / kg / day. , preferably from about 0.01 to about 10 mg / kg / day, and more preferably from about 0.1 to about 5.0 mg / kg / day. For example, for oral administration, the compositions typically contain between about 0.01 mg to about 2000 mg, eg, between about 0.1 mg to about 500 mg, or between 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg / kg / hour during constant rat infusion. Advantageously, the compounds can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times a day.

In either case, the physician, or the experienced person, will be able to determine the actual dosage that will be most suitable for an individual patient, which will likely vary with the route of administration, the type and severity of the disease. the condition to be treated, as well as the species, age, weight, sex, kidney function, liver function and response of the particular patient to be treated. The dosages mentioned above are exemplary of the average case; Of course, there may be individual instances where higher or lower dosage ranges are warranted, and these are within the scope of this invention.

The compounds of the invention may also have the advantage that they can be more effective than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (eg, higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical or chemical properties over compounds known in the prior art, either for use in the aforementioned indications otherwise. In particular, the compounds of the invention may have the advantage that they are more effective and / or exhibit advantageous properties in vivo.

It is contemplated that any method or composition described herein may be implemented with respect to any other method or composition described herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Examples

The invention is illustrated by the following examples, in which the following abbreviations may be used. aq watery

DMF dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

EtOH ethanol

MeOH methanol

MeCN acetonitrile

Pd-C palladium on carbon

sat. saturated

TFA trifluoroacetic acid

THF tetrahydrofuran

min. minutes

h. hours

Hünig's base W, W-diisopropylethylamine

DCM dichloromethane

n-BuOH butan-1-ol

iPrOH propan-2-ol

NEt3 trethylamine

Boc tert-butoxycarbonyl

HATU 3-oxide (1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo- [4,5-b] pyridinium hexafluorophosphate NMP N-methylpyrrolidine

LCMS Liquid Chromatography Electrospray Mass Spectroscopy

NMR nuclear magnetic resonance

NCS N-chlorosuccinimide

Pd (PPha) 4 tetrakis (triphenylphosphine) palladium (0)

B (OMe) to trimethyl borate

n-BuLi n-butyl lithium

Mel iodomethane

NaOMe sodium methoxide

CHCl3 chloroform

MgSO4 anhydrous magnesium sulfate

K2CO3 anhydrous potassium carbonate

NH4OH ammonium hydroxide

Ac2O acetic anhydride

POCl3 phosphorus oxychloride

The starting materials and chemical reagents specified in the syntheses described below are commercially available, for example, from Sigma-Aldrich, Fine Chemicals Combi-Blocks, and other suppliers. In the event that there is a discrepancy between the nomenclature and any graphically represented compound, then it is the latter that presides (unless contradicted by any experimental detail that may be given or unless clear from the context). The final compounds were named using Marvin software version 6.1.

Compound purification can be carried out using silica gel column chromatography or preparative reverse phase HPLC (ACE column, acid gradients with MeCN-H2O containing 0.1% TFA or XBridge column, basic gradients using MeCN-H2O containing contains ammonium bicarbonate) to give the products as their free bases or trifluoroacetic acid salts.

Intermediate 18

6-chloro-4-N- (2-phenylethyl) pyrimidine-2,4-diamine.

To a solution of 4,6-dichloropyrimidin-2-amine (66 mg, 0.40 mmol, 1 eq.) In n-BuOH (2.5 mL) was added 2-phenylethanamine (75 j L, 0.60 mmol, 1.1 eq.) and Hünig's base (100 | jg, 0.60 mmol, 1.1 eq.). The reaction mixture was stirred at 95 ° C for 3 h. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H2O, brine, dried over MgSO4, and concentrated to give the desired product as a yellow solid (88mg, 88%). LCMS [M + H] + 249.

Intermediate 19

4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine.

A mixture of 2-amino-4,6-dydoropyrimidine (0.82 g, 5.0 mmol, 1 eq.), 2,3-dimethylphenylboronic acid (0.75 g, 5.0 mmol, 1 eq.), K ² CO ³ (1.38 g, 10.0 mmol, 2 eq.) And palladium tetrakis (triphenylphosphine) palladium (0) (0.12 g, 0.10 mmol, 0.1 eq.) In 1,4-dioxane (20 ml) and water (5 ml) was heated in a tube sealed at 90 ° C for 2.5 hours. The mixture was passed through a plug of silica using EtOAc as eluent, concentrated, and purified by column chromatography (EtOAc / pentane 1: 4) to give the desired product as a white solid (0.76 g, 65% ). LCMS [M + H] ⁺ 234; ¹ H NMR (400 MHz, CD ³ OD) 8 ^hrs 7.21-7.29 (1H, m), 7.20-7.09 (2H, m), 6.70 (1H, s), 2.34 (3H, s), 2.23 (3H, s ).

Intermediate 20

4-chloro-6- (2,3-dichlorophenyl) pyrimidin-2-amine.

A mixture of 4,6-dichloropyrimidin-2-amine (3.28 g, 20.0 mmol), methanamine (12.0 mL, 24.0 mmol; as a 2 M solution in methanol) and Hünig's base in n-butanol (20 mL) was heated at a temperature of 95 ° C overnight. The mixture was concentrated and the crude was taken up in EtOAc (300 ml) and washed with water (3 x 150 ml). The organic layer was dried over MgSO4, filtered and concentrated to give the desired product as a beige solid (2.90 g, 91%). LCMS [M + H] + 159.

Intermediate 22

6-Chloro-4-N- [2- (4-chlorophenyl) ethyl] pyrimidine-2,4-diamine.

A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol), 2- (4-chlorophenyl) ethan-1-amine (0.56 ml, 3.96 mmol) and Hünig's base (0.80 ml, 4.57 mmol) in n-butanol (5 ml) in a sealed tube at 95 ° C overnight. The mixture was concentrated and the crude was taken up in EtOAc (50 ml) and washed with water (3 x 40 ml). The organic layer was dried over MgSO4, filtered and concentrated to give the desired product as a beige solid (0.61 g, 71%). LCMS [M + H] + 283.

Intermediate 24

4-chloro-6- (3-chloro-2-methylphenyl) pyrimidin-2-amine.

A stirred mixture of 2-amino-4,6-dichloropyrimidine (0.50 g, 3.1 mmol), 3-chloro-2-methylphenylboronic acid (0.57 g, 3.4 mmol), Na2CO3 (1.0 g, 9.8 mmol), tetrakis of Palladium (triphenylphosphine) palladium (0) (88 mg, 0.076 mmol), dioxane (22 ml) and water (8 ml) in a sealed tube at 90 ° C for 2 hours. The solvents were removed in vacuo and the remaining solid was added to EtOAc (20 ml) and washed with water. The organic phase was dried over MgSO4 and removed in empty. The crude material was purified by flash chromatography (EtOAc / petroleum ether 1: 4) to give the desired product as a white solid (365mg, 47%). LCMS [M + H] + 254; 1H NMR (400 MHz, DMSO-d6) S ^h ppm 7.52-7.56 (1 H, dd, Chi = 6.5 Hz, J2 = 2.5 Hz) 7.30-7.33 (2 H, m) 7.26 (2 H, s) 6.79 ( 1H, s) 2.32 (3H, s).

Intermediate 35

4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Step 1: To a suspension of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05 mmol) and Hünig's base (0.80 ml) in 2-propanol (3.0 ml) was added N- (2-aminoethyl) carbamate tert-butyl (586 mg, 3.66 mmol) and the mixture was stirred at 150 ° C for 15 min. The crude mixture was poured into NaHCO3 (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (0-10% MeOH in DCM) provided tert-butyl N- [2 - [(2-amino-6-chloro-pyrimidin-4-yl) amino] ethyl] carbamate (850 mg , 2.95 mmol). Step 2: Tert-butyl N- [2 - [(2-amino-6-chloro-pyrimidin-4-yl) amino] ethyl] carbamate (850 mg, 2.95 mmol), boronic acid (2,3- dimethylphenyl) (532 mg, 3.55 mmol), palladium tetrakis (triphenylphosphine) palladium (0) (34 mg, 0.030 mmol) and K ² CO ³ (1020 mg, 7.39 mmol) in 1,4-dioxane (10 ml) and H ² O (2.0 ml). The vial was purged with nitrogen and the resulting mixture was stirred at 90 ° C for 16 h. The crude mixture was poured into NaHCO3 (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (0-10% MeOH in DCM) provided tert N- [2 - [[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino] ethyl] carbamate -butyl (770 mg, 2.15 mmol).

Step 3: Tert-butyl N- [2 - [[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino] ethyl] carbamate (770 mg, 2.15 mmol) was dissolved in TFA ( 6 ml) and the resulting mixture was stirred for 1 h at room temperature, after which the TFA was distilled off. Purification by column chromatography (5-30% MeOH [containing 1% v / v NH ⁴ OH] in DCM) provided 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine -2,4-diamine (500 mg, 1.94 mmol). LCMS [M + H] ⁺ 258.

Intermediate 36

4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Step 1: A vial was filled with 4,6-dichloropyrimidin-2-amine (500mg, 3.0mmol) and tertbutyl N- (2-aminopropyl) carbamate (640mg, 3.7mmol). Then 2-propanol (3.0 ml) and Hünig's base (0.80 ml) were added and the resulting mixture was heated to 150 ° C using microwave irradiation for 15 min. The mixture was then concentrated and purified by column chromatography (2-10% MeOH in DCM) to yield N- [3 - [(2-amino-6-chloropyrimidin-4-yl) amino] propyl] -carbamate of tert-butyl (788 mg, 2.61 mmol).

Step 2: tert-butyl N- [3 - [(2-amino-6-chloro-pyrimidin-4-yl) amino] propyl] carbamate (790 mg, 2.6 mmol), (2,3-dimethylphenyl boronic acid ) (470 mg, 3.1 mmol), palladium tetrakis (triphenylphosphine) palladium (0) (60 mg, 0.050 mmol) and K ² CO ³ (720 mg 5.2 mmol) were suspended in 1,4-dioxane (6.0 ml) and H ² O (1.5 ml). The resulting mixture was heated at 90 ° C for 16 h and then poured into H ² O and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (1- 0% MeOH in DCM) provided tert N- [3 - [[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino] propyl] carbamate -butyl (800 mg, 2.1 mmol). Step 3: Tert-butyl N- [3 - [[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino] propyl] carbamate (800 mg, 2.1 mmol) was dissolved in TFA and heated under reflux for 1 hr. The TFA was evaporated and the crude residue was purified by Column chromatography (2 ^ -30 % MeOH [containing 1 % v / v NH ⁴ OH] in DCM) to produce 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine- 2,4-diamine (540 mg, 2.0 mmol). LCMS [M + H] ⁺ 272.

