COMPOUNDS

This disclosure relates to compounds useful as CSF-IR inhibitors, in particular to compounds having favourable activity and/or kinase selectivity for use in the treatment of conditions such as cancers. SUMMARY OF THE INVENTION

CSF-IR (Colony Stimulating Factor-1 Receptor) is a type III transmembrane receptor protein tyrosine kinase (RTK) which comprises an extracellular domain containing five repeated Ig domains, a single transmembrane domain, and a split cytoplasmic kinase domain that is interrupted by a kinase insert domain. It is encoded by the c-fms (cellular feline McDonough sarcoma) proto-oncogene (Roussel et al , Nature. (1987) 325(6104):549-552) and it is crucial for the growth, differentiation and survival of the monocyte-macrophage lineage. Related RTKs within this family include stem cell growth factor receptor (c-KIT), fins-like cytokine receptor (FLT3), and platelet derived growth factor receptors (PDGFR). CSF-IR is expressed by monocytic cells, microglia, osteoclasts, Langerhans cells, and in the female reproductive tract and placenta.

The natural ligand of CSF-IR is CSF, Colony Stimulating Factor (Robinson et al , Blood. (1969) 33(3):396-399). Binding of CSF to CSF-IR results in receptor dimerization and auto- phosphorylation of the kinase domain, and to subsequent activation of downstream signalling pathways such as the PI3K/AKT and Ras/MAPK signalling pathways. CSF-IR signalling has been shown to play a physiological role in the immune response, in bone remodelling, and in the reproductive system. In particular, activation of CSF-IR regulates the proliferation, differentiation and survival of macrophages, osteoclasts, and microglia. These cells and CSF-IR signalling pathways also play an important role in the inflammatory process. CSF-IR knockout mouse models show a range of phenotypes including reduced macrophage density and depletion of microglia and osteoclasts.

Consistent with the varied role of CSF-IR, e.g. in different tissues, dysfunction of CSF-IR has been implicated in a number of disease states including cancers, bone osteolysis, and inflammatory disorders such as rheumatoid arthritis and Crohn's disease, renal allograft rejection and obesity. For example, elevated CSF-1 signalling can lead to elevated osteoclast activity and bone loss, resulting in inflammatory bone erosion and the progression of diseases such as arthritis. Additionally, elevated expression or activation of CSF-IR and/or CSF-1 has been identified in patients with prostate, ovarian, breast, pancreatic and a variety of other cancers. Overexpression of CSF-1 is associated with poor prognosis in certain cancers e.g. breast cancer, ovarian cancer and prostate cancer (Lin et al., J. Mammary Gland Biol. Neoplasia. (2002) 7(2): 147-62). Furthermore, the CSF-IR signalling pathway can drive the recruitment of macrophages to the tumor microenvironment. These Tumor-Associated Macrophages (TAMs) are thought to play a role in promoting tumor progression, metastasis and angiogenesis (El-Gamal et al., Med. Res. Rev. (2013) 33(3):599-636; Bingle et al., J. Pathol. (2002) 196(3):254-65). Inhibition of CSF-IR signalling has been shown to decrease the number of TAMs in a tumor specific manner and correlates with extended survival (Strachan et al., Oncoimmunology (2013) 2(12):e26968). TAMs are important drivers of immune escape in the tumor microenvironment and they can help to generate a favourable environment for tumors by heightening immunosuppression, angiogenesis and invasion. CSF-IR inhibitors have been proposed for the treatment of CSF-IR mediated diseases, especially cancer. Blockage of CSF-l/CSF-lR signalling with small molecules inhibitors or monoclonal antibodies is reported to be effective in preclinical model systems and, more recently, in the clinic. Yet, many of the known inhibitors have been shown to be multi-target inhibitors which can have a significant inhibitory activity against other type III RTKs such as PDGFR, c-KIT and FLT. Moreover, many of the known inhibitors have non-optimal in vivo properties (e.g. pharmacokinetic properties) and/or a low activity against CSF-IR.

Burns et al. (Bioorg. Med. Chem. Lett. (2009) 19(4): 1206-9) identify a number of 2-(a- methylbenzylamino) pyrazine compounds as inhibitors of CSF-IR. The tested compounds show little selectivity for CSF-IR over other kinases such as c-Kit, PDGFR and PDGFRa. The study reports that the presence of an amide-containing group at the 3-position of the benzyl ring is required for the potency of the compounds, with both the amide bond proton and the carbonyl group being said to be essential.

There remains a need for inhibitors of CSF-IR, especially inhibitors having a high potency, high selectivity and/or beneficial in vivo properties.

The present inventors have discovered a family of compounds which are useful as inhibitors of CSF-IR. These compounds are particularly suitable for use in pharmaceutical compositions and in medical treatments in which the activity of CSF-1R needs to be modulated.

In a first aspect, the invention provides a compound characterised by formula (I),

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

A is a 5- to 10-membered heteroaryl whose ring atoms consist of C, at least one N and, optionally, O or S;

n is 0, 1, 2 or 3;

m is 0, 1 or 2;

X ¹ is selected from NH, O, S, -CH=N-, and -N=CH-;

L either denotes a direct bond, or it is a group -(CR ⁶ R ⁷ ) _P - in which:

p is 1, 2 or 3, and

each R ⁶ and each R ⁷ is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hy droxyl;

R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; R ² in each case is independently selected from halogen, hydroxyl, carbonitrile, optionally substituted Ci-4-alkyl, and optionally substituted -0(Ci-4-alkyl);

R ³ is an optionally substituted group selected from Ci-g-alkyl, C ₂ -4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; and

R ⁴ and R ⁵ are independently selected from H and Ci-3-alkyl, or R ⁴ and R ⁵ taken together with the carbon atom which is bonded thereto form a 3- to 6-membered cycloalkyl or cycloalkoxy group.

In embodiments:

R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-8-alkyl, C ₂ -8-alkenyl, C ₂ -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S0 ₂ -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from

R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from

R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;

R ² in each case is independently selected from halogen, hydroxyl, carbonitrile,

Ci-4-alkyl, and -0(Ci _-4 -alkyl),

wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or

R ³ is selected from Ci-g-alkyl, C ₂ -4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R\

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, A is selected from a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl and a 10-membered bicyclic heteroaryl.

In embodiments, A is selected from the group consisting of pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, azaindolyl, imidazopyrimidinyl, and pyrazolopyrimidinyl.

In embodiments, A is a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl, or a 10-membered bicyclic heteroaryl.

In embodiments, A is pyramidinyl or pyridinyl. In embodiments, n is 1. In embodiments, R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-4-alkyl, C ₂ -4-alkenyl, C ₂ -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl, amino and halogen. In embodiments, R ¹ in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH ₂ , carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen.

In embodiments, R ⁴ and R ⁵ are both hydrogen. In embodiments, m is 0.

In embodiments, m is 1 and R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In embodiments, X ¹ is selected from -CH=N- and -C=NH-. In embodiments, X ¹ is selected from NH, O and S. In embodiments, X ¹ is S.

In embodiments, L denotes a direct bond. In embodiments, L is -(CR ⁶ R ⁷ ) _P - in which p is 1 or 2, and in which each R ⁶ and each R ⁷ is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hydroxyl.

In embodiments, each R ⁶ and each R ⁷ is hydrogen.

In embodiments, R ³ is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3. In embodiments, R ³ is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from

R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3. In embodiments, R ³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and CONH _2. In embodiments, R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is cyclohexyl substituted with hydroxyl and with fluorine.

In embodiments, R ³ is indanyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, and -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl. In embodiments, R ³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ³ is bicyclo[3.1.0]hexanyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;

wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-C ₁ -3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ³ is bicyclo[3.1.0]hexanyl substituted by hydroxyl and further optionally substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, R ³ is tetrahydropyranyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen;

wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-C1-3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, R ³ is pyridinyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-C1-3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In another aspect or embodiment, the invention provides a compound characterized by formula (II

(Π) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Q\ Q ² _> Q and Q ⁴ are independently selected from N, CH and C(R ^X ), wherein no fewer than one and no more than two of said Q ¹ , Q ² , Q ³ and Q ⁴ may denote N; and

n, m, X ¹ , L, and R ¹ to R ⁵ are as described above.

In embodiments, Q ¹ is N and Q ² , Q ³ and Q ⁴ are CH or C(R ^X ).

In embodiments, Q ¹ and Q ⁴ are both N and Q ² and Q ³ are both CH or CiR ¹ ). In another aspect or embodiment, the invention provides a compound characterized by formula (III

(III)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X ² is selected from N and CH;

R ¹⁰ to R ¹² are each independently selected from H and a group R ¹ as described above; and

m, X ¹ , L, and R ² to R ⁵ are as described above.

In embodiments, X ² is N.

In embodiments, R ¹⁰ is selected from halogen, -C(0)N(R ¹ R ¹⁴ ), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S0 ₂ -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group; wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R is selected from phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl, ethynyl, and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, C3-8-cycloalkyl optionally substituted by hydroxyl or by 1 to 3 halogens, NH ₂ , S0 ₂ CH ₃ , CH ₂ NHS0 ₂ CH ₃ , CH ₂ NHCOCH ₃ , CH ₂ NHC(0)0- ^l Bu, pyrrolidinylmethyl, morpholin-4-ylmethyl, N- methylpyrazolyl, and -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen.

In embodiments, R ¹¹ and R ¹² are independently selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In embodiments, R ¹¹ and R ¹² are both hydrogen.

In another aspect or embodiment, the invention provides a compound characterized by formula IV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

q is 0, 1, 2 or 3;

R ¹⁷ is independently selected from a group R ¹ as described above; and

m, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ are as described above.

In another aspect or embodiment, the invention provides a compound characterized by formula (IV _a ) or (IV _b ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁷ are as described above.

In embodiments, R ¹⁷ is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l ,

-0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^s , and

C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, q is 0 or 1.

In another aspect or embodiment, the invention provides a compound characterized by formula V),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

r is 0, 1, 2 or 3;

R ¹⁸ is independently selected from a group R ¹ as described above; and

m, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ are as described above. In another aspect or embodiment, the invention provides a compound characterized by formula formula (V _a ) or (V _b ),

(V _a )

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁸ are as described above.

In embodiments, R is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^s , and

C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, r is 0 or 1.

In another aspect or embodiment, the invention provides a compound characterized by formula (VI),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R ¹⁹ is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted; and

L, X ¹ , X ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² are as described above.

In embodiments, R ¹⁹ is selected from halogen, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl.

In embodiments, R ¹⁹ is hydrogen.

In another aspect or embodiment, the invention provides a compound characterized by formula (X

(XIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein

R , R and R are independently selected from hydrogen and a group R as described above; and L, R ³ , R ⁴ , R ⁵ and R ¹⁰ are as described above.

In embodiments, two of R , R and R are independently selected from hydrogen, and the other is selected from chlorine, fluorine, methyl optionally substituted by 1-3 fluorine, and methoxyl optionally substituted by 1-3 fluorine.

In another aspect or embodiment, the invention provides a compound selected from the group consisting of Compounds 1 to 180, as defined hereinafter, or a pharmaceutically acceptable salt or prodrug thereof.

In embodiments, the compound is selected from the group consisting of Compound 1, Compound 15, Compound 21, Compound 35, Compound 49, Compound 50, Compound 51, Compound 70, Compound 88, Compound 103, Compound 106, Compound 107, Compound 111, Compound 113, Compound 114, Compound 117, Compound 119, Compound 127, Compound 133, Compound 134, Compound 146, Compound 147, Compound 148, Compound 160, Compound 165, Compound 171, Compound 173 and Compound 180; or a pharmaceutically acceptable salt or prodrug thereof.

In embodiments, the compound has an inhibitory activity (an IC5 ₀ value) against CSF-IR of less than 100 nM.

In embodiments, the compound is selective for CSF-IR over PDGFR by a value of at least 5 times, and/or selective for CSF-IR over PDGFRa by a value of at least 10 times, and/or selective for CSF-IR over c-KIT by a value of at least 20 times, and/or selective for CSF-IR over FLT3 by a value of at least 200 times.

In further aspect, the invention provides a pharmaceutical composition comprising a compound as described above, and at least one pharmaceutically acceptable excipient.

In embodiments, the pharmaceutical composition comprises a further active agent selected from the group consisting of anti-proliferative agents, anti-inflammatory agents, anti- angiogenic agents, chemotherapeutic agents and immunotherapeutic agents. In still further aspect, the invention provides a compound or a pharmaceutical composition as described above, for use in therapy.

In yet further aspect, the invention provides a method for treating a CSF-IR mediated disease in a subject, the method comprising administering to the subject an effective amount of a compound as described above.

In embodiments, the CSF-IR mediated disease is selected from cancer, a bone disorder, an inflammatory disorder, and a neurological disorder. In embodiments, the CSF-IR mediated disease is characterised by overexpression of CSF-IR, by aberrant CSF-IR signalling, by overexpression of CSF-1 and/or IL-34, and/or by mutations in the CSF-IR gene.

In embodiments, the CSF-IR mediated disease is a cancer is selected from breast cancer, cervical cancer, glioblastoma multiforme (GBM), Hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, pancreatic cancer pigmented villondular synovitis (PVNS), prostate cancer, ovarian cancer, Tenosynovial giant cell tumors (TGCT), Endometrial cancer, Multiple myeloma, Myelocytic leukemia, Bone cancer, Renal cancer, Brain cancer and myeloproliferative disorder (MPD).

In embodiments, the method is for treating a subject diagnosed as having a cancer or being at risk of developing a cancer.

In other embodiments, the CSF-IR mediated disease is an inflammatory disorder selected from psoriatic arthritis, arthritis, asthma, thyroiditis, glomerular nephritis, atherosclerosis, psoriasis, Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosis (SLE), cutaneous lupus erythematosus, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), type 1 diabetes, multiple sclerosis and neuroinflammatory conditions. In other embodiments, the CSF-IR mediated disease is a bone disorder selected from osteoporosis, osteoarthritis, periodontitis, periprosthetic osteolysis, and Paget' s disease.

In embodiments, the method comprises administering said compound in combination with another therapeutic intervention for said CSF-IR mediated disease.

In a related aspect, the invention provides a compound as defined above, for use in a method as defined above. In another related aspect, the invention provides the use of a compound as described above, in the manufacture of a medicament for use in a method as described above. DETAILED DESCRIPTION

Although specific embodiments of the present disclosure will now be described with reference to the description and examples, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning (4 ^th ed., Cold Spring Harbor Laboratory Press 2012); the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1 : A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5 ^th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 ^rd edition (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

Numerical designations, e.g. pH, temperature, time, concentration, molecular weight, etc. , including ranges, are approximations which are varied ( + ) or ( - ) by increments of 0.1 or 1.0, where appropriate. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term "about". It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such may be known in the art.

As used in the specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. The term "including" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to".

As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this invention. Use of the term "comprising" herein is intended to encompass, and to disclose, the corresponding statements in which the term "comprising" is replaced by "consisting essentially of or "consisting of.

A "subject," "individual" or "patient" is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets and primates; for example murines, rats, rabbit, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In one embodiment, the mammals include horses, dogs, and cats. In a preferred embodiment, the mammal is a human.

"Administering" is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being inside the subject's body. Such an administration can be by any route including, without limitation, oral, transdermal (e.g. by the vagina, rectum, or oral mucosa), by injection (e.g. subcutaneous, intravenous, parenteral, intraperitoneal, or into the CNS), or by inhalation (e.g. oral or nasal). Pharmaceutical preparations are, of course, given by forms suitable for each administration route.

"Treating" or "treatment" of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.

The term "suffering" as it relates to the term "treatment" refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being "at risk of suffering" from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease. An "effective amount" or "therapeutically effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc.. It is understood, however, that specific dose levels of the therapeutic agents of the present invention for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.

As used herein, the term "pharmaceutically acceptable excipient" encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

As used herein, the term "prodrug" means a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. For example, prodrugs are variations or derivatives of the compounds described herein that have groups cleavable under certain metabolic conditions, which when cleaved, become the compounds described herein, e.g. a compound of formula (I). Such prodrugs then are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds herein may be called single, double, triple, etc. , depending on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, "The Organic Chemistry of Drug Design and Drug Action" pp. 352-401, Academic Press, San Diego, Calif, 1992).

Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of acid compounds with a suitable alcohol, amides prepared by reaction of acid compounds with an amine, basic groups reacted to form an acylated base derivative, etc.. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having, for example, free amino or hydroxyl groups can be converted into prodrugs. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

As used herein, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.

As used herein, the term "alkyl" means a saturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms "Ci-3-alkyl", "Ci-4-alkyl", etc. , have equivalent meanings, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (or 1 to 4, or 4 or 8) carbon atoms and a corresponding number of hydrogen atoms.

As used herein, the term "alkenyl" means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond. Exemplary alkenyl groups include ethenyl, prop-l-enyl, prop-2-enyl, isopropenyl, but-l-enyl, 2-methyl-prop-l-enyl, 2- methyl-prop-2-enyl, etc. Other alkenyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms "C2-6-alkenyl", "C2-8-alkenyl", etc. , have an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 (or 2 to 8) carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon double bond.

As used herein, the term "alkynyl" means an unsaturated linear or branched free radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond. Exemplary alkenyl groups include ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, 3-methyl-but-l-ynyl, etc. Other alkynyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms "C2-6-alkynyl", "C2-8-alkynyl", etc., have an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 (or 2-8) carbon atoms and a corresponding number of hydrogen atoms, which free radical comprises at least one carbon-carbon triple bond.

As used herein, the term "carbocyclic group" means a saturated, partially or fully unsaturated, or aromatic free radical having at least 3 to 9 carbon atoms {i.e. ring atoms) that form a ring. Exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and phenyl. It will be appreciated that the carbocyclic group may be monocyclic or multicyclic (e.g. fused, bridged or spirocyclic systems). In the case of multicyclic carbocyclic groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 9 carbon atoms (i.e. ring atoms). Exemplary carbocyclic groups having such further rings include decalinyl (bicyclo[4.4.0]decanyl), spiro[5.5]undecanyl, octahydronaphthalenyl and naphthalenyl. The term "cycloalkyl" has an equivalent meaning in relation to saturated carbocyclic groups. Thus, cycloalkyl groups are typically C3-io-cycloalkyl groups, e.g. C _3-8 - or C3-6-cycloalkyl groups. Examples of cycloalkyl groups include monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as multicyclic groups such as bicyclo[3.1.0]hexanyl and bicyclo[3.2.1]octanyl. The term "cycloalkenyl" has an equivalent meaning in relation to unsaturated carbocyclic groups. Thus, cycloalkenyl groups are typically C ₃ -io-cycloalkenyl groups, e.g. C _3-8 - or C _{3 -} 6- cycloalkyl groups. Examples of cycloalkyl groups include cyclopropenyl, cyclopentenyl and cyclohexadienyl. The term "aryl" has an equivalent meaning in relation to aromatic carbocyclic groups. Thus, aryl groups are typically C6-io-aryl groups. Examples of aryl groups include phenyl and naphthalenyl, as well as indenyl and indanyl groups.

As used herein, the term "heterocyclic group" means a saturated, partially or fully unsaturated, or aromatic free radical having at least 3 to 6 atoms (i.e. ring atoms) that form a ring, wherein 1 to 5 of said ring atoms are carbon and the remaining 1 to 5 ring atom(s) (i.e. hetero ring atom(s)) are selected independently from the group consisting of nitrogen, sulphur and oxygen. Exemplary heterocyclic groups include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyridinyl and imidazolyl. In the case of multicyclic heterocyclic groups, there are further rings, e.g. 1, 2, 3, or more, further rings, all of which contain from 3 to 6 ring atoms selected from carbon, nitrogen, sulphur and oxygen. Multicyclic heterocyclic rings include fused, bridged and spirocyclic ring systems. Exemplary heterocarbocyclic groups having such further rings include 2-azabicyclo[3.3.0]octanyl, 3,9-diazaspiro[5.5]undecanyl, dihydroindolyl, benzothiophenyl and benzoxazolyl. The term "heterocycloalkyl" has an equivalent meaning in relation to saturated heterocyclic groups. Heterocycloalkyl groups typically contain from 3 to 10 ring atoms, e.g. from 3 to 9 ring atoms or from 3 to 8 ring atoms. Exemplary heterocycloalkyl groups include pyrrolidinyl, morpholinyl, piperidinyl, and piperzinyl. The term "heterocycloalkenyl" has an equivalent meaning in relation to unsaturated heterocyclic groups. Heterocycloalkenyl groups typically contain from 3 to 10 ring atoms, e.g. from 3 to 9 ring atoms or from 3 to 8 ring atoms. Exemplary heterocycloalkenyl groups include 2,5- dihydro-lH-pyrrolyl, 2H-pyranyl, and 3,4-dihydro-2H-pyranyl. The term "heteroaryl" has an equivalent meaning in relation to aromatic heterocyclic groups. Heteroaryl groups typically contain from 5 to 10 ring atoms (e.g. from 6 to 10 ring atoms), and examples of such groups include monocyclic groups such as pyrrolyl, pyridinyl, pyrazinyl, and pyridazinyl, as well as multicyclic groups such as benzofuranyl, benzothiophenyl, indolyl, pyrrolopyridinyl, quinolinyl and pteridinyl.

As used herein, the terms "halo" and "halogen" mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen free radical group or to a halogen atom as such. Those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure.

As used herein, the terms "cyano", "nitrile" and "carbonitrile" mean a free radical having a carbon atom linked to a nitrogen atom via a triple bond. The cyano radical is attached via its carbon atom.

As used herein, the term "nitro" means an NO2 radical which is attached via its nitrogen atom. As used herein, the term "acyl" means a carbon-containing free radical having at least one carbon-oxygen double bond. The acyl radical is attached via the carbon atom of the carbon- oxygen double bond.

As used herein, the terms "hydroxy" and "hydroxyl" mean an OH radical which is attached via its oxygen atom. The term "thio" means an SH radical which is attached via its sulphur atom.

As used herein, the term "amino" generally means a free radical having a nitrogen atom and 1 or 2 hydrogen atoms. As such, the term "amino" typically refers to primary and secondary amines. In that regard, as used herein and in the appended claims, a tertiary amine is represented by the general formula RR ^† N-, wherein R and R ^† are carbon radicals that may or may not be identical. Nevertheless, the term "amino" may be used herein to describe a primary, secondary, and/or tertiary amine, and those of skill in the art will readily be able to ascertain how the term is being used in view of the context of that term.

As used herein, the terms "amido" and "amide" generally mean a free radical having a nitrogen atom bonded directly to a carbonyl (C=0) group. The term is intended, generally, to encompass primary, secondary and tertiary amide radicals, "amido" and "amide" radicals are attached via their carbonyl carbon atom.

As used herein, the term "acylamino" means a free radical containing at least one carbon- oxygen double bond, having an amino group attached to the carbonyl carbon. The acylamino radical is attached via the nitrogen atom of the amino group.

As used herein, the term "sulfonyl" means a free radical containing a sulphur atom which participates in two double bonds with oxygen atoms, i. e. it contains a group -S(=0) ₂ -. The "sulfonyl" radical is attached via the said sulphur atom. The term "aminosulfonyl" means a sulfonyl group which is directly bonded to an amino group as defined herein.

As used herein, the terms "R*" and "S*" denote that the stereochemical designation is racemic. Where two such terms appear in a chemical name, this can denote that the relative configuration at the chiral centers in question is either the same (e.g. "1R*,2R*") or different (e.g. "1R*,2S*"). The prefix "rel-" is used to denote relative configuration in cases where more than two chiral centres are present within the compound.

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

Compositions and methods provided herein may be combined with one or more of any of the other compositions and methods provided herein.

The following abbreviations are used herein:

°C = Celsius

^-NMR = proton nuclear magnetic resonance

AcOH = acetic acid

aq. = aqueous

atm = atmosphere

DBU = l,8-diazabicycloundec-7-ene

DCM = dichloromethane

DIBAL = diisobutylaluminum hydride

DIBAL-D = diisobutylaluminum deuteride

DIEA = N.N-diisopropy lethy lamine

DIPEA = N,N-diisopropylethylamine

DMA = dimethyl acetamide

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

DMSO-d ₆ = dimethyl sulfoxide hexadeuterated

DPPA = diphenylphosphoryl azide

dppf = l.l'-bis(diphenylphosphino)ferrocene

ES ⁺ = electrospray positive ionization

EtOAc = ethyl acetate

h = hour

HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate

HPLC = high pressure liquid chromatography

IPA = isopropanol

M = molar

mCPBA = 3-chloroperbenzoic acid

MeCN = acetonitrile

MHz = megahertz; min = minute

MS = mass spectrometry

MW = microwave

NBS = N-bromosuccinimide

Rochelles salt = Potassium sodium tartrate tetrahydrate

rt = room temperature

TBAF = Tetra-«-butylammonium fluoride

tBuONO = tert-butyl nitrite.

TBSC1 = fc/V-butyldimethylsilyl chloride

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Compounds

The present invention relates to compounds useful as CSF-IR inhibitors. In one aspect, the invention provides a compound characterised by formula (I),

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

A is a 5- to 10-membered heteroaryl whose ring atoms consist of C, at least one N and, optionally, O or S;

n is 0, 1. 2 or 3;

m is 0, 1 or 2;

X is selected from NH, O, S, -CH=N-, and -N=CH-;

L either denotes a direct bond, or it is a group -(CR ⁶ R ⁷ ) _P - in which:

p is 1. 2 or 3, and each R ⁶ and each R ⁷ is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen and hydroxyl;

R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;

R ² in each case is independently selected from halogen, hydroxyl, carbonitrile, optionally substituted Ci-4-alkyl, and optionally substituted -0(Ci-4-alkyl);

R ³ is an optionally substituted group selected from Ci-g-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl; and

R ⁴ and R ⁵ are independently selected from H and Ci-3-alkyl, or R ⁴ and R ⁵ taken together with the carbon atom which is bonded thereto form a 3- to 6-membered cycloalkyl or cycloalkoxy group.

In embodiments:

R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S02-Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; R ² in each case is independently selected from halogen, hydroxyl, carbonitrile, C _h alky 1, and -0(Ci _-4 -alkyl),

wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or

R ³ is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S02-Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments:

R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl, amino and halogen;

R ² in each case is independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci _-4 -alkyl),

wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile; and/or

R ³ is selected from Ci-g-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein each said alkyl, acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl. In embodiments, A is selected from a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl and a 10-membered bi cyclic heteroaryl. In one embodiment, A is selected from the group consisting of pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, azaindolyl, imidazopyrimidinyl, and pyrazolopyrimidinyl.

In embodiments, A is a 6-membered monocyclic heteroaryl, e.g. pyramidinyl, pyridinyl or pyrazinyl (e.g. pyramidinyl or pyridinyl). In other embodiments, A is a 9-membered bicyclic heteroaryl, e.g. imidazo[l,2-c]pyrimidinyl. In other embodiments, A is a 10-membered bicyclic heteroaryl, e.g. quinazolinyl.

In embodiments, n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 0. In other embodiments, n is 0 or 1.

In embodiments, R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C ₂ -8-alkenyl, C ₂ -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S0 ₂ -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ¹ ".

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-4-alkyl, C ₂ -4-alkenyl, C ₂ -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and C _1-3 - alkyl,

-0(Ci-3-alkyl) optionally substituted by 1-3 halogen,

carbonitrile,

S0 ₂ -Ci _-4 -alkyl,

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m , and

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino and Ci-3-alkyl; and wherein R ^p in each case is independently selected from S0 ₂ -Ci _-4 -alkyl, CO-C _M -alkyl, C(0)0-C _M -alkyl, and C _M -alk l.

In other embodiments, R ¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R ⁸ R ⁹ ), -N(R ⁸ R ⁹ ), C ₂ - ₄ -acyl, C _2-4 -acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR ⁸ , sulfonyl, aminosulfonyl, Ci-4-alkyl, C _2- 4-alkenyl, C ₂ -8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl, amino and halogen.

In embodiments, R ¹ in each case is independently selected from halogen, -C(0)N(R ⁸ R ⁹ ), -0(Ci _-4 -alkyl), -C(0)OR ⁸ , sulfonyl, Ci _-4 -alkyl, C ₂ - ₈ -alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and C1-3- alkyl,

-0(Ci-3-alkyl) optionally substituted by 1-3 halogen,

carbonitrile,

S0 ₂ -Ci _-4 -alkyl,

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m , and

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino and Ci-3-alkyl; and wherein R ^p in each case is independently selected from S0 ₂ -Ci _-4 -alkyl, CO-Ci _-4 -alkyl, and C(0)0-Ci _-4 -alkyl.

In other embodiments, R ¹ in each case is independently selected from halogen, -C(0)N(R ⁸ R ⁹ ), -0(Ci _-4 -alkyl), -C(0)OR ⁸ , sulfonyl, Ci _-4 -alkyl, C _2-8 -alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ⁸ and R ⁹ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen.

In embodiments, R ¹ in each case is independently selected from halogen, C ₂ -8-alkynyl, aryl, and heteroaryl,

wherein each said alkynyl, aryl or heteroaryl is optionally substituted by 1 or 2 groups independently selected from:

halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and C _1-3 - alkyl,

-0(Ci-3-alkyl) optionally substituted by 1-3 halogen,

carbonitrile,

S0 ₂ -Ci.3-alkyl,

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m , and

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl and Ci-3-alkyl; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, and C(0)0-Ci _-4 -alkyl. In other embodiments, R ¹ in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH ₂ , carbonitrile, ethynyl, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, Ci-4-alkyl, (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen, S0 ₂ -Ci _-4 -alkyl, CH ₂ NHS0 ₂ -Ci _-4 -alkyl, CH ₂ NHC(0)Ci _-4 -alkyl, CH ₂ NHC(0)OCi _-4 -alkyl, and pyrrolidin-l-ylmethyl.

In other embodiments, R ¹ in each case is independently selected from phenyl, pyridinyl, pyranyl, pyrazolyl, benzimidazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexanyl, tetrahydropyranyl, isoxazolyl, -C(0)NH ₂ , carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen.

In embodiments, n is 1 and R ¹ is independently selected from phenyl, pyridinyl and ethynyl; wherein each may be optionally substituted by up to 3 groups independently selected from: halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m .

carbonitrile,

S0 ₂ -Ci-3-alkyl optionally substituted by 1 to 3 groups independently selected from

R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m , 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m , and CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, n is 1 and R ¹ is selected from phenyl, pyridinyl, and methyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci _-3 -alkyl).

In other embodiments, n is 1 and R ¹ is selected from phenyl, pyridinyl, and ethynyl, wherein each may be optionally substituted by up to 2 groups independently selected from halogen, methyl, methoxyl, carbonitrile, CH ₂ NHSO ₂ CH ₃ , and N-methylpyrazolyl.

In one embodiment, n is 1 and R ¹ is phenyl optionally substituted by 1 to 3 halogen. In another embodiment, n is 1 and R ¹ is pyridine optionally substituted with 1 to 3 halogen. In another embodiment, n is 1 and R ¹ is methyl optionally substituted by 1 to 3 halogen. In another embodiment, n is 1 and R ¹ is carbonitrile. In another embodiment, n is 1 and R ¹ is CI. In another embodiment, n is 1 and R ¹ is Br. In another embodiment, n is 1 and R ¹ is -C(0)NH2. In another embodiment, n is 1 and R ¹ is 2,3-dihydro-6H-pyranyl. In another embodiment, n is 1 and R ¹ is 2,3-dihydrofuranyl.

In one embodiment, n is 1 and R ¹ is phenyl optionally substituted by 1 or 2 substituents selected from fluorine, carbonitrile and methoxyl. In another embodiment, n is 1 and R ¹ is pyridinyl optionally substituted by 1 or 2 substituents selected from fluorine and methoxyl. In other embodiments, n is 0.

In embodiments, R ⁴ and R ⁵ taken together with the carbon atom which is bonded thereto form a cyclopropyl group. In other embodiments, one of R ⁴ and R ⁵ is hydrogen and the other is selected from Ci-3-alkyl (e.g. methyl). In other embodiments, R ⁴ and R ⁵ are both independently selected from Ci-3-alkyl (e.g. both methyl). In a preferred embodiment, R ⁴ and R ⁵ are both hydrogen. As discussed below, isotopically labelled compounds are within the scope of the present disclosure and invention. Thus, the present compounds may have one or more hydrogen atoms replaced with e.g. deuterium. In embodiments where R ⁴ and/or R ⁵ is hydrogen, R ⁴ and/or R ⁵ may optionally be deuterium. In one embodiment, R ⁴ and R ⁵ are both deuterium.

In one embodiment m is 1. In a preferred embodiment, m is 0.

In one embodiment, each R ² is independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In another embodiment, each R ² is independently selected from halogen, Ci-3-alkyl and - 0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from fluorine.

In another embodiment, m is 1 and R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In another embodiment, m is 1 and R ² is selected from fluorine, chlorine, methyl and methoxyl.

In embodiments, X ¹ is -CH=N-. In other embodiments, X ¹ is -C=NH-. In other embodiments, X ¹ is selected from NH, O and S. In another embodiment, X ¹ is NH. In another embodiment, X ¹ is O. In a preferred embodiment X ¹ is S.

In embodiments, L is -(CR ⁶ R ⁷ ) _P - in which p is preferably 1 or 2 (especially in which p is 1) and in which each R ⁶ and each R ⁷ is independently selected from hydrogen and Ci-4-alkyl, wherein each said alkyl is optionally and independently substituted by 1 to 3 groups independently selected from halogen (e.g. fluorine) and hydroxyl.

In embodiments, one of an R ⁶ and R ⁷ attached to the same carbon atom is hydrogen and the other is C _1-4 alkyl, optionally substituted with hydroxyl. In other embodiments, one of an R ⁶ and R ⁷ attached to the same carbon atom is hydrogen and the other is methyl. In still other embodiments, one of an R ⁶ and R ⁷ attached to the same carbon atom is hydrogen and the other is hydroxymethyl. In yet other embodiments, all R ⁶ and R ⁷ groups present are hydrogen. In one embodiment, L is -CH ₂ -.