Intermediate 37

4-chloro-6- (2-chloro-3-methylphenyl) pyrimidin-2-amine.

To a suspension of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq) in dioxane / H2O (5 ml, 4: 1) was added (2-chloro-3-methylphenyl) boronic acid (260 mg, 1.52 mmol, 1 eq) followed by potassium carbonate (421 mg, 3.05 mmol, 2 eq) and Pd (PPh3) 4 (44 mg, 0.04 mmol, 0.025 eq). The resulting mixture was stirred at 90 ° C for 12 h. The solvent was removed in vacuo. The residue was taken up in DMF and purified by preparative to provide the desired product as an off-white solid (166 mg, 43%). LCMS [M + H] + 254; 1H NMR (400 MHz, CDCh) 8h 7.32-7.28 (2H, m), 7.25-7.21 (1H, m), 6.92 (1H, s), 5.31 (2H, brs), 2.42 (3H, s).

Intermediate 39

4-chloro-6- (1H-indol-4-yl) pyrimidin-2-amine.

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1 eq) in dioxane / H ² O (5 ml, 4: 1) was added (1H-indol-4-yl) boronic acid (147 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd (Pph ³ ) ⁴ (26 mg, 0.02 mmol, 0.025 eq). The resulting mixture was stirred at 90 ° C for 12 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to provide the desired product as a yellow solid (111 mg, 50%). LCMS [M + H] ⁺ 245; ¹ H NMR (400 MHz, CDC ^h ) 5 ^h 8.45 (1H, br s), 7.57 (1H, d, J = 7.2 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.35 (1H, t, J = 4.0 Hz), 7.27 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.00-6.99 (1H, m), 5.90 (2H, br s).

General procedures

X = H or Me

General Procedure 2: To a mixture of a suitable chloropyrimidine derivative (1 equiv.) In 1,4-dioxane / water (4: 1) is added the appropriate boronic acid derivative (or boronic ester) (1.3 equiv.), K2CO3 (2 equiv.) And Pd (PPh3) 4 (0.1 equiv.). The mixture is heated at 95 ° C overnight or in a microwave reactor until the reaction is Complete as shown by LCMS. The crude mixture is purified by preparative HPLC to provide the desired product.

X = H, Me

General procedure 3: To a mixture of a suitable doropyrimidine derivative (1 equiv.) Is added Hünig's base (3.4 equiv.) And an appropriate amine (1.6 equiv.) In n-BuOH (500 µl). The mixture is heated to 95 ° C overnight. The crude mixture was purified by preparative HPLC to provide the desired product.

General Procedure 7: A mixture of a suitable 6-aryl-4-chloropyrimidin-2-amine (1 equiv.), A suitable amine (1.5 equiv.) And triethylamine (2 equiv.) In n-butanol (1.5 ml) is heated in a sealed tube at 95 ° C overnight. Concentrated and purified by preparative HPLC to give the desired product.

General Procedure 9: Heat a mixture of a suitable amine (1 equiv.) And a suitable chloropyrimidine derivative (1.2 equiv.) And triethylamine (1.5 equiv.) In 2-propanol (1.0 ml) in a sealed tube at 95 ° C overnight or at 150 ° C for 15 min in a microwave reactor. The reaction mixture is then concentrated and purified by preparative HPLC or silica gel chromatography.

X = CH2, CH2CH2, CH (CHa) 2 or a bond

General procedure 10: a mixture of a 4-N- (aminoalkyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (1.0 equiv.), A suitable sulfonyl chloride (1.2 equiv.) And triethylamine (1.5 equiv.) In DCM or MeCN (1.0 ml) is shaken in a sealed tube at room temperature or 50 ° C. Once complete, the crude mixture is concentrated and purified by preparative HPLC or silica gel chromatography.

General procedure 11: a mixture of 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (1.0 eq.) And the corresponding isocyanate (1.05 eq.) Is dissolved in DCM. The resulting reaction mixture is stirred at room temperature until complete according to LCMS. The mixture is then concentrated and purified by preparative HPLC or silica gel chromatography.

General procedure 12: stir a mixture of 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (1.0 equiv.) And the corresponding heteroaryl chloride (1.5 equiv. ), and Hünig's base (1.5 equiv.) in 2-propanol (0.5 ml) in a sealed tube at 150 ° C in a microwave reactor for 30 min. The crude mixture is then concentrated and purified by preparative HPLC or silica gel chromatography.

Examples

The utility of the compounds of the present invention can be illustrated, for example, by their in vitro activity in the cancer cell viability and clonogenic assay described below. The link between activity in tumor cell clonogenic assay and antitumor activity in the clinical setting has been well established in the art (eg, see ref Silverstini et al Stem Cells 1993, 11 (6), 258-35).

Example 118

6- (2,3-dimethylphenyl) -4-N- (2-phenylethyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 2 from (2,3-dimethylphenyl) boronic acid and 6-chloro-4-N- (2-phenylethyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 319; ¹ H NMR (400 MHz, CD ³ OD) 8 ^h 7.31-7.23 (4H, m), 7.21-7.15 (2H, m), 7.10 (1H, t, J = 7.0 Hz), 7.05 (1H, d, J = 7.0 Hz), 5.77 (1H, s), 3.64-3.50 (2H, m), 2.90 (2H, t, J = 7.6 Hz), 2.31 (3H, s), 2.19 (3H, s).

Example 125

6- (2,3-dimethylphenyl) -4-N- [2- (4-methoxyphenyl) ethyl] pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from 2- (4-methoxyphenyl) ethane-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. ^l C ^m S [M + H] ⁺ 349.

Example 127

6- (2,3-dimethylphenyl) -4-N- [2- (4-methylphenyl) ethyl] pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from 2- (4-methylphenyl) ethan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 333.

Example 128

4-N- [2- (4-chlorophenyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from 2- (4-chlorophenyl) ethane-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 353.

Example 130

6- (2,3-dimethylphenyl) -4-N- (2-phenylpropyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from 2-phenylpropan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 333.

Example 131

6- (2,3-dimethylphenyl) -4-N- (3-phenylpropyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from 3-phenylpropan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 333.

Example 132

6- (2,3-dimethylphenyl) -4-N- (2-phenoxyethyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from (2-aminoethoxy) benzene and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 335.

Example 133

6- (2,3-dimethylphenyl) -4-N- [2- (phenylamino) ethyl] pyrimidine-2,4-diamine.

Prepared according to general procedure 7 from N- (2-aminoethyl) aniline and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 334.

Example 228

6- (2-chloro-3-methylphenyl) -4-N- [2- (4-chlorophenyl) ethyl] pyrimidine-2,4-diamine.

Prepared according to general procedure 3 from 2- (4-chlorophenyl) ethan-1-amine and 4-chloro-6- (2-chloro-3-methylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 373; ¹ H NMR (400 MHz, CD ³ OD) 8 ^h 7.57-7.55 (1H, m), 7.41 (1H, t, J = 7.6 Hz), 7.37 (1H, dd, J = 8.0 and 2.0 Hz), 7.34- 7.28 (4H, m), 6.08 (1H, s), 3.79 (2H, t, J = 7.2 Hz), 2.97 (2H, t, J = 7.2 Hz), 2.49 (3H, s).

Example 231

4-N- [2- (4-chlorophenyl) ethyl] -6- (1H-indol-4-yl) pyrimidine-2,4-diamine.

Prepared according to general procedure 3 from 2- (4-chlorophenyl) ethan-1-amine and 4-chloro-6- (1H-indol-4-yl) pyrimidin-2-amine. LCMS [M + H] ⁺ 364; ¹ H NMR (400 MHz, CD ³ OD) 8 ^h 7.67-7.66 (1H, m), 7.52-7.46 (1H, m), 7.35 7.29 (6H, m), 6.86 (1H, s), 6.44 (1H, s), 3.80 (2H, t, J = 7.2 Hz), 2.95 (2H, t, J = 6.8 Hz).

Example 239 (not according to the invention)

Tert-butyl (3 - ((2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl) amino) -2,2-dimethylpropyl) carbamate.

Prepared according to General Procedure 3 from 4-chloro-6- (3-chloro-2-methylphenyl) pyrimidin-2-amine and tert-butyl N- (3-amino-2,2-dimethylpropyl) carbamate . LCm S [M + H] ⁺ 400.

Example 241

6- (3-chloro-2-methylphenyl) -4-N - [(1R) -1-phenylethyl] pyrimidine-2,4-diamine.

4-chloro-6- (3-chloro-2-methylphenyl) pyrimidin-2-amine (25 mg, 0.098 mmol) and (+) 1-phenylethane-1-amine (0.050 ml) were stirred neat at 150 ° C for 1 hour. The crude material was dissolved in MeOH (2 ml) and purified by preparative HPLC to give the desired product. LCMS [M + H] ⁺ 339; ¹ H NMR (400 MHz, DMSO-d ⁶ ) 5 ^h ppm 9.25 (1 H, d, J = 8.08 Hz) 7.62-7.71 (1 H, m) 7.24-7.47 (7 H, m) 6.23 (0.1 H, s) 6.09 (0.9 H, s) 5.35 (1 H, quin, J = 7.26 Hz) 2.31 (2.7 H, s) 2.13 (0.3 H, s) 1.46-1.57 (3 H, m).

Example 242

6- (3-chloro-2-methylphenyl) -4-N- (2-phenylpropan-2-yl) pyrimidine-2,4-diamine.

4-Chloro-6- (3-chloro-2-methylphenyl) pyrimidin-2-amine (25 mg, 0.098 mmol) and 2-phenylpropan-2-amine (0.050 ml) were stirred neat at 150 ° C for 24 hours. The crude material was dissolved in MeOH (2 ml) and purified by HPLC preparative to give the desired product. LCMS [M + H] +353; 1H NMR (400 MHz, DMSO-d6) S ^h ppm 12.45 (1H, br. S.) 8.96 (1H, br. S.) 7.12-7.79 (8H, m) 6.22 (1H, s) 2.31 (3H, s) 1.79 (6H, br. S.)

Example 247

4-N- [2- (2-dorophenoxy) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

4-doro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (13 mg, 0.054 mmol) and 1- (2-aminoethoxy) -2-chlorobenzene (18 mg, 0.11 mmol) were stirred neat at 150 ° C for 1 hr. The crude material was dissolved in MeOH (1 ml) and purified by preparative HPLC to give the desired product. LCMS [M + H] + 369.

Example 250

6- (2,3-dimethylphenyl) -4-N- [2- (pyridin-3-yloxy) propyl] pyrimidine-2,4-diamine.

4-Chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (12 mg, 0.050 mmol) and 3 - [(1-aminopropan-2-yl) oxy] pyridine (15 mg, 0.10 mmol) were stirred neat at 150 ° C for 1 h. The crude material was dissolved in MeOH (1 ml) and purified by preparative HPLC to give the desired product. LCMS [M + H] + 350.

Example 263

4-N- [2- (4-chlorophenyl) ethyl] -6- (2,3-dichlorophenyl) pyrimidine-2,4-diamine.

A mixture of 4-chloro-6- (2,3-dichlorophenyl) pyrimidin-2-amine (28 mg, 0.10 mmol), 2- (4-chlorophenyl) ethan-1-amine (22 mg, 0.14 mmol) and base Hünig's (36 µl, 0.20 mmol) in n-butanol (2 ml) was heated in a sealed tube at 85 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 393. 1H NMR (400MHz, DMSO-d6) OHppm 12.56 (br s, 1H), 8.90 (br s, 1H), 7.83-7.89 (m, 1H ), 7.51-7.59 (m, 2H), 7.35-7.41 (m, 2H), 7.28-7.34 (m, 2H), 6.11 (s, 1H), 3.63 (q, J = 6.4 Hz, 2 H), 2.89 (t, J = 7.1 Hz, 2H).

Example 266

4-N- [2- (4-chlorophenyl) ethyl] -6- (quinolin-5-yl) pyrimidine-2,4-diamine.

A mixture of 6-chloro-4-N- [2- (4-chlorophenyl) ethyl] pyrimidine-2,4-diamine (34 mg, 0.12 mmol), (quinolin-5-yl) boronic acid (25 mg, 0.14 mmol), potassium carbonate (33 mg, 0.24 mmol) and palladium tetrakis (triphenylphosphine) palladium (0) (7 mg, 0.006 mmol) in 1,4-dioxane / water (4 ml; 4: 1) was heated in a sealed tube at 90 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 376.

Example 267

4-N- [2- (4-chlorophenyl) cyclopropyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (28 mg, 0.12 mmol), 2- (4-chlorophenyl) cyclopropan-1-amine (43 mg, 0.26 mmol) and base Hünig's (90 µl, 0.52 mmol) in n-butanol (2 ml) was heated in a sealed tube at 85 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 365. Example 269

3- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) phenol.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (28 mg, 0.12 mmol), 3- (2-aminoethyl) phenol (23 mg, 0.17 mmol) and Hünig's base (42 pL, 0.24 mmol) in n-butanol (2 ml) was heated in a sealed tube at 85 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 335.

Example 295

4- N - {[1- (4-chlorophenyl) cyclopropyl] methyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (47 mg, 0.20 mmol), [1- (4-chlorophenyl) cyclopropyl] methanamine hydrochloride (65 mg, 0.30 mmol) was heated ) and Hünig's base (70 µl, 0.40 mmol) in n-butanol (1.5 ml) in a sealed tube at 130 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 379.

Example 296

4- (2 - {[2-amino-6- (2,3-dichlorophenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide.

A mixture of 4-doro-6- (2,3-doorophenyl) pyrimidin-2-amine (41 mg, 0.15 mmol), 4- (2-aminoethyl) benzene-1-sulfonamide (45 mg, 0.23 mmol) was heated and Hünig's base (39 µl, 0.23 mmol) in n-butanol (2 ml) in a sealed tube at 90 ° C for 48 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 438. Example 297

4- (2 - {[2-amino-6- (3-chloro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide.

A mixture of 4-chloro-6- (3-chloro-2-methylphenyl) pyrimidin-2-amine (38 mg, 0.15 mmol), 4- (2-aminoethyl) benzene-1-sulfonamide (45 mg, 0.23 mmol) and Hünig's base (39 µl, 0.23 mmol) in n-butanol (2 ml) in a sealed tube at 90 ° C for 48 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] + 418. 1H NMR (400 MHz, DMSO-d6) 8h ppm 12.33 (br. S., 1H), 8.89 (br. S., 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.64-7.68 (m, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.37-7.41 (m, 2H), 7.32 (s, 2H), 6.03 (s , 1H), 3.67 (q, J = 6.7Hz, 2H), 2.98 (t, J = 7.1Hz, 2H), 2.30 (s, 3H).

Example 301

4- (2 - {[2-Amino-6- (2,3-dichlorophenyl) pyrimidin-4-yl] amino} ethyl) phenol.

A mixture of 4-chloro-6- (2,3-dichlorophenyl) pyrimidin-2-amine (25 mg) and 4- (2-aminoethyl) phenol (50 mg) was heated at 150 ° C for 1 h. The mixture was cooled, diluted in methanol, and then purified by preparative HPLC. LCMS [M + H] + 375.

Example 330

4- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (0.12 mmol), 4- (2-aminoethyl) benzene-1-sulfonamide (0.9 eq.) And triethylamine (1.5 eq.) in acetonitrile / ethanol / methanol 5: 3: 2 (1 ml) heated in a sealed tube at 95 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] + 398; 1H NMR (400 MHz, DMSO-d6) 5h ppm 12.28 (1H, br. S.), 8.87 (1H, br. S.), 7.77 (2H, d, J = 8.34 Hz), 7.48 (2 H, d, J = 8.34 Hz), 7.37 (1 H, d, J = 7.33 Hz), 7.32 (2 H, s), 7.23-7.28 (1 H, m), 7.18-7.23 (1 H, m) , 5.99 (1 H, s), 3.67 (2 H, q, J = 6.82 Hz), 2.98 (2 H, t, J = 7.20 Hz), 2.31 (3 H, s), 2.17 (3 H, s) .

Example 331

6- (2,3-Dimethylphenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (0.15 mmol), 2- (4-methanesulfonylphenyl) ethane-1-amine (1.2 eq.) And N, N-diisopropylethylamine ( 2.25 eq.) In n-butanol (0.3 ml) was heated in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] + 397.

Example 333

4- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) benzonitrile.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (0.15 mmol), 4- (2-aminoethyl) benzonitrile (1.2 eq.) And N, N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 ml) was heated in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] + 344; 1H NMR (400 MHz, DMSO-d6) OHppm 12.36 (1H, br. S.), 8.87 (1H, t, J = 5.31 Hz), 7.80 (2 H, d, J = 8.08 Hz), 7.51 ( 2 H, d, J = 8.34 Hz), 7.37 (1 H, d, J = 7.33 Hz), 7.23-7.28 (1 H, m), 7.16-7.22 (1 H, m), 5.98 (1 H, s ), 3.67 (2H, q, J = 6.65Hz), 2.99 (2H, t, J = 7.20Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 335

4- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethoxy) benzonitrile.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (0.15 mmol), 4- (2-aminoethoxy) benzonitrile (1.2 eq.) And N, N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 ml) was heated in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] + 360; 1H NMR (400MHz, DMSO-d6) ^5h ppm 12.37 (1H, br. S.), 9.02 (1H, t, J = 5.31 Hz), 7.77-7.83 (2H, m), 7.37 (1 H, d, J = 7.33 Hz), 7.23-7.29 (1 H, m), 7.18-7.22 (1 H, m), 7.12-7.18 (2 H, m), 6.06 (1 H, s), 4.29 ( 2H, t, J = 5.43Hz), 3.82 (2H, q, J = 5.22Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 341

4-N- [2- (3-Chlorophenyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 2- (3-chlorophenyl) ethan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 353; ¹ H NMR (400 MHz, CDCI ³ ) 8 ^h ppm 2.24 (s, 3H) 2.31 (s, 3H) 2.88 (t, J = 7.07 Hz, 2H) 3.56 (d, J = 5.81 Hz, 2H ) 4.86-5.12 (m, 3H) 5.79 (s, 1H) 7.07-7.15 (m, 3H) 7.17 (q, J = 4.04 Hz, 1H) 7.20-7.26 (m, 3H).

Example 343

4-N- [2- (4-Chlorophenyl) propyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 9 from 2- (4-chlorophenyl) propan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 367; ¹ H NMR (400 MHz, CDCl ³ ) 8h ppm 1.31 (d, J = 7.07 Hz, 3H) 2.23 (s, 3H) 2.31 (s, 3H) 2.97-3.09 (m, 1H) 3.28-3.40 (m, 1H) 3.46-3.66 (m, 1H) 4.74 (br s, 1H) 4.95 (br s, 2H) 5.74 (s, 1H) 7.09-7.14 (m, 2H ) 7.14-7.19 (m, 3H) 7.28-7.33 (m, 2H).

Example 344

6- (2,3-Dimethylphenyl) -4-N- [2- (4-fluorophenyl) ethyl] pyrimidine-2,4-diamine.

Hz, 3 H) 5.77 (s, 4 H) 7.00-7.07 (m, 3 H) 7.08-7.12 (m, 2 H) 7.13-7.22 (m, 5 H) 7.28-7.32 (m, 1 H).Prepared according to general procedure 9 from 2- (4-fluorophenyl) ethane-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 337; ¹ H NMR (400 MHz, CDCl ³ ) 5h ppm 2.23 (s, 3H) 2.29-2.34 (m, 3H) 2.89-2.96 (m, 3H) 3.49-3.60 (m, 1H) 3.76 (d, J = 6.06

Hz, 3H) 5.77 (s, 4H) 7.00-7.07 (m, 3H) 7.08-7.12 (m, 2H) 7.13-7.22 (m, 5H) 7.28-7.32 (m, 1H).