In embodiments, L denotes a direct bond.

In embodiments, R ³ is Ci-g-alkyl optionally substituted by 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, and -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is Ci-5-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen and hydroxyl. In other embodiments, R ³ is C ₂ -6-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen and hydroxyl. In one embodiment, R ³ is 4-methylpentan-l -ol.

In embodiments, R ³ is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r ,

-0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from

R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and

3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ³ is selected from cyclohexyl, bicyclo[3.1.0]hexanyl, phenyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), each optionally substituted with 1 to 5 groups selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r ,

C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , C2-6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^q , C2-6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and 3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ; wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is selected from cyclohexyl, bicyclo[3.1.0]hexanyl, phenyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), each optionally substituted with 1 to 3 groups selected from:

halogen,

hydroxyl,

carbonitrile,

-N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^q , C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

-C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^q ,

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^q , aryl optionally substituted by 1 to 3 groups independently selected from R ^q , and heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^q ;

wherein R ^q in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^r in each case is independently selected from SO2-C1-3- alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is selected from cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is selected from cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl and indanyl (2,3-dihydro-lH-indenyl), optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments R ³ is C3-8-cycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In preferred embodiments, R ³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl or by 1 to 3 halogen, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, CONH ₂ , and -NHS0 ₂ CH _3.

In other embodiments R ³ is C3-8-cycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In preferred embodiments, R ³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and CONH _2. In other preferred embodiments, R ³ is cyclohexyl substituted with hydroxyl. In other preferred embodiments, R ³ is cyclohexyl substituted with hydroxymethyl. In embodiments, R ³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci _-4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is cyclohexyl substituted with -NHSO2CH ₃ . In one embodiment, R ³ is (2- hy droxy)cy clohexan- 1 -yl.

In other embodiments, R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is cyclohexyl substituted with hydroxyl and with fluorine.

In other embodiments, R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci _-4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In other embodiments, R ³ is cyclohexyl substituted with hydroxyl and methyl. In one embodiment, R ³ is 2-methyl(2- hydroxy)cy clohexan- 1 -yl.

In embodiments, R ³ is bicyclo[3.1.0]hexanyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, R ³ is bicyclo[3.1.0]hexan-3-yl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In one embodiment, R ³ is (2- hydroxy)bicyclo[3.1.0]hexan-3-yl.

In other embodiments, R ³ is bicyclo[3.1.0]hexanyl substituted by hydroxyl and further optionally substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, R ³ is (2- hydroxy)bicyclo[3.1.0]hexan-3-yl substituted by a group selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is heterocycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is heterocycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is tetrahydropyranyl (e.g. tetrahydropyran-3-yl or tetrahydropyran- 4-yl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci _-4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In one embodiment, R ³ is

3- hydroxytetrahydropyran-4-yl. In another embodiment, R ³ is 4-hydroxytetrahydropyran-3- yi.

In other embodiments, R ³ is tetrahydropyrany 1 (e.g. tetrahydropyran-3-yl or tetrahydropyran-

4- yl) substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ³ is indanyl (2,3-dihydro-lH-indenyl) optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, and -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-C ₁ -3- alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ³ is indanyl (2,3-dihydro-lH-indenyl) optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, CI, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, and -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl. In preferred embodiments, R ³ is indanyl substituted with hydroxyl. In other preferred embodiments, R ³ is indanyl substituted with hydroxymethyl. In one embodiment, R ³ is 2-hydroxyindan-l-yl.

In other embodiments, R ³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci _-4 -alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci.3-alkyl, CO-Ci _-3 -alkyl, C(0)0-Ci _-3 -alkyl, and Ci _-4 -alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is heteroaryl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ³ is pyridinyl (e.g. pyridine-3-yl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and R ^r , -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; wherein R ^r in each case is independently selected from SO ₂ - Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In embodiments, R ³ is pyridinyl substituted by hydroxyl. In other embodiments, R ³ is pyridinyl substituted by trifluoromethyl. In one embodiment, R ³ is 2- trifluoromethylpyridine-5-yl.

In embodiments, A is a 6-membered monocyclic heteroaryl; n is 1, 2 or 3; R ¹ is selected from halogen, -C(0)N(R ⁸ R ⁹ ) wherein R ⁸ and R ⁹ are independently selected from H and Ci-4-alkyl, sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen; R ⁴ and R ⁵ are independently selected from hydrogen and Ci-3-alkyl; m is 0, 1 or 2; R ² is independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) and Ci-4-alkyl, in which said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen; X ¹ is S; L is -(CR ⁶ R ⁷ ) _p -, p is 1 or 2, and one of the R ⁶ and R ⁷ attached to the same carbon atom in each case is hydrogen and the other is hydrogen or Ci-4-alkyl optionally substituted by hydroxyl; and R ³ is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In another embodiment, A is a 6-membered monocyclic heteroaryl; n is 1, 2 or 3; R ¹ is selected from halogen, -C(0)N(R ⁸ R ⁹ ) wherein R ⁸ and R ⁹ are independently selected from H and Ci-4-alkyl, sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R ^c in which R ^c is selected from hydroxyl and amino and halogen; R ⁴ and R ⁵ are independently selected from hydrogen; m is 0, 1 or 2; R ² is independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) and Ci-4-alkyl, in which said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen; X ¹ is S; L denotes a direct bond; and R ³ is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1 to 5 groups independently selected from selected from halogen, hydroxyl, carbonitrile, -N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R ^d R ^e ) in which R ^d and R ^e are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, the compound is characterized by formula (VII),

(VII) or a pharmaceutically acceptable salt or prodrug thereof, wherein A, n, m, L, and R ¹ to R ⁵ are as defined herein.

In one embodiment, the compound is characterized by formula (II),

(Π)

harmaceutically acceptable salt or prodrug thereof, wherein Q\ Q ² , Q ^M & Q ^{4 are} independently selected from N, CH and C(R ^X ), wherein no fewer than one and no more than two of said Q ¹ , Q ² , Q ³ and Q ⁴ may denote N; and

n, m, X ¹ , L, and R ¹ to R ⁵ are as defined herein.

In embodiments, Q ¹ is N and Q ² , Q ³ and Q ⁴ are CH or C(R ^X ). In other embodiments, Q ² is N, and Q ¹ , Q ³ and Q ⁴ are CH or C(R ^X ). In other embodiments, Q ¹ and Q ³ are both N and Q ² and Q ⁴ are both CH or CiR ¹ ). In preferred embodiments, Q ¹ and Q ⁴ are both N and Q ² and Q ³ are both CH or CiR ¹ ).

In embodiments, the compound is characterized by formula (VIII),

(VIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein n, m, L, Q ¹ to Q ⁴ , and R ¹ to R ⁵ are as defined herein.

In another embodiment, the compound is characterized by formula (III),

(III) or a pharmaceutically acceptable salt or prodrug thereof, wherein

X ² is selected from N and CH;

R ¹⁰ to R ¹² are each independently selected from H and a group R ¹ as defined herein; and m, X ¹ , L, and R ² to R ⁵ are as defined herein.

In embodiments,

R ¹⁰ is selected from H, halogen, carbonitrile, -C(0)N(R ¹ R ¹⁴ ), -N(R ¹ R ¹⁴ ), C ₂ - ₄ -acyl, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR ¹³ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; and

R ¹¹ and R ¹² are independently selected from H, halogen, carbonitrile, -N(R ¹⁵ R ¹⁶ ), -C(0)N(R ¹⁵ R ¹⁶ ), Ci _-4 -alkyl, C ₂ - ₄ -alkynyl, C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxy 1, -0(Ci-4-alkyl), -C(0)OR ¹⁵ , sulfonyl, and aminosulfonyl,

wherein R ¹⁵ and R ¹⁶ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein said alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted.

In an embodiment, R ¹⁰ is selected from H, halogen, carbonitrile, -C(0)N(R ¹ R ¹⁴ ), -N(R ¹ R ¹⁴ ), C2-4-acyl, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR ¹³ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S0 ₂ -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group;

wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and

R ¹¹ and R ¹² are independently selected from H, halogen, carbonitrile, -N(R ¹⁵ R ¹⁶ ), -C(0)N(R ¹⁵ R ¹⁶ ), Ci _-4 -alkyl, C ₂ - ₄ -alkynyl, C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR ¹⁵ , sulfonyl, and aminosulfonyl,

wherein R ¹⁵ and R ¹⁶ are independently selected from H and Ci-3-alkyl, and wherein said alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted by 1 to 3 groups independently selected from halogen and Ci-3-alkyl.

In another embodiment, R ¹⁰ is selected from H, halogen, carbonitrile, C(0)N(R ¹ R ¹⁴ ), -N(R ¹ R ¹⁴ ), C ₂ - ₄ -acyl, C ₂ -4-acylamino, -0(Ci _-8 -alkyl), -C(0)OR ¹³ , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and

wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^f R ) in which R ^f and R are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R ^h in which R ^h is selected from hydroxyl and amino and halogen; and

R ¹¹ and R ¹² are independently selected from H, halogen, carbonitrile, -N(R ¹⁵ R ¹⁶ ), -C(0)N(R ¹⁵ R ¹⁶ ), Ci _-4 -alkyl, C ₂ - ₄ -alkynyl, C ₂ - ₄ -acyl, C ₂ -4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR ¹⁵ , sulfonyl, and aminosulfonyl,

wherein R ¹⁵ and R ¹⁶ are independently selected from H and Ci-3-alkyl, and wherein said alkyl, alkynyl, acyl, acylamino, sulfonyl or aminosulfonyl is optionally substituted by 1 to 3 groups independently selected from halogen and Ci-3-alkyl.

In embodiments, X ² is N. In other embodiments, X ² is CH.

In embodiments, R ¹⁰ is selected from a group R ¹ as defined herein.

In embodiments, R ¹⁰ is selected from halogen, -C(0)N(R ¹ R ¹⁴ ), sulfonyl, Ci _-4 -alkyl, C ₂ -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from: halogen,

hydroxyl,

-N(R ^a R ^b ) in which R ^a and R ^b are independently selected from hydrogen and R ^p , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^m , carbonitrile,

S0 ₂ -Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C3-8-cycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m .

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

C3-8-cycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m .

C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^m , C6-io-aryl optionally substituted by 1 to 3 groups independently selected from R ^m , C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

3- to 8-membered heterocycloalkenyl optionally substituted by 1 to 3 groups independently selected from R ^m ,

5- to 10-membered heteroaryl optionally substituted by 1 to 3 groups independently selected from R ^m ,

CH ₂ NR ⁿ R° in which R ⁿ and R° are independently selected from hydrogen and R ^p or in which R ⁿ and R° taken together with the intervening nitrogen atom form a 3- to 8- membered heterocycloalkyl group; wherein R ^m in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^p in each case is independently selected from S0 ₂ -Ci-4-alkyl, CO-Ci-4-alkyl, C(0)0-Ci-4-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R ¹⁰ is selected from halogen, -C(0)N(R ¹ R ¹⁴ ), sulfonyl, Ci _-4 -alkyl, C ₂ -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ¹³ and R ¹⁴ are independently selected from H, Ci-4-alkyl, cycloalkyl, and heterocycloalkyl, and wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R ^f R ) in which R ^f and R are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, and (Ci-4-alkyl)-R ^h in which R ^h is selected from hydroxyl and amino and halogen.

In other embodiments, R ¹⁰ is selected from halogen, phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl, ethynyl, and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, C3- 8-cycloalkyl optionally substituted by hydroxyl or by 1 to 3 halogens, NH ₂ , SO2CH ₃ , CH2NHSO2CH ₃ , CH2NHCOCH ₃ , CH2NHC(0)0- ^l Bu, pyrrolidinylmethyl, morpholin-4- ylmethyl, N-methylpyrazolyl, and -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen. In preferred embodiments, R ¹⁰ is ethynyl optionally substituted by 1 or 2 groups selected from halogen, Ci-3-alkyl optionally substituted by hydroxyl or by 1 to 3 halogens, cyclopropanyl, tetrahydropyranyl, CH ₂ NHC(0)0- ^l Bu, and pyrrolidinylmethyl. In a preferred embodiment, R ¹⁰ is ethynyl substituted by methyl.

In other embodiments, R ¹⁰ is selected from halogen, phenyl, pyridinyl, pyranyl, pyrazolyl, cyclohexenyl, dihydrofuranyl, cyclopropanyl, cyclohexyl, tetrahydropyranyl, isoxazolyl, aminocarbonyl, carbonitrile, triazolyl, methanesulfonyl and methyl; wherein each may be optionally substituted by 1 to 5 groups independently selected from hydroxyl, Ci-4-alkyl, NH ₂ or halogen. In preferred embodiments, R ¹⁰ is fluorophenyl. In other preferred embodiments, R ¹⁰ is pyridinyl. In other preferred embodiments, R ¹⁰ is phenyl. In other preferred embodiments, R ¹⁰ is bromine. In other preferred embodiments, R ¹⁰ is chlorine. In other preferred embodiments, R ¹⁰ is -C(0)NH ₂ .

In other embodiments, R ¹⁰ is selected from phenyl and pyridinyl, each optionally substituted by 1 to 3 groups selected independently from halogen, hydroxyl, amino, carbonitrile, Ci-3-alkyl optionally substituted by 1 to 3 groups independently selected from halogen, -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen, S0 ₂ CH ₃ , CH ₂ NHC(0)CH ₃ , and CH ₂ NHS0 ₂ CH ₃ . In one embodiment, R ¹⁰ is phenyl optionally substituted by 1 or 2 groups selected from fluorine, methyl, methoxyl and CH ₂ NHSO ₂ CH ₃ . In another embodiment, R ¹⁰ is pyridinyl optionally substituted by 1 or 2 groups selected from fluorine, methyl, methoxyl and CH ₂ NHSO ₂ CH ₃ . In another embodiment, R ¹⁰ is pyridinyl substituted by methoxyl. In other embodiments, R is selected from phenyl, pyridinyl, and methyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl). In one embodiment, R ¹⁰ is phenyl optionally substituted by 1 to 3 halogen. In another embodiment, R ¹⁰ is pyridine optionally substituted with 1 to 3 halogen. In another embodiment, R ¹⁰ is methyl optionally substituted by 1 to 3 halogen. In another embodiment, R ¹⁰ is carbonitrile. In another embodiment, R ¹⁰ is CI. In another embodiment, R ¹⁰ is 2,3-dihydro-6H-pyranyl. In another embodiment, R ¹⁰ is 2,3-dihydrofuranyl.

In other embodiments, R ¹⁰ is hydrogen.

In embodiments, R ¹¹ is selected from H, halogen, carbonitrile, -C(0)N(R ¹⁵ R ¹⁶ ), C _1-3 -alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein R ¹⁵ and R ¹⁶ are independently selected from H and Ci-3-alkyl, and wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In other embodiments, R ¹¹ is selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen.

In one embodiment, R ¹¹ is -C(0)NH ₂ . In preferred embodiments R ¹¹ is hydrogen.

In embodiments, R ¹² is selected from H, halogen, carbonitrile, Ci-3-alkyl, hydroxyl, and -0(Ci-3-alkyl), wherein said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen. In preferred embodiments R ¹² is hydrogen.

In preferred embodiments, both R ¹¹ and R ¹² are hydrogen.

In embodiments, L is -(CR ⁶ R ⁷ ) _P -, in which p is 1 and R ⁶ and R ⁷ are both hydrogen; and R ³ is selected from heterocycloalkyl or heteroaryl, optionally substituted by 1 to 3 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by 1-3 halogen or hydroxyl, F, CI, -0(C _M -alkyl) and CONH _2.

In other embodiments, L is -(CR ⁶ R ⁷ ) _P -, in which p is 1 and one of R ⁶ and R ⁷ is hydrogen and the other is Ci-4-alkyl optionally substituted by hydroxyl; and R ³ is selected from cycloalkyl or heteroaryl, optionally substituted by 1 to 3 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH _2.

In other embodiments, L denotes a direct bond and R ³ is selected from cycloalkyl or heteroaryl, optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci_ 3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH ₂ .

In a preferred embodiment, L denotes a direct bond; and R ³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is (2- hydroxy)cyclohexanyl. In another embodiment, L denotes a direct bond; and R ³ is 2- methyl(2-hydroxy)cyclohexanyl.

In another preferred embodiment, L denotes a direct bond; and R ³ is indanyl, optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is (1 -hydroxy )indanyl or (2-hydroxy)indanyl.

In another preferred embodiment, L denotes a direct bond; and R ³ is tetrahydropyranyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is tetrahydropyranyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, F, -0(Ci-4-alkyl) and CONH ₂ . In one embodiment, L denotes a direct bond; and R ³ is (3-hydroxy)tetrahydropyran-4-yl or (4- hydroxy)tetrahydropyran-3-yl.

In embodiments, the compound is characterized by formula (IX),

(IX) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, L, R ² to R ⁵ , and R ¹⁰ to R ¹² are as defined herein.

In one embodiment, the compound is characterized by formula (IV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

q is 0, 1, 2 or 3;

R ¹⁷ is independently selected from a group R ¹ as defined herein; and

m, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ are as defined herein.