Example 347

4-N- [2- (benzenesulfonyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 2- (benzenesulfonyl) ethan-1-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] ⁺ 383; ¹ H NMR (400 MHz, CDCl ³ ) 5 ^h ppm 2.22 (s, 3H) 2.31 (s, 3H) 3.41 3.46 (m, 2H) 3.86 (q, J = 6.06 Hz, 2H) 5.10 (br s., 2H) 5.41-5.53 (m, 1H) 5.76 (s, 1H) 7.07-7.16 (m, 2H) 7.16-7.20 (m, 1H) 7.57-7.63 (m, 2H) 7.66-7.71 (m, 1H) 7.92-7.97 (m, 2H).

Example 357

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4-chlorobenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 4-chlorobenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 446; ¹ H NMR (400 MHz, CDCl ³ ) 5 ^h ppm 1.72 (quin, J = 6.06 Hz, 2 H) 2.21 (s, 3 H) 2.30 (s, 3 H) 2.90 (d, J = 5.05 Hz, 2 H ) 3.49 (q, J = 6.32 Hz, 2H) 3.44-3.52 (m, 2H) 5.33-5.43 (m, 1H) 5.57 (br. S., 2H) 5.78 (s, 1H) 7.05- 7.09 (m, 1H) 7.09-7.13 (m, 1H) 7.16-7.20 (m, 1H) 7.41-7.46 (m, 2H) 7.79-7.84 (m, 2H).

Example 358

3- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (4-chlorophenyl) urea.

Prepared according to general procedure 11 from 1-chloro-4-isocyanatobenzene and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 425; ¹ H NMR (400 MHz, CD ³ OD) 5h ppm 1.85 (t, J = 6.69 Hz, 2H) 2.23 (s, 3H) 2.34 (s, 3H) 3.28 (overlap with methanol) 3.50-3.61 (m , 2H) 5.97 (s, 1H) 7.15 (s, 1H) 7.17-7.25 (m, 3H) 7.28-7.37 (m, 3H).

Example 359

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3,5-dimethyl-1,2-oxazole-4-sulfonamide.

Prepared according to General Procedure 10 from dimethyl-1,2-oxazole-4-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4- diamine. LCMS [M + H] ⁺ 431; ¹ H NMR (400 MHz, CDCl ³ ) 5h ppm 1.79 (br quin, J = 6.0 Hz, 2H) 2.23 (s, 3H) 2.30 (s, 3H) 2.42 (s, 3H) 2.64 (s , 3H) 3.01 (brq, J = 5.90 Hz, 2H) 3.53 (brq, J = 6.00 Hz, 2H) 5.89 (s, 1H) 7.05-7.13 (m, 2H) 7.18- 7.21 (m, 1H).

Example 361

3- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (2,6-dichloropyridin-4-yl) urea.

Prepared according to General Procedure 11 from 2,6-dichloro-4-isocyanatopyridine and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] + 460; 1H NMR (400 MHz, CDCl3) 8h ppm 1.86 (br. Quint, J = 6.7 Hz, 2H) 2.24 (s, 3H) 2.34 (s, 3H) 3.30-3.34 (m [overlay with MeOH], 2H ) 3.55 (br. S., 3H) 5.98 (s, 1H) 7.11-7.24 (m, 2H) 7.27-7.33 (m, 1H) 7.46 (s, 2H).

Example 362

3- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (3,4-difluorophenyl) urea.

Prepared according to general procedure 11 from 1,2-difluoro-4-isocyanatobenzene and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] + 427; 1H NMR (400 MHz, CDCh) 8h ppm 1.81 1.89 (m, 2H) 2.24 (s, 3H) 2.34 (s, 3H) 3.25-3.30 (m [overlay with MeOH], 2H) 3.55 (br. S ., 2H) 5.98 (s, 1H) 6.94-7.01 (m, 1H) 7.06-7.17 (m, 2H) 7.17-7.23 (m, 1H) 7.27-7.33 (m, 1H) 7.45- 7.54 (m, 1H).

Example 363

N- [3- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propoxy) phenyl] acetamide.

Prepared according to General Procedure 9 from N- [3- (3-aminopropoxy) phenyl] acetamide and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCMS [M + H] + 406; 1H NMR (400 MHz, DMSO-d6) 8h ppm 1.96 (t, J = 6.32 Hz, 2H) 2.02 (s, 3H) 2.15 (s, 3H) 2.25 (s, 3H) 4.00 (t, J = 6.32 Hz, 2H) 5.70 (s, 1H) 5.92 (br. S., 2H) 6.61 (dd, J = 8.46, 1.64 Hz, 1H) 6.85-6.99 (m, 1H) 6.99-7.10 (m, 3H) 7.11-7.19 (m, 2H) 7.31 (s, 1H) 9.88 (s, 1H). A signal from one of the CH2 groups overlaps with the solvent peaks and is not observed by NMR.

Example 367

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-bromobenzamide.

4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (1.0 eq) was dissolved in THF (0.50 ml) and NMP (0.050 ml), then Et3N ( 1.5 eq) and 3-bromobenzoyl chloride (1.2 eq). The resulting reaction mixture was stirred at room temperature overnight. The mixture was then concentrated and purified by column chromatography. LCMS [M + H] + 454; 1H NMR (400 MHz, CDCh) 8h ppm 1.80-1.89 (m, 2H) 2.23 (s, 3H) 2.30 (s, 3H) 2.37 2.59 (m, 1H) 3.47-3.58 (m, 4H) 5.14 (br. S., 2H) 5.55-5.69 (m, 1H) 5.85 (s, 1H) 7.07-7.13 (m, 2H) 7.17 (dd, J = 6.19, 2.91 Hz, 1H) 7.31 (t, J = 7.83 Hz, 1 H) 7.63 (ddd, J = 7.89, 1.96, 1.01 Hz, 1 H) 7.75 (dd, J = 7.83, 1.01 Hz, 1 H) 7.98 (t, J = 1.77 Hz, 1 HOUR).

Example 368

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzamide.

In a vial, 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (1.0 eq) was dissolved in NMP (0.050 ml) and THF (0.50 ml), then Et3N (1.5 eq) and benzoyl chloride (1.0 eq) were added. The resulting reaction mixture was stirred at room temperature for 1 hr. The mixture was then concentrated and purified by column chromatography. LCMS [M + H] + 376; 1H NMR (400 MHz, CDCh) 8 ppm 1.86 (t, J = 6.06 Hz, 2H) 2.22 (s, 3H) 2.29 (s, 3H) 3.54 (dt, J = 12.32, 6.09 Hz, 4H) 5.36-5.54 (m, 1H) 5.89 (s, 1H) 6.14-6.31 (m, 1H) 7.06-7.13 (m, 2H) 7.16-7.20 (m, 1H) 7.40-7.46 (m, 2 H) 7.47-7.53 (m, 1H) 7.80-7.85 (m, 2H).

Example 374

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-cyanobenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 3-cyanobenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] + 437; 1H NMR (400 MHz, CDCh) 8h ppm 1.70 1.82 (m, 4H) 2.23 (s, 3H) 2.31 (s, 3H) 2.98 (d, J = 5.31 Hz, 2H) 3.54 (d, J = 5.81 Hz, 2H) 4.71-4.80 (m, 1H) 5.29 (br. S., 2H) 5.76 (s, 1H) 7.07-7.21 (m, 3H) 7.59-7.65 (m, 1H) 7.82 (dt, J = 7.64, 1.36 Hz, 1H) 8.14 (dq, J = 7.96, 0.97 Hz, 1H) 8.18-8.21 (m, 1H).

Example 375

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4-methanesulfonylbenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 4-methanesulfonylbenzene-1-sulfonyl chloride and 4- N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] + 490; 1H NMR (400 MHz, CDCh) 8h ppm 1.73-1.80 (m, 2H) 2.23 (s, 3H) 2.32 (s, 3H) 2.95-3.01 (m, 2H) 3.08 (s, 3H) 3.51 -3.58 (m, 2H) 4.69-4.77 (m, 1H) 5.31 (s, 2H) 5.77 (s, 1H) 7.08-7.21 (m, 3H) 8.09 (q, J = 8.76 Hz, 4 H).

Example 376

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzenesulfonamide.

Prepared according to General Procedure 10 from benzenesulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 412; ¹ H NMR (400 MHz, CDCl ^a ) 8 ppm 1.72 (dt, J = 12.06, 5.97 Hz, 2H) 1.76-1.89 (m, 1H) 2.22 (s, 3H) 2.31 (s, 3H) 2.93 (q, J = 6.15 Hz, 2H) 3.49 (q, J = 6.40 Hz, 2H) 4.70-4.82 (m, 1H) 5.28 (br. s., 2H) 5.72-5.74 (m, 1H ) 7.08-7.15 (m, 2H) 7.16-7.20 (m, 1H) 7.45-7.51 (m, 2H) 7.52-7.57 (m, 1H) 7.87-7.92 (m, 2H).

Example 377

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -3-fluorobenzene-1-sulfonamide.

Step 1: tert-butyl N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) carbamate (prepared in Example 239) (180 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (2 ml) and stirred under reflux for 1 hr. The TFA was evaporated and the crude residue was purified by silica gel chromatography using a gradient of 2-30% MeOH [containing ^{1% v / v NH 4} OH] in DCM which provided 4-N- (3- amino-2,2-dimethyl-propyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (110 mg, 0.37 mmol). LCMS [M + ^h ] + 300.

Step 2: N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -3-fluorobenzene-1-sulfonamide was prepared according with general procedure 10 starting from 3-fluorobenzene-1-sulfonyl chloride and 4-N- (3-amino-2,2-dimethyl-propyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4 -diamine (prepared in step 1). LCMS [M + H] ⁺ 458; ¹ H NMR (400 MHz, CDCl ^a ) 8h ppm 0.92 (s, 6H) 2.16-2.20 (m, 3H) 2.29 (s, 3H) 2.69 (d, J = 7.07 Hz, 2H) 3.38 (d , J = 6.82 Hz, 2H) 5.91 (s, 1H) 6.53 (s, 1H) 7.04-7.08 (m, 1H) 7.09-7.15 (m, 1H) 7.23-7.30 (m, 1H) 7.38-7.45 (m, 1H) 7.46-7.56 (m, 2H) 7.64 (d, J = 7.83 Hz, 1H).