In embodiments, R ¹⁷ is independently selected from halogen, hydroxyl, carbonitrile, -I^R'R ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4-acylamino, -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl. In a preferred embodiment, R ¹¹ is hydrogen.

In embodiments, q is 0, 1 or 2. In other embodiments, q is 0. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 0 or 1.

In embodiments, R ¹⁷ is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l ,

-0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^s , and

C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ¹⁷ is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , and

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, and

Ci-3-alkyl optionally substituted by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl and Ci-3-alkyl optionally substituted by 1 to 3 halogen.

In other embodiments, R ¹⁷ is independently selected from halogen, hydroxyl, carbonitrile, -I^R'R ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, q is 0, or q is 1 and R ¹⁷ is selected from:

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 halogen, and

Ci-4-alkyl optionally substituted by 1 to 3 halogen,

wherein R ^l in each case is independently selected from SO2CH ₃ and Ci-3-alkyl optionally substituted by 1 to 3 halogen.

In other embodiments, q is 1 and R ¹⁷ is independently selected from halogen, hydroxyl, carbonitrile, -I^R'R ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C ₂ -4- acylamino, -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, the compound is characterized by formula (X),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁷ are as defined herein.

In one embodiment, the compound is characterized by formula (IV _a ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁷ are as defined herein.

Compounds characterized by formula (IV _a ) demonstrate inter alia a good inhibitory activity towards CSF-1R.

In embodiments, R ¹⁰ is selected from halogen, C2-4-alkynyl, aryl, and heteroaryl, wherein each said alkynyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl optionally substituted by 1-3 halogen; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are independently selected from H; m is 0 or 1 ; R ² is selected from halogen, Ci-4-alkyl optionally substituted by 1-3 halogen, and -0(Ci-4-alkyl) optionally substituted by 1-3 halogen; and X ¹ is S. In a preferred embodiment, q is 0.

In other embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0. In other embodiments, R is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH, one of R ⁴ and R ⁵ is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R ² is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0.

In other embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C _2-8 - alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are both hydrogen; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0.

In embodiments, the compound is characterized by formula (X _a ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁷ are as defined herein.

In one embodiment, the compound is characterized by formula (IV _b ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁷ are as defined herein.

Compounds characterized by formula (IV _b ) display inter alia a good selectivity for CSF-IR over other kinases, such as c-KIT, PDGFRa, PDGFR and/or FLT-3.

In embodiments, R ¹⁰ is selected from halogen, C ₂ -4-alkynyl, aryl, and heteroaryl, wherein each said alkynyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl) optionally substituted by 1-3 halogen, carbonitrile, C3-8-cycloalkyl, CH ₂ NHS0 ₂ -Ci-3-alkyl, S0 ₂ -Ci-3-alkyl, Ci-4-alkyl optionally substituted by 1-3 halogen, 3- to 8-membered heterocycloalkyl optionally substituted by 1-3 halogen, and heteroaryl optionally substituted by 1 to 3 groups independently selected from halogen and methyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are independently selected from H; m is 0 or 1; R ² is selected from halogen, Ci-4-alkyl optionally substituted by 1-3 halogen, and -0(Ci-4-alkyl) optionally substituted by 1-3 halogen; and X ¹ is S. In one embodiment, q is 0.

In embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C ₂ -4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0. In other embodiments, R is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH, one of R ⁴ and R ⁵ is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R ² is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0.

In other embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are both hydrogen; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, q is 0.

In embodiments, the compound is characterized by formula (X _b ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁷ are as defined herein.

In one embodiment, the compound is characterized by formula (V),

(V) or a pharmaceutically acceptable salt or prodrug thereof, wherein

r is 0, 1, 2 or 3;

R ¹⁸ is independently selected from a group R ¹ as defined herein; and

m, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ and R ¹¹ are as defined herein. In a preferred embodiment, R ¹¹ is hydrogen.

In embodiments, R ¹⁸ is independently selected from halogen, hydroxyl, carbonitrile, -N(R ^k R') in which R ^k and R ¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C3-8-cycloalkyl, C2-4- acylamino, -C(0)N(R ^k R') in which R ^k and R ¹ are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments, r is 0, 1 or 2. In other embodiments, r is 0. In other embodiments, r is 1. In other embodiments, r is 2. In other embodiments, r is 0 or 1.

In embodiments, R ¹⁸ is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , -C(0)N(R ¹ R ^J ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , C ₂ -6-alkenyl optionally substituted by 1 to 3 groups independently selected from R ^s , and

C ₂ -6-alkynyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, amino, and Ci-3-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl, CO-Ci-3-alkyl, C(0)0-Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R ¹⁸ is independently selected from:

halogen,

hydroxyl,

carbonitrile,

-N R'R- ¹ ) in which R ¹ and R ^J are independently selected from hydrogen and R ^l , -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from R ^s , and

Ci-4-alkyl optionally substituted by 1 to 3 groups independently selected from R ^s , wherein R ^s in each case is independently selected from halogen, hydroxyl, and Ci-3-alkyl optionally substituted by 1 to 3 halogen; and wherein R ^l in each case is independently selected from S0 ₂ -Ci-3-alkyl and Ci-3-alkyl optionally substituted by 1 to 3 halogen.

In embodiments, R ¹⁸ is independently selected from halogen, hydroxyl, carbonitrile, -N(R ^k R') in which R ^k and R ¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen, C2-4-acylamino, -C(0)N(R ^k R') in which R ^k and R ¹ are independently selected from hydrogen and Ci-3-alkyl, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, each R ¹⁸ is attached to a saturated carbon atom within the indane moiety. In other embodiments each R ¹⁸ is attached to an unsaturated carbon atom within the indane moiety. In other embodiments at least one R ¹⁸ is attached to a saturated carbon atom within the indane moiety and at least one R ¹⁸ is attached to an unsaturated carbon atom within the indane moiety. In embodiments, the compound is characterized by formula (XI),

(XI) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁸ are as defined herein.

In one embodiment, the compound is characterized by formula (V _a ),

(V„) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁸ are as defined herein. In a preferred embodiment, R ¹¹ is hydrogen.

In embodiments, the compound is characterized by formula (XI _a ),

(XIa) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁸ are as defined herein.

In another embodiment, the compound is characterized by formula (V _b ),

(V„) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X ¹ , X ² , R ² , R ⁴ , R ⁵ , R ¹⁰ , R ⁿ and R ¹⁸ are as defined herein. In a preferred embodiment, R ¹¹ is hydrogen.

In embodiments, the compound is characterized by formula (X¾),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, R ² , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ and R ¹⁸ are as defined herein.

Compounds characterized by formula (V) or formula (XI), and especially by formula (V _a ) or formula (XI _a ), demonstrate inter alia a good inhibitory activity towards CSF-1R, and may also display a particularly high selectivity for CSF-1R over other kinases, such as c-KIT, PDGFRa, PDGFR and/or FLT-3.

In embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxy 1, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, r is O.

In other embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH, one of R ⁴ and R ⁵ is hydrogen and the other is Ci-3-alkyl; m is 0 or 1; R ² is selected from halogen, hydroxyl, carbonitrile, Ci_ 4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, r is 0.

In other embodiments, R ¹⁰ is selected from halogen, -C(0)NH ₂ , sulfonyl, Ci-4-alkyl, C2-4- alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said sulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -NH ₂ , -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl and Ci-4-alkyl; R ¹¹ is hydrogen; X ² is N or CH; R ⁴ and R ⁵ are both hydrogen; m is 0 or 1 ; R ² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X ¹ is S, O or NH. In a preferred embodiment, r is 0.

embodiment, the compound is characterized by formula (VI),

(VI) or a pharmaceutically acceptable salt or prodrug thereof, wherein

R ¹⁹ is selected from hydrogen and a group R ² as defined herein; and

L, X ¹ , X ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² are as defined herein. In a preferred embodiment, R ¹¹ and R ¹² are both hydrogen. In embodiments, R ¹⁹ is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted.

In one embodiment, R is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile.

In embodiments, R ¹⁹ is selected from halogen, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl. In other embodiments, R ¹⁹ is hydrogen.

In embodiments, R ¹⁹ is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen. In embodiments, R ¹⁹ is methoxyl. In other embodiments, R ¹⁹ is ethoxyl. In other embodiments, R is halogen (e.g. fluorine). In other embodiments, R is methyl.

In embodiments, the compound is characterized by formula (XII),

(XII) or a pharmaceutically acceptable salt or prodrug thereof, wherein L, R ³ to R ⁵ , R ¹⁰ to R ¹² and R ¹⁹ are as defined herein.

In one embodiment, the compound is characterized by formula (XIII),

(XIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein

19 20 21 2

R , R and R are independently selected from hydrogen and a group R as defined herein; and

L, R ³ , R ⁴ , R ⁵ and R ¹⁰ are as defined herein. 19 20 21

In embodiments, R , R and R are independently selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted.

19 20 21

In one embodiment, R , R and R are all independently selected from hydrogen.

19 20 21

In other embodiments, two of R , R and R are independently selected from hydrogen, and the other is selected from halogen, hydroxyl, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen.

In other embodiments, two of R , R and R are independently selected from hydrogen, and the other is selected from chlorine, fluorine, methyl optionally substituted by 1-3 fluorine, and methoxyl optionally substituted by 1-3 fluorine.

In one embodiment, L is -CH ₂ - or a direct bond; R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) optionally substituted by 1-3 halogen, and Ci-4-alkyl optionally substituted by 1-3 halogen; R ⁴ and R ⁵ are independently selected from hydrogen; R ¹⁹ is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen; and R ²⁰ and R ²¹ are both hydrogen.

In another embodiment, L is -CH ₂ - or a direct bond; R ³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -0(Ci-4-alkyl) optionally substituted by 1-3 halogen, and Ci-4-alkyl optionally substituted by 1-3 halogen; R ⁴ and R ⁵ are independently selected from hydrogen; R ²¹ is selected from hydrogen, halogen, hydroxyl, carbonitrile, Ci-3-alkyl, and -0(Ci-3-alkyl), wherein each said alkyl is optionally substituted by 1-3 halogen; and R ¹⁹ and R ²⁰ are both hydrogen.

In one embodiment, the compound is characterized by formula (XIV),

(XIV) or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R ⁴ , R ⁵ , R ¹⁰ , R ¹⁷ and R to R ²¹ are as defined herein.

In embodiments, the compound is characterized by formula (XIV _a ) or formula (XlV _b ),

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R ⁴ , R ⁵ , R ¹⁰ , R ¹⁷ and R to R ²¹ are as defined herein. In one embodiment, q is 0.

In a preferred embodiment, the compound is a compound of formula (XIV _a ) in which R ¹⁹ and R ²⁰ are both hydrogen; and in which R ²¹ is halogen (e.g. fluorine). In another preferred embodiment, the compound is a compound of formula (XlV _b ) in which R ¹⁹ is selected from fluorine, chlorine, methyl and methoxyl; and in which R ²⁰ and R ²¹ are both hydrogen. In another preferred embodiment, the compound is a compound of formula (XlV _b ) in which R ¹⁹ and R ²⁰ are both hydrogen; and in which R ²¹ is halogen (e.g. fluorine).

In one embodiment, the compound is characterized by formula (XV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein r, R ⁴ , R ⁵ , R ¹⁰ and R ¹⁸ to R ²¹ are as defined herein.

In embodiments, the compound is characterized by formula (XV _a ) or formula (XV _b ),

(xv _a )

or a pharmaceutically acceptable salt or prodrug thereof, wherein r, R ⁴ , R ⁵ , R ¹⁰ and R ¹⁸ to R ²¹ are as defined herein

In one embodiment, q is 0.

In a preferred embodiment, the compound is a compound of formula (XV _a ) in which R ¹⁹ is selected from fluorine and methoxyl; and in which R ²⁰ and R ²¹ are both hydrogen. In another preferred embodiment, the compound is a compound of formula (XV _a ) in which R ¹⁹ and R ²⁰ are both hydrogen; and in which R ²¹ is halogen (e.g. fluorine).

In one aspect, the compound is selected from the group consisting of Compounds 1 to 180:

Compound 9 (lR*,2S*)-2-(((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[ d]thiazol- 2-yl)amino)methyl)cy clohexan- 1 -ol

Compound 10 (lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino)methyl)benzo[d]th iazol-2- yl)amino)cyclohexan-l -ol

Compound 11 ((lR*,2R*)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[ d]thiazol- 2-yl)amino)cyclohexyl)methanol

Compound 12 (lR,2R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- y l)amino)cy clopentan- 1 -ol

Compound 13 (lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cy clopentan- 1 -ol

Compound 14 (lR,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cyclohexan-l -ol

Compound 15 (lS,2R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cyclohexan-l -ol

Compound 16 ((lR*,2S*)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[ d]thiazol- 2-yl)amino)cyclohexyl)methanol

Compound 17 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(l-(tetrahydrofura n-2- yl)ethyl)benzo[d]thiazol-2-amine

Compound 18 (l-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thiazol- 2- yl)amino)cyclopentyl)methanol

Compound 19 (S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thiaz ol-2- yl)amino)-2-cy clohexylethan- 1 -ol

Compound 20 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-((tetrahydro-2H-py ran-2- yl)methyl)benzo[d]thiazol-2-amine

Compound 21 (lS*,6R*)-6-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d ]thiazol- 2-yl)amino)-2,2-difluorocyclohexan-l-ol

Compound 22 (lS,2R)-l-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)-2,3-dihydro-lH-inden-2-ol

Compound 23 (lS*,2S*)-Nl-(6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d ]thiazol- 2-yl)cyclohexane-l ,2-di amine

Compound 24 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-isobutylbenzo[d]th iazol-2- amine

Compound 25 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-((tetrahydro-2H-py ran-4- yl)methyl)benzo[d]thiazol-2-amine

Compound 26 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(2- methoxybenzyl)benzo[d]thiazol-2-amine

Compound 27 (lR,2R)-2-((6-(l-((6-chloropyrazin-2-yl)amino)ethyl)benzo[d] thiazol-2- yl)amino)cyclohexan-l -ol

Compound 28 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(2- methoxyphenyl)benzo[d]thiazol-2-amine

Compound 29 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-phenylbenzo[d]thia zol-2- amine Compound 30 (S)-6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(l- cyclohexylethyl)benzo[d]thiazol-2-amine

Compound 31 N-benzyl-6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thia zol-2- amine

Compound 32 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(4- methoxyphenyl)benzo[d]thiazol-2-amine

Compound 33 (S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thiaz ol-2- y l)amino)-2-pheny lethan- 1 -ol

Compound 34 (2S,3S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)-3-methylpentan-l -ol

Compound 35 (lR,2S)-l-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)-2,3-dihydro-lH-inden-2-ol

Compound 36 (R)-6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(l- cyclohexylethyl)benzo[d]thiazol-2-amine

Compound 37 (R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thiaz ol-2- yl)amino)-2-pheny lethan- 1 -ol

Compound 38 (R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]thiaz ol-2- yl)amino)-2-cy clohexylethan- 1 -ol

Compound 39 (R)-6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(l-(2- methoxyphenyl)ethyl)benzo[d]thiazol-2-amine

Compound 40 N-cyclohexyl-6-((quinazolin-4-ylamino)methyl)benzo[d]thiazol -2-amine

Compound 41 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-(4- methoxybenzyl)benzo[d]thiazol-2-amine

Compound 42 6-(((6-chloropyrazin-2-yl)amino)methyl)-N-((6-(trifluorometh yl)pyridin- 3-yl)methyl)benzo[d]thiazol-2-amine

Compound 43 N-Cyclohexyl-6-((pyrazin-2-ylamino)methyl)benzo[d]thiazol-2- amine

Compound 44 N-cyclohexyl-6-((pyridin-3-ylamino)methyl)benzo[d]thiazol-2- amine

Compound 45 (lR,2R)-2-((6-(((5-chloropyridin-3-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cyclohexan-l -ol

Compound 46 N-cyclohexyl-6-((pyrimidin-5-ylamino)methyl)benzo[d]thiazol- 2-amine

Compound 47 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl) amino)pyrazine-2-carboxamide

Compound 48 (lR,2R)-2-((6-(((6-phenylpyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cyclohexan-l -ol

Compound 49 (lR,2R)-2-((6-(((6-(2-fluorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 50 ( 1 R,2R)-2-((6-(((6-(py ridin-3 -y l)py razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 51 (lR,2R)-2-((6-(((6-(l-methyl-lH-pyrazol-4-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 52 (lR,2R)-2-((6-(((6-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 53 (lR,2R)-2-((6-(((6-cyclopropylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 54 (lR,2R)-2-((6-(((6-(cyclopent-l-en-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 55 (lR,2R)-2-((6-(((6-(3,5-dimethylisoxazol-4-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 56 (lR,2R)-2-((6-(((6-(4,4-dimethylcyclohex-l-en-l-yl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 57 (lR,2R)-2-((6-(((6-(l-methyl-lH-pyrazol-5-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 58 ( 1 R,2R)-2-((6-(((6-(4,5-dihy dro- 1 H-py rrol-3 -y l)py razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 59 (lR,2R)-2-((6-(((6-(l,2,3,6-tetrahydropyridin-4-yl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 60 (lR,2R)-2-((6-(((6-(l,2,5,6-tetrahydropyridin-3-yl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 61 (lR,2R)-2-((6-(((6-(4,5-dihydrofuran-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 62 (lS,2S)-2-((6-(((6-phenylpyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl)amino)cyclohexan-l -ol

Compound 63 (lS*,6R*)-2,2-difluoro-6-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 64 (lR,2R)-2-((6-(((6-(4-fluorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 65 (lR,2R)-2-((6-(((6-methylpyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- yl) amino)cyclohexan-l-ol

Compound 66 (lR,2R)-2-((6-(((6-(tert-butyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 67 (lR,2R)-2-((6-(((6-(pyridin-2-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 68 (lR,2R)-2-((6-(((6-(tetrahydro-2H-pyran-4-yl)pyrazin-2- yl)amino)methyl) benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 69 N-Cyclobutyl-6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benz o[d] thiazol-6-yl)methyl)amino)pyrazine-2-carboxamide

Compound 70 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl)amino)-N-methylpyrazine-2-carboxamide

Compound 71 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl)amino)-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxam ide

Compound 72 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl)amino)-N-(oxetan-3-yl)pyrazine-2-carboxamide Compound 73 N-cyclopropyl-6-(((2-(((lR,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)amino)py razine- 2-carboxamide

Compound 74 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl)amino)-N,N-dimethylpyrazine-2-carboxamide

Compound 75 N-ethyl-6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]t hiazol-6- yl)methyl)amino)pyrazine-2-carboxamide

Compound 76 6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 - yl)methyl)amino)-N-isopropylpyrazine-2-carboxamide

Compound 77 (lR,2R)-2-[(4-Methoxy-6-{[(6-phenylpyrazin-2-yl)amino]methyl }-l,3- benzothiazol-2-yl)amino] cy clohexan- 1 -ol

Compound 78 (1 S,2S)-2-[(4-methoxy-6- { [(6-phenylpyrazin-2-yl)amino] methyl} -1,3- benzothiazol-2-yl)amino] cy clohexan- 1 -ol

Compound 79 (lR,2S)-l-[(4-methoxy-6-{[(6-phenylpyrazin-2-yl)amino]methyl }-l,3- benzothiazol-2-yl)amino]-2,3-dihydro-lH-inden-2-ol

Compound 80 (lS,2R)-l-[(6-{[(6-phenylpyrazin-2-yl)amino]methyl}-l,3-benz othiazol- 2-yl)amino]-2,3-dihydro-lH-inden-2-ol

Compound 81 (lR,2S)-l-[(6-{[(6-phenylpyrazin-2-yl)amino]methyl}-l,3-benz othiazol- 2-yl)amino]-2,3-dihydro-lH-inden-2-ol

Compound 82 (lR,2R)-2-((6-(((6-(3-fluorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 83 (lR,2R)-2-((6-(((6-(3-(2-hydroxypropan-2-yl)phenyl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 84 (lR,2R)-2-((6-(((6-(6-methylpyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 85 (lS*,2S*)-l-methyl-2-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 86 (lR,2R)-2-((6-(((6-ethynylpyrazin-2-yl)amino)methyl)benzo[d] thiazol-2- yl)amino)cyclohexan-l -ol

Compound 87 (lR,2R)-2-((6-(((6-(2-methylpyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 88 ( 1 R,2R)-2-((6-(((6-(prop- 1 -yn- 1 -y l)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 89 (lR,2R)-2-((6-(((6-(2,4-dichlorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 90 (lR,2R)-2-((6-(((6-(2-methoxypyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 91 (lR,2R)-2-((6-(((6-(5-fluoropyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 92 (lR,2R)-2-((6-(((6-(m-tolyl)pyrazin-2-yl)amino)methyl)benzo[ d]thiazol- 2-y l)amino)cy clohexan- 1 -ol Compound 93 (lR,2R)-2-((6-(((6-(3-chlorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 94 (lR,2R)-2-((6-(((6-(3-amino-4-methylphenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 95 (lR,2R)-2-((6-(((6-(4-(hydroxymethyl)phenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 96 N-(3-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thi azol-6- yl)methyl)amino)pyrazin-2-yl)benzyl)methanesulfonamide

Compound 97 (lR,2R)-2-((6-(((6-(2,4-difluorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 98 (lR,2R)-2-((6-(((6-(5-methoxypyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 99 (lR,2R)-2-((6-(((6-(2,3-difluorophenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 100 (lR,2R)-2-((6-(((6-(3-(pyrrolidin-l-ylmethyl)phenyl)pyrazin- 2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 101 N-(3-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thi azol-6- yl)methyl)amino)pyrazin-2-yl)benzyl)acetamide

Compound 102 (lR,2R)-2-((6-(((6-(2-fluoro-4-(methylsulfonyl)phenyl)pyrazi n-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 103 (lR,2R)-2-((6-(((6-(3-hydroxy-3-methylbut-l-yn-l-yl)pyrazin- 2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 104 (lR,2R)-2-((6-(((6-(3-amino-3-methylbut-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 105 (lR,2R)-2-((6-(((6-(cyclopropylethynyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 106 (lR,2R)-2-((6-(((6-(3-hydroxyprop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 107 tert-but l (3-(6-(((2-(((lR,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)amino)py razin-2- yl)prop-2-yn-l -yl)carbamate

Compound 108 (lR*,2R*)-l-methyl-2-((6-(((6-(prop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 109 (lR*,2R*)-2-((6-(((6-ethynylpyrazin-2-yl)amino)methyl)benzo[ d]thiazol- 2-yl)amino)-l -methylcyclohexan-1 -ol

Compound 110 (lR,2R)-2-((6-(((6-((tetrahydro-2H-pyran-4-yl)ethynyl)pyrazi n-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 111 (lR,2R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 112 (lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 113 (lR,2S)-l-((6-(((6-chloropyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)-2,3-dihydro-lH-inden-2-ol

Compound 114 (lR,2R)-2-((4-methoxy-6-(((6-(prop-l -yn-1 -yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 115 (lR,2R)-l-methyl-2-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 116 (lS,2S)-l-methyl-2-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 117 (lR,2R)-2-((6-(((6-(3-chlorophenyl)pyrazin-2-yl)amino)methyl )-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 118 ( 1 S ,2S)-2-((5 -fluoro-6-(((6-pheny lpy razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 119 (lR,2R)-2-((6-(((6-(2,4-difluorophenyl)pyrazin-2-yl)amino)me thyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 120 (1 S *,2S *)-l -methyl-2-((6-(((6-(prop- 1 -yn-1 -yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 121 (lR,2R)-2-((6-(((6-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyrazi n-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 122 (lR,2R)-2-((6-(((6-(3-morpholinoprop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 123 (lR,2R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7- fluorobenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 124 (lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino)methyl-d2)benzo[d ]thiazol- 2-y l)amino)cy clohexan- 1 -ol

Compound 125 (lR,2R)-2-((6-(((6-(prop-l -yn-1 -yl)pyrazin-2-yl)amino)methyl- d2)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 126 (lR,2R)-2-((6-(((6-phenylpyrazin-2-yl)amino)methyl-d2)benzo[ d]thiazol- 2-y l)amino)cy clohexan- 1 -ol

Compound 127 (lS,2S)-2-((4-methoxy-6-(((6-(prop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 128 3-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazo l-6- yl)methyl)amino)pyrazin-2-yl)benzonitrile

Compound 129 4-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazo l-6- yl)methyl)amino)pyrazin-2-yl)benzonitrile

Compound 130 (lR,2R)-2-((6-(((6-(2-methoxyphenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 131 (lR,2R)-2-((6-(((6-(3-methoxyphenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 132 (lR,2R)-2-((6-(((6-(4-methoxyphenyl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 133 (lS,2S)-2-((4-methyl-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 134 (lR,2R)-2-((4-fluoro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 135 (lS,2S)-2-((4-fluoro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 136 ( 1 R,2R)-2-((6-(((6-(3 -fluoro-2-methoxy pheny l)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 137 ( lR,2R)-2-((6-(((6-(4-fluoro-2-methoxy pheny l)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 138 ( 1 R,2R)-2-((6-(((6-(5 -fluoro-2-methoxy pheny l)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 139 3-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazo l-6- yl)methyl)amino)pyrazin-2-yl)-4-methoxybenzonitrile

Compound 140 (lR,2R)-2-((6-(((6-(4-methoxypyridin-3-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 141 (lR,2R)-2-((6-(((6-(2-methoxy-5-methylpyridin-3-yl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 142 (lR,2R)-2-((6-(((6-(5-fluoro-2-methoxypyridin-3-yl)pyrazin-2 - yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 143 (lR,2R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2- y l)amino)- 1 -methy Icy clohexan- 1 -ol

Compound 144 (lR,2R)-2-((6-(((6-(3-hydroxy-3-methylbut-l-yn-l-yl)pyrazin- 2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohe xan-l-ol

Compound 145 (lR,2R)-2-((6-(((6-(3-hydroxyprop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohe xan-l-ol

Compound 146 3-(6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)-4- methoxybenzo[d]thiazol-6-yl)methyl)amino)pyrazin-2-yl)-4- methoxybenzonitrile

Compound 147 (lR,2R)-2-((4-chloro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 148 (lS,2S)-2-((4-chloro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 149 rel-(lR,2R,3R,5R)-3-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)bicyclo[3.1.0]hex an-2-ol

Compound 150 ( lR,2R)-2-((6-(((6-(4-chloro-2-methoxy pheny l)py razin-2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohe xan-l-ol

Compound 151 ( lR,2R)-2-((6-(((6-(5-chloro-2-methoxy pheny l)py razin-2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohe xan-l-ol

Compound 152 (lR,2R)-2-((6-(((6-(4-chlorophenyl)pyrazin-2-yl)amino)methyl )-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 153 (lR,2R)-2-((6-(((6-(2-chlorophenyl)pyrazin-2-yl)amino)methyl )-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 154 (lR,2R)-2-((6-(((6-(2,4-dichlorophenyl)pyrazin-2-yl)amino)me thyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 155 (lR,2R)-2-((6-(((6-(2,5-dichlorophenyl)pyrazin-2-yl)amino)me thyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 156 (lR,2R)-2-((4-methoxy-6-(((6-(2-(trifluoromethoxy)phenyl)pyr azin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 157 (lR,2R)-2-((6-(((6-(2-ethylphenyl)pyrazin-2-yl)amino)methyl) -4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 158 (lS,2S)-2-((7-chloro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 159 (lS,2S)-2-((5-chloro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 160 6-(((6-chloropyrazin-2-yl)amino)methyl)-4-methoxy-N-((tetrah ydro-2H- pyran-4-yl)methyl)benzo[d]thiazol-2-amine

Compound 161 4-methoxy-6-(((6-phenylpyrazin-2-yl)amino)methyl)-N-((tetrah ydro-2H- pyran-4-yl)methyl)benzo[d]thiazol-2-amine

Compound 162 4-methoxy-6-(((6-phenylpyrazin-2-yl)amino)methyl)-N-((6- (trifluoromethyl)pyridin-3-yl)methyl)benzo[d]thiazol-2-amine

Compound 163 (lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7- fluorobenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 164 ( 1 S ,2S)-2-((5 -chloro-6-(((6-chloropyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 165 (R)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)-4-methylpentan-l-ol

Compound 166 (lS,2S)-2-((7-fluoro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 167 (lR,2R)-2-((7-fluoro-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 168 (R)-2-((4-methoxy-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)-4-methylpentan-l -ol

Compound 169 (lR,2R)-2-((6-(((6-(2-(difluoromethoxy)phenyl)pyrazin-2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohe xan-l-ol

Compound 170 (lS,2S)-2-((7-fluoro-6-(((6-(prop-l-yn-l-yl)pyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 171 (1 R,2R)-2-((7-fluoro-6-(((6-(prop- 1 -yn- 1 -y l)py razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 172 (lR,2S)-l-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7- fluorobenzo[d]thiazol-2-yl)amino)-2,3-dihydro-lH-inden-2-ol

Compound 173 N-((lS*,2S*)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexyl)methanesulfonam ide

Compound 174 ( 1 S ,2S)-2-((7-chloro-6-(((6-(prop- 1 -yn- 1 -y l)py razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 175 N-((lS*,2S*)-2-((4-methoxy-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2- yl)amino)cyclohexyl)methanesulfonamide

Compound 176 rel-(lS,2R,3R,5S)-3-((6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)bicyclo[3.1.0]hex an-2-ol

Compound 177 (3S,4S)-3-((6-(((6-chloropyrazin-2-yl)amino)methyl)-4- methoxybenzo[d]thiazol-2-yl)amino)tetrahydro-2H-pyran-4-ol

Compound 178 (3S*,4R*)-4-((4-methoxy-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)tetrahydro-2H-pyr an-3-ol

Compound 179 (3S,4S)-3-((4-methoxy-6-(((6-phenylpyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)tetrahydro-2H-pyr an-4-ol

Compound 180 (3 S ,4S)-3 -((4-methoxy-6-(((6-(prop- 1 -yn- 1 -y l)py razin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)tetrahydro-2H-pyr an-4-ol or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound is selected from the group consisting of Compounds 1 to 81 or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 43, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 67, 68, 69, 70, 73, 74, 75, 76, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 3, 5, 7, 8, 9, 10, 11, 14, 15, 16, 17, 19, 20, 21, 22, 26, 30, 33, 34, 35, 36, 38, 45, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 61, 62, 63, 64, 65, 67, 68, 70, 76, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 3, 7, 8, 9, 10, 11, 14, 19, 21, 30, 35, 36, 38, 48, 49, 50, 51, 52, 53, 54, 61, 62, 63, 64, 67, 80 and 81; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 3, 10, 11, 35, 48, 49, 50, 52, 54, 62, 63, 64, 67, 81, 82, 83, 84, 85, 86, 88, 90, 91, 93, 94, 95, 96, 97, 98, 99, 101, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 118, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 145, 146, 147, 148, 151, 153, 158, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 174, 175, 177, 178 and 179; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 3, 11, 14, 15, 21, 30, 35, 38, 49, 50, 51, 64, 67, 70 and 71; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 50, 51, 64, 70 and 71; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 3, 8, 11, 14, 15, 16, 21, 22, 35, 49, 50, 51, 67 and 71 ; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 15, 35, 38, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 35, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 62, 85, 88, 90, 108, 110, 113, 114, 115, 120, 125, 127, 130, 138, 139, 140, 141, 142, 146, 151, 161, 166, 170 and 179; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 49, 50, 51 and 70; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 35, 50 and 51 ; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 35, 50 and 51 ; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 15, 21, 35, 49, 50, 51, 70, 88, 103, 106, 107, 111, 113, 114, 117, 119, 127, 133, 134, 146, 147, 148, 160, 165, 171, 173 and 180; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 35, 50, 51, 106, 111, 113, 114, 119, 127, 134, 146, 147, 160, 165, 171, 173 and 180; or a pharmaceutically acceptable salt or prodrug thereof.

The compounds of the invention are useful as kinase inhibitors. In particular, compounds of the invention are useful as inhibitors of CSF-1R. Assays for determining the inhibitory activity of compounds against CSF-1R (e.g. against mouse or human CSF-1R, or a fragment thereof having protein kinase activity) are known in the art and are also set out in the following Examples. The activity values listed below may, for example, be determined according to an assay as set out in the following Examples. In embodiments, compounds of the invention have an IC5 ₀ value (e.g. an inhibitory activity against CSF-IR in a cell-free assay), of less than 1 μΜ, less than 750 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM or less than 5 nM.

In embodiments, compounds of the invention have an IC5 ₀ value (e.g. an inhibitory activity against CSF-IR in a cell-based assay), of less than 2 μΜ, less than 1 μΜ, less than 750 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 75 nM, or less than 50 nM.

The compounds of the invention may be selective for CSF-IR over other kinases, e.g. c-KIT, PDGFRa, PDGFR and/or FLT3. In particular, the compounds of the invention may selectively inhibit the activity of CSF-IR over other kinases, e.g. c-KIT, PDGFRa, PDGFR and/or FLT3. Assays for determining the selectivity of a compound for CSF-IR over other kinases are known in the art. Examples of assays for determining the selectivity of a compound for CSF-IR over other kinases are also set out in the following Examples. The selectivity values listed below may, for example, be determined according to the assays set out in the following Examples.

In embodiments, the compounds of the invention are selective for CSF-IR over another kinase by a value of at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, at least 100 times, at least 150 times, at least 200 times, at least 250 times, at least 300 times, at least 350 times, at least 400 times, at least 450 times, at least 500 times, at least 1000 times, or at least 1500 times . By "selective" is meant that the concentration of compound which results in 50% maximal inhibition (IC ₅₀ ) of said another kinase is at least the stated factor more than the concentration of compound which results in 50% maximal inhibition of CSF-IR. Thus, a compound having an IC5 ₀ value of 10 nM against CSF-IR, and having an IC5 ₀ value of 200 nM against another kinase, is selective for CSF-IR over said another kinase by a value of 20 times. In embodiments, the compounds of the invention are selective for CSF-IR over PDGFR by a value of at least 2.5 times, at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 25 times or at least 30 times.