Example 378

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -4- (morpholin-4-sulfonyl) benzene-1-sulfonamide . Step 1: tert-butyl N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) carbamate (prepared in Example 239) (180 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (2 ml) and stirred under reflux for 1 hr. The TFA was evaporated and the crude residue was purified by silica gel chromatography using a gradient of 2-30% MeOH [containing ^{1% v / v NH 4} OH] in DCM which provided 4-N- (3- amino-2,2-dimethyl-propyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (110 mg, 0.37 mmol). LCMS [M + H] ⁺ 300.

Step 2: N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -4- (morpholin-4-sulfonyl) benzene- 1-sulfonamide was prepared according to general procedure 10 from 4- (morpholin-4-sulfonyl) benzene-1-sulfonyl chloride and 4-N- (3-amino-2,2-dimethyl-propyl) - 6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine (prepared in step 1 above). LCMS [M + H] ⁺ 589; ^1H NMR (400 MHz, CDCH) 8h ppm 0.92 (s, 6 H) 2.18 (d, J = 0.51 Hz, 3 H) 2.28 (s, 3 H) 2.71 (d, J = 6.82 Hz, 2 H) 2.99 -3.06 (m, 4H) 3.38 (d, J = 6.82 Hz, 2H) 3.70-3.78 (m, 4H) 5.93 (s, 1H) 6.94 (s, 1H) 7.03-7.08 (m, 1 H) 7.09-7.15 (m, 1 H) 7.25 (d, J = 7.58 Hz, 1 H) 7.42 (s, 1 H) 7.87 (d, J = 8.59 Hz, 2 H) 8.02 (d, J = 8.59 Hz , 2H).

Example 381

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-fluorobenzene-1-sulfonamide.

Prepared according to General Procedure 9 from 3-fluorobenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 430.

Example 382

N- {4 - [(3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) sulfamoyl] -phenyl} acetamide.

Prepared according to General Procedure 10 from 4-acetamidobenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 469.

Example 384

N- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -3-fluorobenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 3-fluorobenzene-1-sulfonyl chloride and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 416.

Example 385

N- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -4-methoxybenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 4-methoxybenzene-1-sulfonyl chloride and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 428.

Example 388

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4,5-dydorothiophene-2-sulfonamide.

Prepared according to General Procedure 10 from 4,5-dichlorothiophene-2-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCm S [M + H] ⁺ 486.

Example 389

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide.

Prepared according to General Procedure 10 from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) -pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 464.

Example 391

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1,2-dimethyl-1H-imidazole-4-sulfonamide.

Prepared according to General Procedure 10 from 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidin-2, 4-diamine. LCMS [M + H] ⁺ 430; ¹ H NMR (400 MHz, CD ³ OD) Sh ppm 7.69 (s, 2H), 7.33-7.38 (m, 1H), 7.21-7.27 (m, 1H), 7.16-7.20 (m, 1H) , 6.00 (s, 1H), 3.71 (s, 3H), 3.58 (s, 2H), 3.06 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.80-1.90 (m, 2H).

Example 392

N- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide.

Prepared according to General Procedure 10 from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) -pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 450.

Example 393

4-N- {2 - [(1,3-benzoxazol-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 12 from 2-chloro-1,3-benzoxazole and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 375.

Example 394

6- (2,3-Dimethylphenyl) -4-N- (4-phenylbutan-2-yl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 9 from 4-phenylbutan-2-amine and 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine. LCm S [M + H] ⁺ 347.

Example 397

6 - [(2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-3-carbonitrile.

Prepared according to General Procedure 12 from 6-chloropyridine-3-carbonitrile and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 360; ¹ H NMR (400 MHz, CD ³ OD) 8h ppm 8.32-8.34 (m, 1H), 7.59-7.64 (m, 1H), 7.34-7.38 (m, 1H), 7.22-7.27 (m, 2 H), 7.15-7.18 (m, 1H), 6.55-6.59 (m, 1H), 5.97 (s, 1H), 3.72 3.77 (m, 3H), 3.66-3.71 (m, 3H), 2.36 (s, 4H), 2.24 (s, 3H).

Example 398

4-N- {2 - [(3-Bromo-1,2,4-thiadiazol-5-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 12 from 3-bromo-5-chloro-1,2,4-thiadiazole and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidin-2, 4-diamine. LCMS [M + H] ⁺ 420.

Example 401

N- (2 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -4-methanesulfonylbenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 4-methanesulfonylbenzene-1-sulfonyl chloride and 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 476; ¹ H NMR (400 MHz, CD ³ OD) 8 ^h ppm 8.10-8.14 (m, 3H), 8.05-8.09 (m, 3H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1H), 7.05-7.08 (m, 1H), 5.73-5.76 (m, 1H), 3.42-3.49 (m, 2H), 3.14 (s, 6H), 2.31 (s, 4H), 2.18 (s, 3H).

Example 402

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-methanesulfonylbenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 3-methanesulfonylbenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 490; ¹ H NMR (400 MHz, CDC ^h ) 5 ^h ppm 8.43- 8.45 (m, 1 H), 8.18 (ddd, J = 7.8, 1.8, 1.0 Hz, 3 H), 8.11 (ddd, J = 7.8, 1.8, 1.0 Hz, 3H), 7.67-7.73 (m, 1H), 7.15 7.19 (m, 1H), 7.09-7.13 (m, 1H), 7.08 (d, J = 2.0 Hz, 1H), 5.74 (s, 1H), 5.31 (br. s., 2H), 4.82-5.00 (m, 1H), 3.50 (d, J = 5.8Hz, 2H), 3.09 (s, 3H), 2.94 (d, J = 4.0 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 1.71 (t, J = 5.8 Hz, 2H).

Example 403

N- (3 - {[2-Amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -2-methanesulfonylbenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 2-methanesulfonylbenzene-1-sulfonyl chloride and 4-N- (3-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 490; ¹ H NMR (400 MHz, CD ³ OD) 5 ^h ppm 8.20-8.33 (m, 3H), 8.10-8.17 (m, 1H), 7.84-7.90 (m, 5H), 7.68-7.80 (m, 3H), 7.16-7.21 (m, 3H), 7.12 (s, 3H), 7.08 (d, J = 1.5 Hz, 3H), 5.74 (s, 3H), 3.46 (s, 3H), 3.43 (s, 8H), 3.32-3.36 (m, 3H), 3.07 (t, J = 6.7 Hz, 5H), 2.31 (s, 8H), 2.19 (s, 3H), 1.66 (t , J = 6.7 Hz, 5H).

Example 414

4- (2 - {[2-amino-6- (3-chloro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide.

A mixture of 4-chloro-6- (3-chloro-2-methyl-phenyl) pyrimidin-2-amine (0.14 mmol), 4- (2-aminoethyl) -N, N-dimethylbenzenesulfonamide (1.0 eq.) Was heated. and N, N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 ml) in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] ⁺ 446. Example 415

4- (2 - {[2-amino-6- (2,3-dichlorophenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide.

A mixture of 4-chloro-6- (2,3-dichlorophenyl) pyrimidin-2-amine (0.13 mmol), 4- (2-aminoethyl) -N, N-dimethylbenzenesulfonamide (1.0 eq.) And N, N-diisopropylethylamine (2.25 eq.) In n-butanol (0.3 ml) was heated in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] ⁺ 466.

Example 416

4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (0.15 mmol), 4- (2-aminoethyl) -N, N-dimethylbenzenesulfonamide (1.0 eq.) And N, N-diisopropylethylamine (2.25 eq.) In n-butanol (0.3 ml) was heated in a sealed tube at 110 ° C overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M + H] ⁺ 426.

Example 417

4-N- {1 - [(4-Chlorophenyl) methyl] cyclopropyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

A mixture of 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine (47 mg, 0.20 mmol), 1 - [(4-chlorophenyl) methyl] cyclopropan-1-amine hydrochloride (52 mg, 0.24 mmol) and triethylamine (50 µL, 0.36 mmol) in n-butanol (3 ml) in a sealed tube at 130 ° C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M + H] ⁺ 379.

Example 423

4-N- [2- (4-Chlorophenyl) ethyl] -6- (1H-pyrrol-2-yl) pyrimidin-2,4-diamine.

Prepared according to General Procedure 10 from 6-chloro-4-N- [2- (4-chlorophenyl) ethyl] pyrimidine-2,4-diamine and (1-tert-butoxycarbonylpyrrol-2-yl) boronic acid . The t-butoxycarbonyl group was removed during the work up. LCMS [M + H] ⁺ 314; ¹ H NMR (400 MHz, CD ³ OD) S ^h ppm 7.29-7.33 (m, 5H), 7.27 (s, 2H), 7.10-7.13 (m, 1H), 6.88-6.92 (m, 1H ), 6.33-6.37 (m, 1H), 6.12 (s, 1H), 3.70-3.76 (m, 2H), 2.91-2.96 (m, 2H).

Example 424

N- (4 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} butyl) -4-methanesulfonylbenzene-1-sulfonamide.

Prepared according to General Procedure 10 from 4- (methylsulfonyl) -benzenesulfonyl chloride and 4-N- (4-aminobutyl) -6- (2,3-dimethylphenyl) -pyrimidine-2,4-diamine. LCMS [M + H] ⁺ 504; ¹ H NMR (400 MHz, CD ³ OD) S ^h ppm 8.12 8.17 (m, 2H), 8.06-8.10 (m, 2H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1 H), 7.05-7.09 (m, 1H), 5.76-5.79 (m, 1H), 3.18 (s, 3H), 2.94-2.99 (m, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 1.50-1.66 (m, 4H).

Example 426

4- (2 - {[2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide.

Prepared according to General Procedure 2 from 4- [2 - [(2-amino-6-chloro-pyrimidin-4-yl) amino] ethyl] benzenesulfonamide and 3-cyano-2-methyl-benzeneboronic acid. LCMS [M + H] ⁺ 409; ¹ H NMR (400 MHz, CD ³ OD) OR ^H ppm 7.80-7.86 (m, 2 H), 7.70 (dd, J = 7.8, 1.3 Hz, 1 H), 7.53 (d, J = 6.8 Hz, 1 H ), 7.37-7.47 (m, 3H), 5.80 (s, 1H), 3.65 (br. S., 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.49 (s, 3H ).

Example 441

4-N- {2 - [(6-chloropyridazin-3-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 12 from 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine and 3,6-dichloropyridazine. [M + H] ⁺ 370.

Example 442

2 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-4-carbonitrile.

Prepared according to General Procedure 12 from 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine and 2-chloropyridine-4-carbonitrile. LCMS [M + H] ⁺ 360.

Example 443

6 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-3-sulfonamide.

Prepared according to General Procedure 12 from 4-N- (2-aminoethyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine and 6-chloropyridine-3-sulfonamide. LCMS [M + H] ⁺ 414.

Example 444

1-N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzene-1,4-disulfonamide.

Prepared according to General Procedure 10 from 4-N- (4-aminopropyl) -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine and 4- (aminosulfonyl) benzenesulfonyl chloride. LCMS [M + H] ⁺ 491; ¹ H NMR (400 MHz, CD ³ OD) S ^h ppm 8.04- 8.08 (m, 2 H), 7.98-8.02 (m, 2 H), 7.28 (d, J = 7.1 Hz, 1 H), 7.16-7.22 (m, 1 H), 7.15 (d, J = 1.5 Hz, 1 H), 5.91 (s, 1 H), 3.48 (d, J = 1.5 Hz, 2 H), 2.98 (t, J = 6.8 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.78 (t, J = 6.8 Hz, 2H).

Example 445

6- (2,3-dichlorophenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine.

Prepared according to General Procedure 2 from 6-chloro-4-N- [2- (4-methylsulfonylphenyl) ethyl] pyrimidine-2,4-diamine and 2,3-dichlorobenzene boronic acid. LCMS [M + H] ⁺ 437; ¹ H NMR (400 MHz, CD ³ OD) S ^h ppm 7.90 (d, J = 8.6 Hz, 2 H), 7.78 (t, J = 4.9 Hz, 1 H), 7.56 (d, J = 8.6 Hz, 2 H), 7.49 (dd, J = 4.9, 0.6 Hz, 2H), 6.08 (s, 1H), 3.84 (s, 2H), 3.06-3.11 (m, 5H).

Example 447

6- (2,3-dimethylphenyl) -4-N- {2 - [(3-methoxyphenyl) amino] ethyl} pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 4-doro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and N '- (3-methoxyphenyl) ethane-1,2-diamine. LCMS [M + H] ⁺ 364; 1H NMR (400 MHz, CDCh) Sh ppm 7.18-7.26 (m, 1H), 7.01-7.07 (m, 1H), 6.96-7.00 (m, 1H), 6.95 (t, J = 2.0 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.76 (dd, J = 8.3, 2.0 Hz, 1 H), 5.91 (s, 1 H), 3.82 (d, J = 4.8 Hz, 2 H ), 3.75 (s, 3H), 3.48 (br. S., 2H), 2.24 (s, 3H), 2.10 (s, 3H).

Example 448

6- (2,3-dimethylphenyl) -4-N- {2 - [(3-fluoro-4-methylphenyl) amino] ethyl} pyrimidine-2,4-diamine.

Step 1: A vial was filled with 2-fluoro-4-iodo-1-methyl-benzene (240 mg, 1.0 mmol), ethane-1,2-diamine (0.20 ml, 3.0 mmol), CuCl (9.9 mg, 0.10 mmol) and KOH (110 mg, 2.0 mmol). The vial was then purged with nitrogen and sealed. The mixture was stirred at room temperature for 16h, after that the mixture was extracted with EtoAc. The combined organic phases were dried, concentrated and purified by column chromatography to provide N '- (3-fluoro-4-methyl-phenyl) ethane-1,2-diamine.

Step 2: A mixture of 6- (2,3-dimethylphenyl) -4-chloropyrimidin-2-amine (30 mg, 0.13 mmol), N '- (3-fluoro-4-methyl-phenyl) ethane-1 was heated , 2-diamine (20 mg, 0.12 mmol) and diisopropylethylamine (0.040 ml, 0.23 mmol) in 2-propanol (0.50 ml) in a sealed tube at 150 ° C for 30 min in a microwave reactor. The reaction mixture was then concentrated and purified by preparative HPLC. LCMS [M + H] ⁺ 366; 1H NMR (400 MHz, CD ³ OD) S ^h ppm 7.33 7.37 (m, 1H), 7.21-7.27 (m, 1H), 7.15-7.18 (m, 1H), 6.93-6.99 (m, 1H ), 6.38-6.45 (m, 2H), 5.99 (s, 1H), 3.72 (s, 2H), 3.39 (s, 2H), 2.36 (s, 3H), 2.24 (s, 3H ), 2.11 (d, J = 1.5 Hz, 3H).

Example 449

4-N- {2 - [(3,4-dichlorophenyl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and N '- (3,4-dichlorophenyl) ethane-1,2-diamine. LCMS [M + H] ⁺ 402; 1H NMR (400 MHz, CD ³ OD) S ^h ppm 7.33-7.37 (m, 1H), 7.24 (s, 1H), 7.18 (m, 2H), 6.76 (d, J = 2.8 Hz, 1H ), 6.57 (dd, J = 8.8, 2.8 Hz, 1H), 5.97 (s, 3H), 3.69-3.73 (m, 2H), 3.37 3.42 (m, 2H), 2.35 (s, 3H ), 2.23 (s, 3H).

Example 450

4-N- {2 - [(5-chloropyridin-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to General Procedure 9 from 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and N '- (5-chloro-2-pyridyl) ethane-1,2-diamine. LCMS [M + H] ⁺ 369; 1H NMR (400 MHz, CDCh) Sh ppm 7.61-7.69 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.10-7.22 (m, 3H), 6.17 (br. S., 1H), 3.71 (br. S., 4H), 2.33 (s, 3H), 2.24 (s, 3H).

Example 451

4-N- {2 - [(5-bromopyridin-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and N '- (5-bromo-2-pyridyl) ethane-1,2-diamine. LCMS [M + H] ⁺ 413; 1H NMR (400 MHz, CD ³ OD) Sh ppm 8.07 (dd, J = 2.3, 0.8 Hz, 1 H), 7.86 (dd, J = 9.3, 2.3 Hz, 2 H), 7.33-7.37 (m, 2 H ), 7.24 (t, J = 7.6 Hz, 1 H), 7.15-7.19 (m, 1 H), 6.90 (dd, J = 9.5, 0.6 Hz, 1 H), 6.03 (s, 1 H), 3.77- 3.82 (m, 2H), 3.64-3.69 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 452

4 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] benzene-1-sulfonamide.

Prepared according to general procedure 9 from 4-chloro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and 4- (2-aminoethylamino) benzenesulfonamide. LCMS [M + H] ⁺ 413; 1H NMR (400 MHz, CD ³ OD) S ^h ppm 7.64 (d, J = 9.1 Hz, 2H), 7.33-7.37 (m, 1H), 7.24 (s, 1H), 7.15-7.19 (m, 1H), 6.70 (d, J = 9.1 Hz, 2H), 6.00 (s, 1H), 3.72-3.77 (m, 2H), 3.45-3.50 (m, 2H), 2.35 (s, 3 H), 2.24 (s, 3H).

Example 454

6- (2,3-dimethylphenyl) -4-N- {2 - [(pyridin-3-yl) amino] ethyl} pyrimidine-2,4-diamine.

Prepared according to general procedure 9 from 4-doro-6- (2,3-dimethylphenyl) pyrimidin-2-amine and N '- (3-pyridyl) ethane-1,2-diamine. LCMS [M + H] ⁺ 335; ¹ H NMR (400 MHz, CD ³ OD) 8 ^hr ppm 8.10-8.12 (m, 1H), 7.97-8.00 (m, 1H), 7.72-7.80 (m, 2H), 7.34-7.38 (m, 1 H), 7.22-7.27 (m, 1 H), 7.19 (dd, J = 1.0, 0.5 Hz, 1 H), 6.04 (s, 1 H), 3.75-3.80 (m, 2 H), 3.54 (t , J = 6.2 Hz, 2H), 2.36 (s, 3H), 2.25 (s, 3H).

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Biological examples

Biological example 1

MTH1 enzyme assay and determination of IC50 value

MTH1 catalyzes the hydrolysis of dGTP to dGMP and PPi. By coupling the reaction to excess added pyrophosphatase, PPi is converted to Pi which can be detected using the Malachite Green Assay Reagent. Briefly, for the determination of the IC50 value, the compound to be analyzed is diluted in assay buffer in a series of 1: 3 dilutions generating 12 different compound concentrations that give a final DMSO concentration of 1% in the assay well. MTH1 diluted in assay buffer (100 mM Tris-acetate, 40 mM NaCl, 10 mM magnesium acetate, 1 mM DTT and 0.005% Tween 20) fortified with E. coli pyrophosphatase (0.8 U / ml) is added to a concentration 4.8 nM final. Add dGTP diluted in Assay Buffer to a final concentration of 100 | ^j M. The reaction mixture is incubated with shaking for 15 minutes at 22 ° C. To 100 µl of the reaction mixture, add 25 µl of Malachite Green Assay Reagent (0.095% Malachite Green in 17% H2SO4, 1.5% Ammonium Molybdate, 0.17% Tween 20) followed by incubation with shaking for 15 minutes at 22 ° C. The absorbance of the assay plate is read at 630 nm using an EnVision Multilabel plate reader. The IC50 value is determined by fitting a dose response curve to the data points using nonlinear regression analysis and the equation Y = Lower (Upper-Lower) / (1 10A ((LogIC50-X) * HillSlope) ), where Y is the absorbance read at 630 nm and X is log [composite].