In embodiments, the compounds of the invention are selective for CSF-IR over PDGFRa at a value of at least 5 times, at least 10 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, or at least 100 times.

In embodiments, the compounds of the invention are selective for CSF-IR over c-KIT by a value of at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 150 times, at least 200 times, at least 300 times, at least 400 times, at least 500 times, or at least 1000 times more.

In embodiments, the compounds of the invention are selective for CSF-IR over FLT3 by a value of at least 100 times, at least 200 times, at least 500 times, at least 1000 times, at least 1500 times, or at least 2000 times.

Salts

Presently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g. by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained. Presently disclosed compounds that are positively charged, e.g. containing a quaternary ammonium, may also form salts with the anionic component of various inorganic and/or organic acids.

Acids which can be used to prepare pharmaceutically acceptable salts of compounds are those which can form non-toxic acid addition salts, e.g. salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Presently disclosed compounds that are acidic in nature, e.g. compounds containing a tetrazole moiety, are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g. by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, e.g. under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents may be employed in order to ensure completeness of reaction and maximum product yields of the desired solid salt.

Bases which can be used to prepare the pharmaceutically acceptable base addition salts of compounds are those which can form non-toxic base addition salts, e.g. salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g. potassium and sodium), alkaline earth metal cations (e.g. calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines.

Prodrugs

Pharmaceutically acceptable prodrugs for use according to the present disclosure are derivatives of CSF-1R inhibitors, e.g. compounds characterized by formula (I), which can be converted in vivo into the compounds described herein. The prodrugs, which may themselves have some activity, become fully pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or through enzymatic degradation. Methods for preparing prodrugs of compounds as described herein would be apparent to one of skill in the art based on the present disclosure. Stereochemistry

Stereoisomers (e.g. cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g. R- and S- enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

For example, where the group R ³ contains one or more chiral carbon atoms, the compounds of the invention may exist predominantly as a single enantiomer (or diastereomer), or as a mixture of isomers (e.g. enantiomers or diastereomers).

In embodiments, the compounds of the invention are present as a racemic mixture, e.g. said R- and S- isomers (or all enantiomers or diastereomers) are present in approximately equal amounts. In other embodiments the compounds of the invention are present as a mixture of isomers in which one enantiomer (or diastereomer) is present in an enantiomeric excess of at least about 5%, 10%, 25%, 40%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, e.g. about 100%.

Methods for preparing enantioenriched and/or enantiopure compounds would be apparent to the person of skill in the art based on the present disclosure. Examples of such methods include chemical resolution (e.g. crystallization) and chiral chromatography.

The compounds presently disclosed may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, all tautomers are within the scope of the present disclosure.

Where compounds are characterized by structural formulae that indicate stereochemical information, the invention extends to mixtures of one or more of said compounds characterized by the said structural formulae. Thus, in embodiments, the invention provides a mixture of compounds characterized by formulae (IV _a ) and (IVb), or pharmaceutically acceptable salts or prodrugs of one or more thereof. In other embodiments, the invention provides a mixture of compounds characterized by formulae (V _a ) and (¼,), or pharmaceutically acceptable salts or prodrugs of one or more thereof.

Other forms

Pharmaceutically acceptable hydrates, solvates, polymorphs, etc. , of the compounds described herein are also within the scope of the present disclosure. Compounds as described herein may be in an amorphous form and/or in one or more crystalline forms. Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, H, ¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0,

31 32 35 18 36

P, P, S, F, and CI, respectively. Deuterated compounds, e.g. compounds of the invention which have one or more hydrogen atoms replaced by deuterium, are preferred. Pharmaceutical compositions

The present disclosure provides pharmaceutical compositions comprising at least one compound of the invention, e.g. a compound characterized by formula (I), and at least one pharmaceutically acceptable excipient, e.g. for use according to the methods disclosed herein.

The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.

A pharmaceutical composition or dosage form of the invention can include an agent and another carrier, e.g. compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g. sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this invention, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.

Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Additional carriers include polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g. cyclodextrins, such as 2-hydroxypropyl- - cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g. polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g. phospholipids, fatty acids), steroids (e.g. cholesterol), and chelating agents (e.g. EDTA).

The present disclosure also provides pharmaceutical compositions, and kits comprising said compositions, which contain at least one compound as described herein, e.g. a compound characterized by formula (I), and at least one further pharmaceutically-active agent. These pharmaceutical compositions and kits may be adapted to allow simultaneous, subsequent and/or separate administration of the compound and the further active agent. For example, the compound and the further active agent may be formulated in separate dosage forms, e.g. in separate tablets, capsules, lyophilisates or liquids, or they may be formulated in the same dosage form, e.g. in the same tablet, capsule, lyophilisate or liquid. Where the compound and the further active agent are formulated in the same dosage form, the compound and the further active agent may be present substantially in admixture, e.g. within the core of a tablet, or they may be present substantially in discrete regions of the dosage form, e.g. in separate layers of the same tablet.

A further aspect of the present invention provides a pharmaceutical composition comprising: (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) a further active agent; and (iii) a pharmaceutically acceptable excipient. Another aspect of the present invention provides a kit comprising (i) a compound as described herein, e.g. a compound characterized by formula (I); (ii) instructions for the use of the compound in therapy, e.g. in a method as described herein; and (iii) optionally a further active agent.

In embodiments, the further active agent is an anti-proliferative agent, an anti-inflammatory agent, an anti-angiogenic agent, a chemotherapeutic agent, or an immunotherapeutic agent.

The pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. The pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g. by using an enteric coating. Examples of embedding compositions include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g. , Remington's). The compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.

Chemical synthesis

An illustrative synthetic scheme (Scheme I) is shown below for the preparation of compounds characterised by formula (I) in which groups R ⁴ and R ⁵ are both hydrogen:

E

Scheme I

In step (i) of Scheme I, the compound A (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is reduced, e.g. using DIBAL. Nucleophilic aromatic substitution, e.g. using sodium methanethiolate, leads to intermediate B. In step (ii), hydroxyl substitution, e.g. using DPPA and DBU, and subsequent hydrogenation using e.g. a Lindlar catalyst yields intermediate C. In step (iii), cyclic group A (which may be protected if necessary, e.g. if substituted), which carries a leaving group "LG", participates in a nucleophilic substitution or coupling reaction to yield intermediate D. The nucleophilic substitution reaction in step (iii) may, for example, be a nucleophilic aromatic substitution using an appropriate aryl halide in the case where the cyclic group A is aromatic or heteroaromatic and LG is a halogen. In step (iv), oxidation, e.g. using mCPBA, and treatment with a selective amine, gives the target compound E. Alternatively, compounds as disclosed herein may be prepared using the following synthetic methodology:

Scheme II

In step (i) of Scheme II, the compound A is reduced to intermediate F. In step (ii), hydroxyl substitution, e.g. using DPP A and DBU, yields organic azide intermediate G. Subsequent nucleophilic aromatic substitution or coupling with amine H2N-L-R ³ leads to intermediate H in step (iii) that, upon hydrogenation, gives amine I in step (iv). Reaction of I with cyclic group A (protected, if necessary) which carries a leaving group "LG", gives the target compound E.

Schemes I and II may be varied to obtain other compounds as disclosed herein. For example, where the cyclic group A is substituted in target compound E with an alkyl, alkenyl, alkynyl or (hetero)aryl group {i.e. R ¹ ), the target compound may be obtained using the substituted cyclic group R ^X -A-LG in step (iii) of Scheme I or in step (v) of Scheme II. Alternatively, the target compound may be prepared using a cyclic group A-LG which is substituted by a halide or a pseudohalide {e.g. a triflate, or alkoxy group) at the position to be substituted by R ¹ . This yields a corresponding product, E' which may then be coupled with either (a) an organoboron species, e.g. R ¹ -B(OH) ₂ , in a Suzuki reaction; (b) an organozinc species, e.g. (R ^x ) ₂ Zn, in a Negishi reaction; or (c) an alkyne, e.g. in a Sonogashira reaction. The coupled product may optionally be further reacted, e.g. reduced, to yield the desired final product. These steps are illustrated below in Schemes III and IV:

E' (R) = H Scheme III

In Scheme III, the group "Y" is a halide or a pseudohalide (e.g. a triflate, or alkoxy group). Coupling under conditions appropriate for Suzuki, Negishi or Sonogashira reaction yields the product E, in which R ¹ is typically a group that contains at least one carbon-carbon double or triple bond. Unsaturated bonds in an R ¹ group may be reduced, e.g. as illustrated in Scheme IV in which a compound E is catalytically hydrogenated to yield the corresponding product.

E (reduced)

Scheme IV

Compounds of formula (I) in which R ⁴ and/or R ⁵ are other than hydrogen may be obtained, for example, by modifying the above-mentioned schemes according to the following Scheme V:

In step (i) of Scheme V, the intermediate B (which may be prepared according to Scheme I above) is oxidised to the corresponding aldehyde J, e.g. using MnC>2 in DCM. Intermediate J is reacted in step (ii) with a Grignard reagent in which the alkyl group corresponds to a group R ⁴ , e.g. with R ⁴ -MgBr in a solvent such as THF. This reaction yields intermediate K which is converted in step (iii) into the corresponding chloride, L, e.g. using SOCI2 or PCI ₃ in a solvent such as pyridine. In step (iv), cyclic group A (which may be protected if necessary, e.g. if substituted), which carries a primary amine group, is reacted with L to yield intermediate M. In step (v), oxidation, e.g. using mCPBA, and treatment with a selective amine, gives the target compound N.

By way of a further example, Scheme VI below provides a route to compounds of Formula (VI) in which group X ¹ is S and R ⁴ and R ⁵ are both hydrogen:

In step (i) of Scheme VI, compound O is converted into benzothiazole P, e.g. by treatment with potassium thiocyanate and bromine in acetic acid. In step (ii), intermediate P is transformed to bromide Q, e.g. by treatment with copper bromide and t-BuONO. Reduction in step (iii), e.g. using DIBAL, and substitution in step (iv), e.g. with DPP A in DBU, leads to intermediate azide S. Nucleophilic aromatic substitution or coupling in step (v), e.g. using H ₂ N-L-R ³ in DIEA, followed by reduction in step (vi), e.g. using PdVC and H ₂ , gives intermediate amine U. Introduction of the heterocycle in step (vii) leads to product V. As would be appreciated, where V contains halogen atoms on the aromatic ring (e.g. at position R ¹⁰ ), a further coupling step, e.g. using a Pd catalyst, may be employed to obtain other compounds of formula (VI).

An illustrative synthetic scheme (Scheme VII) for the preparation of compounds characterised by e.g. formula (XIII) is shown below:

Scheme VII

In step (i) of Scheme VII, the aniline compound W (which may be commercially available, or prepared according to general synthetic methodology known to the person of skill in the art) is converted to its corresponding benzothiazole, e.g. using KSCN and Br ₂ , which is subsequently brominated in step (ii), e.g. using CuBr ₂ and tBuONO, to yield compound X. The product of step (ii) is further brominated in step (iii), e.g. using NBS and benzoic peroxyanhydride, to yield compound Y, which is then converted to the corresponding azide compound Z, e.g. using NaN ₃ . Nucleophilic aromatic substitution or coupling in step (v), e.g. using H ₂ N-L-R ³ under elevated temperature, followed by reduction in step (vi), e.g. using PdVC and H ₂ , gives intermediate amine AB. Introduction of the heterocycle in step (vii) leads to product AC. As would be appreciated, where AC contains a halogen atom at position R ¹⁰ , a further coupling step, e.g. using a Pd catalyst, may be employed to obtain other compounds of formula (XIII).

An illustrative synthetic scheme (Scheme VIII) for the preparation of intermediates of the type H ₂ N-L-R ³ , in which L is a direct bond and R ³ is bicyclo[3.1.0]hexan-2-ol, is shown below:

AD AE

AF AG

Scheme VIII

In step (i), the isoindoline compound AD (acting as a protected aminocyclopentene) is hydroxylated, e.g. using SeC>2, to yield an anti product AE. The cyclopentenol portion is converted to the corresponding bicyclo[3.1.0]hexanol AF, e.g. using diethylzine and diiodomethane, and the isoindoline function is removed, e.g. using hydrazine in ethanol, to yield the free amine AG which can be used directly in the reactions illustrated herein.

Other methods for the preparation of the present compounds would be apparent to the skilled person on the basis of the present disclosure, especially the following Examples.

Medical indications

The compounds described herein, and pharmaceutical compositions containing them, are useful in therapy, in particular in the therapeutic treatment of CSF-IR mediated disorders in a subject. Subjects to be treated according to the methods described herein include vertebrates, such as mammals. In preferred embodiments the mammal is a human patient.

The present invention provides a method for treating a CSF-IR mediated disease in a subject, the method comprising administering to the subject an effective amount of a compound as defined herein, e.g. a compound characterised by formula (I). Also provided is a compound as defined herein, e.g. a compound characterised by formula (I), for use in a method of treating a CSF-IR mediated disease in a subject. Further provided is the use of a compound as defined herein, e.g. a compound characterised by formula (I), in the manufacture of a medicament for use in a method of treating a CSF-IR mediated disease in a subject.

CSF-IR and its ligands have been implicated in a number of disease states, including cancers; bone disorders such as osteolysis; inflammatory disorders such as rheumatoid arthritis, atherosclerosis and inflammatory bowel disease; and neurological disorders such as Alzheimer's disease, ALS and brain injury.

In embodiments, the CSF-IR mediated disease is selected from cancer, a bone disorder, an inflammatory disorder, and a neurological disorder.

CSF-IR can mediate the development and/or progression of disease in a number of ways including: aberrant signalling, overexpression of CSF-IR, CSF-IR gene mutations, overexpression of its ligands CSF-1 and IL-34, and/or through its role in the development and proliferation of macrophages, microglia and osteoclasts.

In embodiments, the CSF-IR mediated disease is characterised by overexpression of CSF-IR. In embodiments, the CSF-IR mediated disease is characterised by aberrant CSF-IR signalling. In embodiments, the CSF-IR mediated disease is characterised by overexpression of CSF-1 and/or IL-34. In embodiments, the CSF-IR mediated disease is characterised by mutations in the CSF-IR gene.

Cancer

Overexpression of CSF-IR and its ligand CSF-1 occurs in a significant number of cancer types, for example in tenosynovial giant-cell tumors, breast, ovarian, prostate and endometrial cancers. Levels of CSF-IR and CSF-1 correlate with tumor progression, cell invasiveness and adverse prognosis. In non-metastatic breast cancer, CSF-IR expression can be associated with decreased overall survival patients (Kluger et al, Clin. Cancer Res. (2004) 10(l,Pt. l): 173-7). A high level of expression of CSF-IR in tumor stromal cells, but not cancer cells themselves, may be a marker for lower survival in Hodgkin lymphoma (Koh et al, Am. J. Clin. Pathol. (2014) 141(4):573-83). High expression levels of CSF-1 have also been reported to associate with higher histological tumor grading, metastases and poor prognosis in various cancer types including breast cancer, ovarian cancer and prostate (Lin et al, supra). In particular, high systemic levels of CSF-1 have been associated with late stage metastatic cancers, for example in men with prostate cancer metastatic to bone, and in women with advance metastatic breast cancer. Macrophage differentiation and proliferation is dependent on CSF-IR signalling pathways and recruitment to the tumor environment is driven by chemokines including CSF-1. Upon recruitment to the tumor microenvironment, tumor associated macrophages (TAMs) release pro-angiogenic factors, proteases important for invasion, and other growth factors involved in the growth and motility of tumor cells.

TAMs are associated with a number of cancers and high TAM levels can correlate with angiogenesis and malignancy progression. In particular, high numbers of TAMs have been identified as a poor prognostic factor in several cancer types including breast cancer, prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer and Hodgkin's lymphoma (Bingle et al , 2002, supra; Pollard et al, Nat. Rev. Cancer. (2004) 4(l):71-78). Reduction in the number of TAMs in a variety of preclinical models has been demonstrated to correlate with extended survival.

Inhibition of CSF-IR signalling is reported to reduce angiogensis, decrease growth of malignant cells, improve prognosis, prevent or reduce tumor progression and reduce the number of TAMs, in various cancer models, such as models of gastrointestinal stromal tumor, breast cancer, osteosarcoma, lung carcinoma and prostate cancer (Pyonteck et al , Nat. Med. (2013) 19(10): 1264-1272; Strachan et al, 2013, supra; Laoui et al, Front. Immunol. (2014) 5:a.489).

Accordingly, in one embodiment the CSF-IR mediated disease is a cancer. In embodiments, the cancer is associated with high levels of tumor associated macrophages (TAMs). In embodiments, the cancer is associated with overexpression of CSF-IR and/or CSF-1. In embodiments, the cancer is associated with CSF-IR mutations. Methods for assessing TAMs, CSF-IR, CSF-1 and CSF-IR mutations are described herein and/or known to the skilled person.