Using this methodology, the following representative IC50 values were derived. Examples: 127, 131, 132, 228, 231, 266, 267, 269, 295, 296, 301, 330, 331, 333, 335, 343, 359, 361, 363, 367, 374, 376, 381, 389, 391, 397, 402, 403, 415, 416, 424, 426, 443, 444, 445, 447, 451, 454 had IC50s of less than 200 nM

Examples: 241, 242, 347, 378, 384, 423, had IC50 between 200 nM and 2 jM

Biological example 2: MTH1 siRNA knockdown and cell survival

The cells were cultured in a suitable medium supplemented with 10% FBS and PeSt at 10 U / ml. On day 1, cells were seeded at approximately 30% confluence in 6-well plates in complete medium. The next day, the medium was aspirated and fresh medium without antibiotics was added. Cells were transfected with All-stars untargeted RNA (NT RNA, Qiagen) and MTH1 siRNA (5'-CGACGACAGCUACUGGUUU-3 ') and interferin (Polyplus) according to the manufacturer's protocol. On day 5, cells were trypsinized, counted and seeded again for clonogenic growth in 10 cm plates at 500 cells / plate or washed with PBS and scraped in lysis buffer (10 mM Hepes pH 7.1, NaCl 50 mM, 0.3 M sucrose, 0.1 mM EDTA, 0.5% Triton X100, 1 mM DTT and 1x protease inhibitor, cocktail (Pierce)) and processed for Western immunoprecipitation. Immunoprecipitates were stained with anti-MTH1 antibody (rabbit polyclonal, HPA, KTH, Sweden) and anti-tubulin (mouse monoclonal, Sigma Aldrich). After an additional 7-10 days, survival plates were fixed / stained with 4% methylene blue in MeOH and colonies were counted manually. Figure 1 shows the effect on cell survival after depletion of MTH1 siRNA in various human normal and cancer cell lines.

Biological Example 3: Cell Survival Assay

Cells are grown in DMEM GlutaMAX ™ or other suitable cell medium and seeded in cell culture plates (100mm x 20mm) (500 cells / plate) and incubated in 5% CO2 at 37 ° C. After 5 hours of incubation, cells are treated with compound at various concentrations and left in the incubator for 7-14 days depending on the cell line. Clonogenic survival is measured by fixing and staining cells with methylene blue (4 g / L in methanol) and the number of colonies is counted and compared to the vehicle-treated plates. Figure 2 shows how an MTH1 inhibitor (not according to the invention) reduces cell survival in various cancer cell lines, with less effect on normal immortalized cells (VH10 and BJ hTERT).

Biological Example 4: Cell Viability Assay

The cells are seeded in 96-well plates (1500 cells / well) in DMEM GlutaMAX ™ or other suitable medium depending on the cell line and incubated overnight in 5% CO2, 37 ° C. The cells are then treated with compound or vehicle and left in an incubator for 3 days until stained with resazurin. Cells are incubated in resazurin (diluted in a suitable medium) at 37 ° C for 2 hours before measuring fluorescence.

Claims (17)

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: R1 represents heteroaryl selected from benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3 -yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl, whose heteroaryl is connected to the pyrimidine of formula I through a carbon atom of the heteroaryl ring, and whose heteroaryl is optionally substituted with one or more substituents selected from Y1 or -C 1-6 alkyl optionally substituted with one or more Y2; or aryl represented by

E3 and E4 represent hydrogen; and E1 represents -F and E2 represents -F, -CI, -CH3 or -CF3; or E1 represents -Cl and E2 represents -F, -CI, -CH3 or -CF3; or E1 represents -CH3 and E2 represents -F, -CI, -CH3, -CF3 or -CN; R2 represents hydrogen; R3 represents -C2-6 alkyl substituted with Z1; each Y1 independently represents halogen, -CN, -C (O) Ra, -C (O) N (Rb) Rc, -C (O) ORd, -N (Re) Rf, -N (Rg) C (O) Rh, -N (Ri) C (O) ORj, -N (Rk) C (O) N (Rl) Rm, -NO2, -N (Rn) S (O) 2Ro, -ORp, -OC (O) Rq, -OS (O) 2Rr, -S (O) mRs, -S (O) 2N (R ') Ru, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6-14 aryl members optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; each Ra, Rb, Rc, Rd, Re, Rg, Rh, Ri, Rk, R1, Rm, Rn, Rp, Rq, Rs, R * and Ru independently represents hydrogen, -C 1-6 alkyl optionally substituted with one or more substituents selected from W1, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more plus heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or either of two Rb and Rc, Re and Rf, R1 and Rm and / or R * and Ru are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring contains optionally one or two additional heteroatoms and whose ring is optionally substituted with one or more substituents selected from W2, C1-3 alkyl optionally substituted with one or more substituents selected from W1 and = O; each Rf, Rj, Ro and Rr independently represent -C 1-6 alkyl optionally substituted with one or more substituents selected from W1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, optionally 6-14-membered aryl substituted with one or more substituents selected from W3 or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; each Y2 independently represents halogen, -CN, -C (O) Rb1, -C (O) N (Rc1) Rd1, -C (O) ORe1, -N (Rf1) Rg1, -N (Rh1) C (O) Ri1, -N (Rj1) C (O) ORk1, -N (Rl1) C (O) N (Rm1) Rn1, -N (Ro1) S (O) 2Rp1, -ORq1, -OC (O) Rr1, - OS (O) 2Rs1, -S (O) mRt1, -S (O) 2N (Ru1) Rv1, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from W1, 6-14 membered aryl optionally substituted with one or more selected substituents from W2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W2; each Rb1, Rc1, Rd1, Re1, Rf1, Rh1, Ri1, Rj1, Rl1, Rm1, Rn1, Ro1, Rq1, Rr1, hydrogen, C1-6 alkyl optionally substituted by one or more substituents selected from W1, 3 to heterocycloalkyl 12 membered optionally substituted with one or more substituents selected from W2, 6 to 14 membered aryl optionally substituted with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; or either of two Rc1 and Rd1, Rf1 and Rg1, Rm1 and Rn1 and / or Ru1 and Rv1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, whose ring optionally contains one or two additional heteroatoms and which ring is optionally substituted with one or more substituents selected from W2, C1-3 alkyl optionally substituted with one or more substituents selected from W1 and = O; each Rg1, Rk1, Rp1 and Rs1 independently represent C1-6 alkyl optionally substituted with one or more substituents selected from W1, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from W2, optionally substituted 6- to 14-membered aryl with one or more substituents selected from W3, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W3; Z1 represents -C (O) N (Rc2) Rd2, -N (Rf2) Rg2, -N (Rh2) C (O) Ri2, -N (Rl2) C (O) N (Rm2) Rn2, -N (Ro2 ) S (O) 2Rp2, -ORq2, -S (O) mRt2, -S (O) 2N (Ru2) Rv2, or aryl represented by

Rc2, Rf2, Rh2, Rl2, Rm2, Ro2, and Ru2 represent hydrogen; and Rd2, Rg2, Ri2, Rn2 Rp2, Rq2, Rt2 and Rv2 represent 6 to 14 membered aryl optionally substituted with one or more substituents selected from W6, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W6; each W1 independently represents halogen, -CN, -N (Rf3) Rg3, -N (Rh3) C (O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3 ) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, -OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, heterocycloalkyl 3 to 12 membered optionally substituted with one or more substituents selected from G1, 6 to 14 membered aryl optionally substituted with one or more substituents selected from G2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2, o = O; each W2, W3, and W6 independently represents halogen, -Ra3, -CN, -C (O) Rb3 -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C (O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, - OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, aryl from 6 to 14 membered optionally substituted with one or more substituents selected from G2, 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2, o = O ; W7 and W11 represent hydrogen; each W8 and W10 independently represent halogen, -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (ON (Rf3) Rg3, -N (Rh3) C (O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3, -OC (O) Rr3, - OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3-12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, 6-14 membered aryl optionally substituted with one or more substituents selected from G2, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2; W9 represents halogen, -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C (O ) Ri3, -N (Rj3) C (O) ORk3, -N (R13) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3x, -OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, optionally substituted 6- to 14-membered aryl with one or more substituents selected from G2, or heteroaryl 5 to 10 membered containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2; each Ra3 Rb3 Rc3 Rd3 Re3 Rf3 Rh3 Ri3 Rj3 Rl3 Rm3 Rn3 ^ro 3 Rq3 Rr3 Rt3 Ru3 and Rv3 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more G3; or either of two Rc3 and Rd3, Rf3 and Rg3, Rm3 and Rn3 and / or Ru3 and Rv3 are linked together to form, together with the nitrogen atom to which they are attached, a 4 to 6 membered ring, which ring optionally contains one or more heteroatoms and whose ring is optionally substituted with one or more G2; each Rg3, Rk3, Rp3, and Rs3 independently represent C1-6 alkyl optionally substituted with one or more G3; Rq3x represents C2-6 alkyl optionally substituted with one or more G3; each G1 and G2 independently represent halogen, -Ra4, -CN, -C (O) Rb4, -C (O) N (Rc4) Rd4, -C (O) ORe4, -N (Rf4) Rg4, -N (Rh4 ) C (O) Ri4, -N (Rj4) C (O) ORk4, -N (Rl4) C (O) N (Rm4) Rn4, -N (Ro4) S (O) 2Rp4, -ORq4, -OC ( O) Rr4, -OS (O) 2Rs4, -S (O) mRt4, -S (O) 2N (Ru4) Rv4, o = O; G3 represents halogen, -CN, -C (O) Rb4, -C (O) N (Rc4) Rd4, -C (O) ORe4, -N (Rf4) Rg4, -N (Rh4) C (O) Ri4, -N (Rj4) C (O) ORk4, -N (Rl4) C (O) N (Rm4) Rn4, -N (Ro4) S (O) 2Rp4, -ORq4, -OC (O) Rr4, -OS ( O) 2Rs4, -S (O) mRt4, -S (O) 2N (Ru4) Rv4, o = O; each Ra4, Rb4, Rc4, Rd4, Re4, Rf4, Rh4, Ri4, Rj4, Rl4, Rm4, Rn4, Ro4, Rq4, Rr4, Rt4, Ru4 and Rv4 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more -F; or either of two Rc4 and Rd4, Rf4 and Rg4, Rm4 and Rn4 and / or Ru4 and Rv4 are linked together to form, together with the nitrogen atom to which they are attached, a 3 to 6 membered ring, which ring is optionally substituted by one or more -F, -CH3, -CH2CH3, -CHF2, -CF3, -CH2CF3 or = O; each Rg4, Rk4, Rp4 and Rs4 independently represents C1-6 alkyl optionally substituted with one or more -F; and each m independently represents 0, 1 or 2. 2. A compound as claimed in claim 1, wherein R1 represents heteroaryl. 3. A compound as claimed in claim 1, wherein R1 represents