In one embodiment the cancer is selected from breast cancer, cervical cancer, glioblastoma multiforme (GBM), Hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, pancreatic cancer pigmented villondular synovitis (PVNS), prostate cancer, ovarian cancer, Tenosynovial giant cell tumors (TGCT), Endometrial cancer, Multiple myeloma, Myelocytic leukemia, Bone cancer, Renal cancer, Brain cancer and myeloproliferative disorder (MPD). In embodiments, administration of the compounds as disclosed herein can treat subjects diagnosed as having a cancer or being at risk of developing a cancer. In embodiments, administration of compounds as disclosed herein improves prognosis, reduces angiogenesis, reduces number of tumor associated macrophages (TAMs), decreases growth of malignant cells and/or prevents or reduces tumor progression.

Inflammatory disease

Overexpression of CSF-IR has been associated with a number of inflammatory disorders, for example, rheumatoid arthritis, atherosclerosis, Crohn's disease, inflammatory bowel diseases, sarcoidosis, glomerulonephritis, allograft rejection and arteriosclerosis.

Macrophages play a key role in chronic inflammation and increased levels of these cells can correlate with disease severity. They are an important source of pro-inflammatory cytokines such as TNFa and IL-lb, which can induce CSF-1 expression in different cell types. This contributes to monocyte recruitment, differentiation and proliferation and further TNFa and IL-lb expression, resulting in a positive feedback loop which may help to drive chronic inflammation.

Rheumatoid arthritis is an inflammatory autoimmune disease caused by the accumulation of macrophages in the connective tissue and synovial fluid. CSF-lR/CSF-1 mediated signalling has been suggested to contribute to macrophage proliferation and infiltration into the synovial tissue. Inhibition of CSF-IR can decrease disease progression, decrease the destruction of bone and cartilage, and decrease the number of macrophages present in the joints of patients with collagen-induced arthritis.

Increased numbers of renal macrophage and high expression of CSF-1 is associated with several forms of immune mediate nephritis such as lupus nephritis. Reduced creatinine clearance is related to high renal CSF-1 levels. In a lupus nephritis mouse model, a CSF-IR antibody decreased macrophage recruitment and proliferation at sites of renal inflammation.

Microglia cells play an important role in the immune response within the central nervous system and are thought to play a role in regulating the neuroinflammatory response associated with brain disease. CSF-IR signalling is important for the proliferation and survival of microglial in the adult brain, and CSF-IR knockout mice are devoid of microglia. Proliferation and activation of microglia is a hallmark of several neuroinflammatory diseases including experimental autoimmune encephalomyelitis (EAE), HIV encephalitis, neurodegenerative conditions such as Alzheimer's disease and ALS, stroke and brain injury. Increased microglial proliferation correlates with increased upregulation of CSF-IR and with disease severity in some cases. CSF-1 has been reported to promote inflammation in Alzheimer's disease and ALS. In mouse models of Alzheimer's disease treatment with CSF- 1R inhibitors reportedly blocks microglial proliferation, depletes microglia populations and promotes a shift in anti -inflammatory profile (Luo et al , J. Exp. Med. (2013) 210(1): 157-72; Dagher et al, J. Neuroinflammation (2015) 12: 139; Olmos-Alonso et al, Brain (2016) 139(Pt.3):891-907).

Accordingly, in one embodiment, the CSF-1 R mediated disease is an inflammatory disorder. In embodiments, the inflammatory disorder is associated with high levels of macrophages or microglia. In embodiments, the inflammatory disorder is associated with increased expression of CSF-1R and/or CSF-1. In embodiments the inflammatory disorder is selected from psoriatic arthritis, arthritis, asthma, thyroiditis, glomerular nephritis, atherosclerosis, psoriasis, Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosis (SLE), cutaneous lupus erythematosus, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), type 1 diabetes, multiple sclerosis and neuroinflammatory conditions such as HIV encephalitis, Alzheimer's disease and ALS.

Bone disease

Osteoclasts are multinucleated cells of hematopoietic origin which are able to resorb bone and play a key role in several skeletal diseases including osteoporosis, inflammatory osteolysis and bone erosion. An increase in the number of osteoclast cells and an imbalance in the number of osteoclast-osteoblasts cells results in an abnormally high bone resorption rate.

CSF-1 and CSF-1R play an important role in osteoclast survival and differentiation. Mice with a single point mutation in CSF-1 are reported to have decreased levels of osteoclast cells and developed osteopetrosis; whilst removal of CSF-1 from osteoclast cultures results in osteoclast apoptosis. Osteoporosis is a bone disease mediated by loss of osteoblasts and increased osteoclast dependent bone resorption. Treatment of an osteoporosis mouse model with an anti-CSF-1 antibody was reported to preserve bone density and inhibit bone resorption (Sauter et al, J. Leukoc. Biol. (2014) 96(2):265-274). Paget's disease is a bone metabolism disorder associated with increased bone turnover. Mutations have been identified in a number of genes, including CSF-1, which are associated with the regulation of osteoclast function which predispose individuals to Paget's disease. CSF-1 also has a potential role in the pathogenesis of periodontitis, an inflammatory disease of teeth which is associated with bone reabsorption (Rabello et al , Biochem. Biophys. Comm. (2006) 3(l):791-796). Studies have also shown that inhibition of CSF-1R contributes to bone protection. For example, treatment with an inhibitor of CSF-IR is reported to inhibit bone degradation in osteoclast cultures, rat calvaria and rat fetal long bones (Conway et al, Proc. Natl. Acad. Sci. USA (2005) 102(44): 16078-16083).

Accordingly, in one embodiment, the CSF-IR mediated disease is a bone disorder selected from osteoporosis, osteoarthritis, periodontitis, periprosthetic osteolysis, and Paget' s disease.

Combination therapies

In embodiments, the treatment of a CSF-IR mediated disease as disclosed herein is achieved by administering a compound of the invention in combination with another therapeutic intervention for said CSF-IR mediated disease. The other therapeutic intervention may be performed before, during and/or after administering the compound of the invention.

In embodiments, the other therapeutic intervention includes the administration of a pharmaceutical agent as disclosed herein, especially an anti-proliferative agent, an antiinflammatory agent, an anti-angiogenic agent, a chemotherapeutic agent, or an immunotherapeutic agent. In embodiments the other therapeutic intervention is adoptive t- cell transfer. In other embodiments, the other therapeutic intervention is radiotherapy.

Administration and dosages

A presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g. intravenous, intraperitoneal, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation. In one embodiment, the compound or pharmaceutical composition is formulated for systemic administration, e.g. via a non-parenteral route. In another embodiment, the compound or pharmaceutical composition is formulated for oral administration, e.g. in solid form. Such modes of administration and the methods for preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st ed., American Society of 15 Health-System Pharmacists 2007).

In solid dosage forms for oral administration (e.g. capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium lauryl sulphate, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, silica, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- actives, and/ or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.

In embodiments, the pharmaceutical compositions are administered orally in a liquid form. Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g. cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents, and the like. Suspensions, in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g. lecithin or acacia); nonaqueous vehicle (e.g. almond oil, oily esters or ethyl alcohol); and/or preservative (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The active ingredient(s) can also be administered as a bolus, electuary, or paste.

For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.

In embodiments, the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like. In related embodiments, the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g. intravenous, intramuscular, intra-arterial, subcutaneous, and the like).

Presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The pharmaceutical compositions can be in the form of sterile injections. The pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. To prepare such a composition, the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate. To improve solubility, a dissolution enhancing or solubilising agent can be added or the solvent can contain 10-60% w/w of propylene glycol or the like.

The pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile inj ectable solutions or dispersions just prior to use. Such pharmaceutical compositions can contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.

Examples of suitable aqueous and nonaqueous carriers, which can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, in order to prolong the effect of an active ingredient, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered active ingredient is accomplished by dissolving or suspending the compound in an oil vehicle. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants or infusion devices. Materials for use in the preparation of microspheres and/or microcapsules include, but are not limited to, biodegradable/bioerodible polymers such as polyglactin, poly-(isobut l cyanoacrylate), poly(2-hydroxyethyl-L- glutamine) and poly(lactic acid). Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies. Materials for use in implants can be non- biodegradable, e.g. polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(gly colic acid) or poly(ortho esters).

For topical administration, a presently disclosed compound may be formulated as an ointment or cream. Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, presently disclosed compounds may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the presently disclosed compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.

Generally, the agents and compositions described herein are administered in an effective amount or quantity sufficient to inhibit CSF-1R in the subject receiving the agent or composition. Typically, the dose can be adjusted based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. The effective amount may also vary depending on the mode of administration, e.g. intravenous versus oral, as well as on the nature of the composition, e.g. rapidly disintegrating versus slow release compositions. Determination of an effective amount is within the capability of those skilled in the art. Generally, an effective amount for administration to a subject is in the range of about 0.1 to 1000 mg/kg.

In other aspects, the invention provides a dosage form or pharmaceutical composition as described herein for use in therapy, e.g. for use in a method as defined herein.

Ill Having been generally described herein, the follow non-limiting examples are provided to further illustrate this invention.

EXAMPLES

Examples 1 to 81 - Chemical synthesis

Example 1: ( 1R, 2R)-2-( ( 6-( f ( 6-chloropyrazin-2-yl)amino)methyl)benzo[ d]thiazol-2-yl)amino) cyclohexan-l-ol TFA salt

(2-Bromobenzo[d]thiazol-6-yl)methanol: To a solution of ethyl 2-bromobenzo[d]thiazole-

6-carboxylate (1.00 g, 3.49 mmol) in DCM (17 ml) at -78 °C was added DIBAL-H in toluene (7.5 ml, 7.5 mmol, 1.0 M) slowly over 5 min and the resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at -78 °C with 1 M Rochelle salt (10 mL) and allowed to warm to rt over 30 min. The aqueous layer was extracted with 1 : 10 IPA/DCM (3 x 10 mL) and the combined organics were dried over MgS04, filtered, and concentrated. The title compound was isolated as a pale yellow solid (841 mg, 99%). MS (ES+) C ₈ H ₆ BrNOS requires: 243, found: 244 [M+H] ⁺ . ^X H NMR (600 MHz, Chloroform-^ δ 7.96 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 4.83 (d, J = 5.8 Hz, 2H), 1.81 (t, J = 5.9 Hz, 1H).

(2-(Methylthio)benzo[d]thiazol-6-yl)methanol: To a solution of (2-bromobenzo[d]thiazol- 6-yl)methanol (0.80 g, 3.3 mmol) in THF (11 mL) was added sodium methanethiolate (0.345 g, 4.92 mmol) and the resulting mixture was stirred at rt for 12 h. The reaction was diluted with Et^O (5 mL) and filtered through Celite. The volatiles were removed under reduced pressure. The title compound was isolated as an orange-brown oil (653 mg, 94%). MS (ES+) C ₉ H ₉ NOS2 requires: 211, found: 212 [M+H] ⁺ . ^X H NMR (600 MHz, Chloroform-i ) δ 7.83 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.39 (dd, J= 8.3, 1.6 Hz, 1H), 4.79 (d, J = 5.1 Hz, 2H), 2.80 (s, 3H).

6-(Azidomethyl)-2-(methylthio)benzo[d]thiazole: To a solution of (2-(methylthio)benzo [d]thiazol-6-yl)methanol (650 mg, 3.08 mmol) in THF (10 mL) at 0 °C were added diphenyl phosphorazidate (796 μΐ, 3.69 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (556 μΐ, 3.69 mmol) and the resulting mixture was stirred at rt for 15 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (708 mg, 97%) as a colorless liquid. MS (ES+) C ₉ H ₈ N ₄ S2 requires: 236, found: 237 [M+H] ⁺ . ^l H NMR (600 MHz, Chloroform-^ δ 7.86 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.36 (dd, J = 8.3, 1.7 Hz, 1H), 4.45 (s, 2H), 2.80 (s, 3H).

(2-(Methylthio)benzo[d]thiazol-6-yl)methanamine: A reaction vessel was charged with 6- (azidomethyl)-2-(methylthio)benzo[d]thiazole (0.70 g, 2.9 mmol), Lindlar catalyst (0.315 g, 0.148 mmol) and EtOH (15 mL) under an atmosphere of N ₂ . The suspension was degassed with N ₂ for 5 min and purged with H ₂ for 5 min. The reaction mixture was stirred under an atmosphere of H ₂ at 1 atm for 2 h. The reaction mixture was purged with N ₂ , filtered through Celite, and concentrated under reduced pressure to give the title compound as a pale yellow oil that slowly solidified (615 mg, 99%). MS (ES+) C ₉ H1 ₀ N2S2 requires: 210, found: 211 [M+H] ⁺ . ^l H NMR (600 MHz, DMSO-c¾) δ 7.93 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 8.2, 1.6 Hz, 1H), 3.81 (s, 2H), 2.78 (s, 3H).

6-Chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyraz in-2-amine: To a solution of 2,6-dichloropyrazine (283 mg, 1.90 mmol) and (2-(methylthio)benzo[d]thiazol-6- yl)methanamine (200 mg, 0.951 mmol) in dioxane (3.2 mL) was added K ₂ CO ₃ (263 mg, 1.90 mmol) and the resulting mixture was stirred at 120 °C for 12 h. The mixture was concentrated. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (271 mg, 88%) as a yellow solid. MS (ES+) C1 ₃ H11CIN4S2 requires: 322, found: 323 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c¾) δ 8.11 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.44 (dd, J= 8.4, 1.7 Hz, 1H), 4.57 (d, J= 5.8 Hz, 2H), 2.78 (s, 3H).

6-Chloro-N-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methy l)pyrazin-2-amine: To a suspension of 6-chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyraz in-2-amine (270 mg, 0.836 mmol) in DCM (8.4 mL) at 0 °C was added m-CPBA (206 mg, 0.836 mmol) in DCM (0.5 mL) and the resulting mixture was stirred at 0 °C for 6 h. The solution was diluted with sat. NaHCC (3 mL) and extracted with DCM (3 x 3 mL). The volatiles were removed under reduced pressure to give the title compound (273 mg, 96%) as a yellow amorphous material. MS (ES+) C1 ₃ H11CIN4OS2 requires: 338, found: 339 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c e) δ 8.22 (s, 1H), 8.19 (t, J= 6.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.60 (dd, J= 8.5, 1.7 Hz, 1H), 4.65 (d, J = 5.9 Hz, 2H), 3.07 (s, 3H). (ii?,2i?)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)benzo[d ]thiazol-2-yl)amino) cyclohexan-l-ol TFA salt: To a solution of 6-chloro-N-((2-(methylsulfinyl)benzo[d]thiazol- 6-yl)methyl)pyrazin-2-amine (18 mg, 0.053 mmol) in DMA (212 μΐ) was added (lR,2R)-2- aminocyclohexanol (18 mg, 0.16 mmol) and DIEA (9.3 μΐ, 0.053 mmol) and the resulting mixture was stirred at 120 °C for 12 h. The dark mixture was diluted with MeOH, acidified with TFA, and purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H ₂ O, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) to give the title compound (15 mg, 72%) as a tan solid. MS (ES+) Ci ₈ H ₂ oClN ₅ OS requires: 389, found: 390 [M+H] ⁺ . ^l H NMR (600 MHz, DMSO-c¾) δ 9.01 (s, 1H), 8.06 (t, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.74 - 7.67 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H), 7.29 (d, 1H), 4.48 (d, J = 5.5 Hz, 2H), 3.57 - 3.50 (m, 1H), 3.36 (td, J = 9.5, 4.2 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.94 - 1.88 (m, 1H), 1.71 - 1.61 (m, 2H), 1.32 - 1.22 (m, 4H).

The following examples in Table 1 were prepared analogously to Example 1.

Table 1:

1 -ol

1 -ol - 1 -ol 6-(((6-chloropyrazin-2- yl)amino)methyl)-N-(4-

41 411 412

methoxybenzy l)benzo [d]thiazol

-2 -amine

6-(((6-chloropyrazin-2- yl)amino)methyl)-N-((6-

42 450 451 (trifluoromethy l)py ridin-3 - yl)methyl)benzo[d]thiazol-2- amine

Example 43: N-Cyclohexyl-6-((pyrazin-2-ylamino)methyl)benzo[d]thiazol-2- amine TFA salt

N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amin e: To a suspension of 2- iodopyrazine (110 mg, 0.53 mmol) and (2-(methylthio)benzo[d]thiazol-6-yl)methanamine (75 mg, 0.36 mmol) in DMSO (713 μΐ) were added copper (2.3 mg, 0.036 mmol) and cesium acetate (137 mg, 0.713 mmol) and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1 % TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) to give the title compound (61 mg, 68%) as a brown amorphous material. MS (ES+) C13H12N4S2 requires: 288, found: 289 [M+H] ⁺ . ¾ NMR (600 MHz, Acetone-c¾) δ 8.67 (br s, 1H), 8.33 - 8.00 (m, 3H), 7.97 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, OH), 4.78 (s, 2H), 2.80 (s, 3H).