where: E3 and E4 represent hydrogen; and E1 represents -F and E2 represents -F, -Cl, -CH3 or -CF3; or E1 represents -Cl and E2 represents -F, -Cl, -CH3 or -CF3; or E1 represents -CH3 and E2 represents -F, -Cl, -CH3, -CF3 or -CN. 4. A compound as claimed in any one of claims 1 to 3, wherein: Z1 represents

and (a) W8 and W10 are independently selected from hydrogen, -F, -CI, -CH3, -CN, and -CF3; and W9 is selected from -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C (O ) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3x, -OC (O) Rr3, -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3- to 12-membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, optionally substituted 6- to 14-membered aryl with one or more substituents selected from G2, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2; or (b) W9 and W10 are independently selected from hydrogen, -F, -CI, -CH3, -CN, and -CF3; and W8 is selected from -Ra3, -CN, -C (O) Rb3, -C (O) N (Rc3) Rd3, -C (O) ORe3, -N (Rf3) Rg3, -N (Rh3) C ( O) Ri3, -N (Rj3) C (O) ORk3, -N (Rl3) C (O) N (Rm3) Rn3, -N (Ro3) S (O) 2Rp3, -ORq3x, -OC (O) Rr3 , -OS (O) 2Rs3, -S (O) mRt3, -S (O) 2N (Ru3) Rv3, 3 to 12 membered heterocycloalkyl optionally substituted with one or more substituents selected from G1, 6 to 14 membered aryl optionally substituted with one or more substituents selected from G2, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from G2. 5. A compound as claimed in any one of claims 1 to 4, wherein: W8 and W10 represent hydrogen and W9 represents -F, -CI, -CH3, cyclopropyl, -CF3, -CN, -NH2, -N (CH3) 2, -N (H) C (O) CH3, -N (H ) C (O) OC (CH3) 3, -SO2CH3, -SO2NH2, -S (O) 2N (CH3) 2, -S (O) 2-4-morpholinyl, 4-methylpiperazin-1-yl, 4-methyl -piperidin-1-ylmethyl or 1,2,3-thiadiazol-4-yl. 6. A compound as claimed in any one of claims 1 to 3, wherein: Z1 represents -N (Rf2) Rg2, Rf2 represents hydrogen and Rg2 represents 6 to 14 membered aryl optionally substituted with one or more substituents selected from W6, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted with one or more substituents selected from W6 7. A compound as claimed in any one of claims 1 to 3, wherein: Z1 represents -ORq2 and Rq2 represents 6 to 14 membered aryl optionally substituted with one or more substituents selected from W6, or 5 to 10 membered heteroaryl containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur optionally substituted by one or more substituents selected from W6. 8. A compound as claimed in any one of claims 1, 2, 3, 6 or 7, wherein: W6 represents -F, -Cl, -Br, -CH3, cyclopropyl, -CF3, -CN, -N (CH3) 2, -SO2CH3, -SO2NH2 or -SO2N (CH3) 2. 9. A compound as claimed in claim 1, selected from: 6- (2,3-dimethylphenyl) -4-N- (2-phenylethyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- [2- (4-methoxyphenyl) ethyl] pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- [2- (4-methylphenyl) ethyl] pyrimidine-2,4-diamine; 4-N- [2- (4-chlorophenyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- (2-phenylpropyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- (3-phenylpropyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- (2-phenoxyethyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- [2- (phenylamino) ethyl] pyrimidine-2,4-diamine; 6- (2-chloro-3-methylphenyl) -4-N- [2- (4-chlorophenyl) ethyl] pyrimidine-2,4-diamine; 4-N- [2- (4-chlorophenyl) ethyl] -6- (1H-indol-4-yl) pyrimidine-2,4-diamine; 6- (3-chloro-2-methylphenyl) -4-N - [(1R) -1-phenylethyl] pyrimidine-2,4-diamine; 6- (3-chloro-2-methylphenyl) -4-N- (2-phenylpropan-2-yl) pyrimidine-2,4-diamine; 4-N- [2- (2-dorophenoxy) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- [2- (pyridin-3-yloxy) propyl] pyrimidine-2,4-diamine; 4-N- [2- (4-dorophenyl) ethyl] -6- (2,3-dydorophenyl) pyrimidine-2,4-diamine; 4-N- [2- (4-dorophenyl) ethyl] -6- (quinolin-5-yl) pyrimidine-2,4-diamine; 4-N- [2- (4-dorophenyl) cidopropyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 3- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) phenol; 4- N - {[1- (4-dorophenyl) cidopropyl] methyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4- (2 - {[2-amino-6- (2,3-dydorophenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 4- (2 - {[2-amino-6- (3-doro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dydorophenyl) pyrimidin-4-yl] amino} ethyl) phenol; 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 6- (2,3-dimethylphenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine; 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) benzonitrile, 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethoxy) benzonitrile, 4-N- [2- (3-dorophenyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4-N- [2- (4-dorophenyl) propyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- [2- (4-fluorophenyl) ethyl] pyrimidine-2,4-diamine; 4-N- [2- (benzenesulfonyl) ethyl] -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4-dorobenzene-1-sulfonamide; 3- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (4-dorophenyl) urea; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3,5-dimethyl-1,2-oxazole-4-sulfonamide; 3- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (2,6-dydoropyridin-4-yl) urea; 3- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1- (3,4-difluorophenyl) urea; N- [3- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propoxy) phenyl] acetamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-bromobenzamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-cyanobenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4-methanesulfonylbenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzenesulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -3-fluorobenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} -2,2-dimethylpropyl) -4- (morpholine-4-sulfonyl) benzene-1-sulfonamide ; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-fluorobenzene-1-sulfonamide; N- {4 - [(3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) sulfamoyl] phenyl} acetamide; N- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -3-fluorobenzene-1-sulfonamide; N- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -4-methoxybenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -4,5-dydorothiophene-2-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -5-doro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -1,2-dimethyl-1H-imidazole-4-sulfonamide; N- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -5-doro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; 4-N- {2 - [(1,3-benzoxazol-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- (4-phenylbutan-2-yl) pyrimidine-2,4-diamine; 6 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-3-carbonitrile, 4-N- {2 - [(3-bromo-1,2,4-thiadiazol-5-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; N- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -4-methanesulfonylbenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -3-methanesulfonylbenzene-1-sulfonamide; N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) -2-methanesulfonylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (3-doro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dydorophenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 4-N- {1 - [(4-dorophenyl) methyl] cidopropyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4-N- [2- (4-dorophenyl) ethyl] -6- (1H-pyrrol-2-yl) pyrimidine-2,4-diamine; N- (4 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} butyl) -4-methanesulfonylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 4-N- {2 - [(6-doropyridazin-3-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 2 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-4-carbonitrile, 6 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-3-sulfonamide; 1-N- (3 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} propyl) benzene-1,4-disulfonamide; 6- (2,3-dydorophenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- {2 - [(3-methoxyphenyl) amino] ethyl} pyrimidine-2,4-diamine; 6- (2,3-dimethylphenyl) -4-N- {2 - [(3-fluoro-4-methylphenyl) amino] ethyl} pyrimidine-2,4-diamine; 4-N- {2 - [(3,4-dydorophenyl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4-N- {2 - [(5-doropyridin-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4-N- {2 - [(5-bromopyridin-2-yl) amino] ethyl} -6- (2,3-dimethylphenyl) pyrimidine-2,4-diamine; 4 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] benzene-1-sulfonamide; and 6- (2,3-dimethylphenyl) -4-N- {2 - [(pyridin-3-yl) amino] ethyl} pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof. 10. A compound as claimed in claim 1, selected from: 4-N- [2- (4-dorophenyl) ethyl] -6- (2,3-dydorophenyl) pyrimidine-2,4-diamine; 4- (2 - {[2-amino-6- (2,3-dydorophenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 4- (2 - {[2-amino-6- (3-doro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) benzene-1-sulfonamide; 6- (2,3-dimethylphenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine; 4- (2 - {[2-amino-6- (3-chloro-2-methylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dichlorophenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 4- (2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) -N, N-dimethylbenzene-1-sulfonamide; 6 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] pyridine-3-sulfonamide; 6- (2,3-dichlorophenyl) -4-N- [2- (4-methanesulfonylphenyl) ethyl] pyrimidine-2,4-diamine; and 4 - [(2 - {[2-amino-6- (2,3-dimethylphenyl) pyrimidin-4-yl] amino} ethyl) amino] benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical formulation comprising a compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 12. A compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in treating cancer. 13. A compound for use as claimed in claim 12, wherein the cancer is selected from soft tissue cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung cancers / diseases: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancers / diseases: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, vipoma), small intestine (adenocarcinoma, vipoma), small intestine (adenocarcinoma, vipoma) lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Cancers / diseases of the genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle ( seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver cancers / diseases: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone cancers / diseases: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronphroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromixofibroma, osteoid osteoma, and giant cell tumors; Nervous system cancers / diseases: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oliigoderogloma multiforme, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancers / diseases: uterus (endometrial carcinoma), cervix (cervical carcinoma, pretumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], thecal granulosa cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Cancers / hematologic diseases: blood and bone marrow (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin cancers / diseases: malignant melanoma, bas cell carcinoma ales, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi moles, lipoma, angioma, dermatofibroma, keloids; adrenal gland cancers / diseases, neuroblastoma, neurofibromatosis, and head and neck cancers. 14. A compound for use as claimed in claim 12, wherein the cancer is selected from the group consisting of breast cancers, prostate cancers, lung cancers, esophageal cancers, colon cancers, brain cancers, cancers of skin, ovarian cancers, testicular cancers, neurofibromatosis and leukemias. 15. A compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. 16. A combination product comprising: (A) a compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof; and (B) one or more other therapeutic agent (s) that is / are useful in the treatment of a disease as defined in claim 13 or 14, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 17. A combination product as claimed in claim 16, wherein component (B) is selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, Topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors; kinase inhibitors; angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and inhibitors of cell cycle signaling.