N-Cyclohexyl-6-((pyrazin-2-ylamino)methyl)benzo[d]thiazol -2-amine TFA salt: The title compound was prepared according to step (iv) of Scheme I using cyclohexylamine as the amine. Briefly, N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2-amin e was oxidised using mCPBA and then treated with cyclohexylamine to yield the title compound. MS (ES+) C1 ₈ H21N5S requires: 339, found: 340 [M+H] ⁺ . ^l H NMR (600 MHz, DMSO-c¾) δ 8.69 (s, 1H), 7.98 (s, 1H), 7.92 (d, J= 3.0 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.60 (s, 1H), 7.36 (d, J= 8.2 Hz, 1H), 7.26 (d, J= 6.5 Hz, 1H), 4.49 (s, 2H), 3.78 - 3.55 (m, 1H), 2.03 - 1.94 (m, 2H), 1.78 - 1.70 (m, 2H), 1.62 - 1.54 (m, 1H), 1.40 - 1.13 (m, 5H).

The following examples in Table 2 were prepared analogously to Example 43.

Table 2:

Example 47: 6-(((2-(((lR, 2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl) amino)pyrazine-2-carboxamide TFA salt

6-(((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)amino)pyrazin e-2-carboxamide: To a solution of 6-chloropyrazine-2-carboxamide (75 mg, 0.47 mmol) and (2- (methylthio)benzo[d]thiazol-6-yl)methanamine (50 mg, 0.24 mmol) in DMA (475 μΐ) was added DIEA (46 μΐ, 0.26 mmol) and the resulting mixture was stirred at 120 °C for 2 h. The mixture was concentrated. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM with 0.2% NH ₄ OH) to give the title compound (43 mg, 55%) as a tan solid. MS (ES+) C14H13N5OS2 requires: 331, found: 332 [M+H] ⁺ . ^l H NMR (500 MHz, DMSO-c¾) δ 8.22 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.94 - 7.89 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.48 (d, J= 9.5 Hz, 1H), 4.72 (d, J= 5.8 Hz, 2H), 2.78 (s, 3H).

6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6 -yl)methyl)amino) pyrazine-2-carboxamide TFA salt: The title compound was prepared analogously to the final step of Example 1. Briefly, to a solution of 6-(((2-(methylthio)benzo[d]thiazol-6- yl)methyl)amino)pyrazine-2-carboxarnide in DMA was added (7i?,2i?)-2-aminocyclohexanol and DIEA. The resulting mixture was stirred at elevated temperature to yield the title compound. MS (ES+) Ci ₉ H ₂ 2N ₆ 0 ₂ S requires: 398, found: 399 [M+H] ⁺ . ^l NMR (600 MHz, DMSO-c¾) δ 9.54 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.95 - 7.85 (m, 2H), 7.81 (s, 1H), 7.64 (s, 1H), 7.47 - 7.32 (m, 2H), 4.65 (d, J = 4.6 Hz, 2H), 3.96 (s, 1H), 3.58 - 3.42 (m, 1H), 3.36 (td, J = 9.6, 4.2 Hz, 1H), 2.05 - 1.99 (m, 1H), 1.94 - 1.88 (m, 1H), 1.69 - 1.62 (m, 2H), 1.32 - 1.15 (m, 4H).

Example 48: ( 1R, 2R)-2-( ⁽ 6-( ( ( 6-phenylpyrazin-2-yl)amino)methyl)benzo[ dJthiazol-2- yl) amino) cyclohexan-l-ol TFA salt

(lR,2R)-2-((6-(((6-phenylpyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2-yl)amino) cyclohexan-l-ol TFA salt: A suspension of (lR,2R)-2-((6-(((6-chloropyrazin-2- yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (35 mg, 0.081 mmol), phenylboronic acid (15 mg, 0.12 mmol) and sodium carbonate (21 mg, 0.20 mmol) in dioxane (645 μΐ) and water (161 μΐ) was degassed with N ₂ for 5 min. Tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 8.1 μιτιοΐ) was added and the mixture was degassed with N ₂ for an additional 5 min. The reaction mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H ₂ 0, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) to give the title compound (31 mg, 89%) as a pale yellow foam solid. MS (ES+) C24H25N5OS requires: 431, found: 432 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c¾) δ 9.44 (s, 1H), 8.30 (s, 1H), 8.02 - 7.97 (m, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.49 - 7.39 (m, 5H), 4.63 (s, 2H), 3.52 (s, 1H), 3.40 - 3.31 (m, 1H), 2.05 - 1.97 (m, 1H), 1.95 - 1.87 (m, 1H), 1.69 - 1.60 (m, 2H), 1.33 - 1.19 (m, 4H).

The following examples in Table 3 were prepared analogously to Example 48.

Table 3:

Example 65: ( 1R, 2R)-2-( ⁽ 6-( ( ⁽ 6-methylpyrazin-2-yl)amino)methyl)benzo[d]thiazol-2-yl) amino) cyclohexan-l-ol TFA salt

(lR,2R)-2-((6-(((6-methylpyrazin-2-yl)amino)methyl)benzo[d]t hiazol-2-yl)amino) cyclohexan-l-ol TFA salt: A solution of bis(tri-t-but lphosphine)palladium(0) (2.9 mg, 5.7 μιηοΐ) and (lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino)methyl)benzo[d]th iazol-2-yl)amino) cyclohexanol (50 mg, 0.12 mmol) in THF (1.15 mL) was degassed with N ₂ for 1 min. Dimethylzinc in heptane (345 μΐ, 0.345 mmol, 1.0 M) was added and the mixture was degassed with N2 for an additional 2 min. The reaction mixture was heated to 40 °C and stirred for 1 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM with 0.5% NH ₄ OH) to give the title compound (37 mg, 78%) as an off-white solid. MS (ES+) C1 ₉ H2 ₃ N5OS requires: 369, found: 370 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c¾) δ 7.85 (d, J = 7.5 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J= 1.7 Hz, 1H), 7.55 (s, 1H), 7.35 (t, J= 5.9 Hz, 1H), 7.29 (d, J= 8.2 Hz, 1H), 7.17 (dd, J = 8.2, 1.7 Hz, 1H), 4.73 (d, J = 5.1 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.55 - 3.49 (m, 1H), 3.35 (tt, J = 9.2, 4.6 Hz, 1H), 2.24 (s, 3H), 2.08 - 2.02 (m, 1H), 1.88 (dd, J = 10.6, 5.0 Hz, 1H), 1.62 (dd, J= 16.8, 9.9 Hz, 2H), 1.27 - 1.18 (m, 4H).

The following examples in Table 4 were prepared analogously to Example 65.

Table 4:

Example 68: ( 1R, 2R)-2-( ⁽ 6-( ( ( 6-( tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol TFA salt

(lR,2R)-2-((6-(((6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)am ino)methyl)

benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol TFA salt: A reaction vessel was charged with (lR,2R)-2-((6 ((6 3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)aniino)methyl)benzo[d ]thiazol- 2-yl)amino)cyclohexanol (17 mg, 0.039 mmol - Compound 52), palladium on carbon (8.3 mg, 7.8 μηιοΐ, 10 wt%) and EtOH (390 μΐ) under an atmosphere of N ₂ . The suspension was degassed with N ₂ for 5 min and purged with H ₂ for 5 min. The reaction mixture was stirred under an atmosphere of H ₂ at 1 atm for 24 h. The reaction mixture was purged with N ₂ , filtered through Celite, and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H ₂ 0, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) followed by silica gel chromatography (0 - 10 % MeOH in DCM w/ 0.5% NH40H) to give the title compound (1.6 mg, 9%) as a white solid. MS (ES+) C ₂ 3H ₂₉ N ₅ 0 ₂ S requires: 439, found: 440 [M+H] ⁺ . ^l NMR (600 MHz, Methanol-^) δ 7.68 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.56 (s, 2H), 4.06 - 3.97 (m, 2H), 3.61 - 3.50 (m, 3H), 3.44 (dt, J= 9.6, 4.9 Hz, 1H), 2.81 (tt, J = 11.8, 3.9 Hz, 1H), 2.21 - 2.11 (m, 1H), 2.07 - 1.97 (m, 1H), 1.94 - 1.82 (m, 2H), 1.80 - 1.68 (m, 4H), 1.45 - 1.23 (m, 4H). Example 69: N-Cyclobutyl-6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benz o[d] thiazol-6- yl)methyl)amino)pyrazine-2-carboxamide TFA salt

6-(Azidomethyl)-2-bromobenzo[d]thiazole TFA salt: To a solution of (2- bromobenzo[d]thiazol-6-yl)methanol (18.5 g, 75.8mmol) in dry THF (400 ml) at 0 °C were added DPPA (25 g, 91 mmol) and DBU (13.8 g, 91 mmol) and the resulting mixture was stirred at rt for 15 h. The crude mixture was purified via silica gel chromatography (12 - 35% EtOAc in Hexanes) to give 6-(azidomethyl)-2-bromobenzo[d]thiazole (12.4 g, 60.8%) as a pale yellow liquid that slowly solidified over time. MS (ES+) C2 ₃ H2 ₉ N5O2S requires: 267.9, found: 271 [M+H] ⁺ .

(lR,2R)-2-(6-(azidomethyl)benzo[d]thiazol-2-ylamino)cyclohex anol: A mixture of 6-(azidomethyl)-2-bromobenzo[d]thiazole (1.6 g, 5.95 mmol), (lR,2R)-2-aminocyclohexanol (1.37 g, 11.9 mmol) and DIEA (1.54 g, 11.9 mmol) in 20 mL of DMA was stirred at 90 °C for 6hs. The reaction mixture was cooled to rt, diluted with water, extracted with EtOAc (3 x30mL). The combined organic exacts was washed with brine, dried and concentrated. The crude was purified via silica gel chromatography (25-50% EtOAc in Hexanes) to provide (lR,2R)-2-(6-(azidomethyl)benzo[d]thiazol-2-ylamino)cyclohex anol (1.2 g, 66.5%) as a yellow liquid. MS (ES+) Ci ₄ Hi ₇ N ₅ OS, requires: 303, found: 304[M+H] ⁺ .

(lR,2R)-2-(6-(aminomethyl)benzo[d]thiazol-2-ylamino)cyclohex anol: A mixture of (lR,2R)-2-(6-(azidomethyl)benzo[d]thiazol-2-ylamino)cyclohex anol (900 mg, 3 mmol) and Pd/C(300 mg) in 40 mL of MeOH was stirred at rt for 16 h. The reaction mixture was filtered to afford (1R, 2R)-2-(6-(aminomethyl)benzo[d]thiazol-2-ylamino)cyclohexanol (750 mg, 90%) as a yellow solid. MS (ES+) Ci ₄ Hi ₉ N ₃ OS requires: 277, found: 278[M+H]+.

6-Chloro-N-cyclobutylpyrazine-2-carboxamide: To a suspension of 6-chloropyrazine-2- carboxylic acid (100 mg, 0.631 mmol), HATU (288 mg, 0.757 mmol), and cyclobutanamine (49 mg, 0.69 mmol) in DMF (1.26 mL) at 0 °C was added DIEA (220 μΐ, 1.26 mmol) and the resulting mixture was stirred at rt for 2 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (84 mg, 63%) as an off-white solid. MS (ES+) C ₉ H1 ₀ CIN ₃ O requires: 211, found: 212 [M+H] ⁺ . ^X H NMR (600 MHz, Chloroform-c δ 9.28 (s, 1H), 8.75 (s, 1H), 7.72 (s, 1H), 4.66 - 4.53 (m, 1H), 2.50 - 2.38 (m, 2H), 2.13 - 1.98 (m, 2H), 1.87 - 1.73 (m, 2H).

N-Cyclobutyl-6-(((2-(((lR,2R)-2-hydroxycyclohexyl)amino)benz o[d]thiazol-6-yl)methyl) amino)pyrazine-2-carboxamide TFA salt: To a solution of 6-chloro-N-cyclobutylpyrazine- 2-carboxamide (38 mg, 0.18 mmol) and (lR,2R)-2-((6-(aminomethyl)benzo[d]thiazol-2- yl)amino)cyclohexanol (25 mg, 0.090 mmol) in DMA (361 μΐ) was added DIEA (16 μΐ, 0.090 mmol) and the resulting mixture was stirred at 120 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H ₂ 0, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) to give the desired product as a brown residue (22 mg). The residue was repurified via silica gel chromatography (0 - 10 % MeOH in DCM with 0.5% NH ₄ OH) to give the title compound (11 mg, 27%) as an off-white solid. MS (ES+) C ₂₃ H2 ₈ N ₆ 0 ₂ S requires: 452, found: 453 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c¾) δ 8.38 (d, J = 8.6 Hz, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.92 - 7.79 (m, 2H), 7.69 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 4.74 (s, 1H), 4.61 (d, J = 5.5 Hz, 2H), 4.48 - 4.32 (m, 1H), 3.59 - 3.47 (m, 1H), 3.33 - 3.31 (m, 1H), 2.24 - 2.00 (m, 5H), 1.94 - 1.83 (m, 1H), 1.74 - 1.56 (m, 4H), 1.34 - 1.07 (m, 4H).

The following examples in Table 5 were prepared analogously to Example 69.

Table 5:

\ car oxam e Example 77: ( 1R, 2R)-2-( 4-Methoxy-6-( ( 6-phenylpyrazin-2-ylamino)methyl)benzo[ djthiazol- 2-ylamino)cyclohexanol TFA salt

Methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate: A solution of methyl 4- amino-3-methoxybenzoate (12 g, 14 mmol) in AcOH (15 mL) was added to a mixture of KSCN (5.4 g, 55 mmol) in AcOH (15 mL) at 0 °C. Subsequently, a solution of Br ₂ (0.8 mL, 15 mmol) in AcOH (6 mL) was added dropwise. The reaction mixture was stirred at rt for 16 h. Water was added and the pH was adjusted to ~8 by adding sat. Na ₂ C0 ₃ solution dropwise. The mixture was filtered to afford methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (3.2 g, 97%) as a yellow solid. MS (ES+) C10H10N2O3S requires: 238 found: 239 [M+H] ⁺ .

Methyl 2-bromo-4-methoxybenzo[d]thiazole-6-carboxylate: To a solution of CuBr ₂ (4.5 g, 20 mmol) in MeCN (40 mL) was added t-BuONO (2.8 g, 27 mmol) at 0 °C dropwise, followed by the addition of methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (3.2 g, 13 mmol) in one portion. The reaction mixture was stirred at rt for 4 h. The solvent was evaporated under reduced pressure. EtOAc and water were added, the mixture was filtered and the layers were separated. The organic layer was dried and concentrated to afford the title compound (2 g, 49%) as a yellow solid. MS (ES+) Ci ₀ H ₈ BrNO ₃ S requires: 301, found: 302, 304 [M+H] ⁺ .

(2-Bromo-4-methoxybenzo[d]thiazol-6-yl)methanol: To a solution of methyl 2-bromo-4- methoxybenzo[d]thiazole-6-carboxylate (2 g, 6.6 mmol) in THF (30 mL) was added DIBAL (16.6 mL, 16.6 mmol) at 0 °C. The reaction mixture was stirred at rt for 3 h. Subsequently, the reaction was diluted with water, filtered and the filtrate was extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (1.7 g, 94%) as a yellow oil. MS (ES+) C ₉ H ₈ BrN0 ₂ S requires: 274, found: 274, 276[M+H]+.

6-(Azidomethyl)-2-bromo-4-methoxybenzo[d]thiazole: To a solution of (2-bromo-4- methoxybenzo[d]thiazol-6-yl)methanol (1.7 g, 6.2 mmol) in dry THF (30mL) was added DPPA (2.0 g, 7.4 mmol) and DBU (1.1 g, 7.4 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was purified via silica gel chromatography (25% to 50% EtOAc in hexanes) to give the title compound (1.7 g, 91%) as a yellow oil. MS (ES+) C ₉ H ₇ BrN ₄ OS requires: 299, found: 299, 301 [M+H]+.

(lR,2R)-2-(6-(Azidomethyl)-4-methoxybenzo[d]thiazol-2-ylamin o)cyclohexanol: A mixture of 6-(azidomethyl)-2-bromo-4-methoxybenzo[d]thiazole (566 mg, 1.89 mmol), (lR,2R)-2-aminocyclohexanol (325 mg, 2.83 mmol) and DIEA (487 mg, 3.77 mmol) in DMA (5 mL) was stirred at 90 °C for 24 h. The reaction mixture was cooled to rt, it was diluted with water and extracted with EtOAc (3 x20 mL). The combined organic exacts were washed with brine, dried and concentrated. The residue was purified via silica gel chromatography (33% to 75% EtOAc in hexanes) to provide the title compound (500 mg, 79%) as a yellow oil. MS (ES+) C15H1 ₉ N5O2S, requires: 333, found: 334[M+H] ⁺ .

(lR,2R)-2-(6-(Aminomethyl)-4-methoxybenzo[d]thiazol-2-ylamin o)cyclohexanol: A mixture of (lR,2R)-2-(6-(azidomethyl)-4-methoxybenzo[d]thiazol-2-ylamin o)cyclohexanol (500 mg, 1.5 mmol) and Pd/C (100 mg) in MeOH (5 mL) was stirred at rt for 16 h under H ₂ atmosphere. The reaction mixture was filtered and concentrated to afford the title compound (400 mg, 86%) as a yellow oil. MS (ES+) C15H21N ₃ O2S requires: 307, found: 308[M+H]+.

(lR,2R)-2-(6-((6-Chloropyrazin-2-ylamino)methyl)-4-methox ybenzo[d]thiazol-2- ylamino)cyclohexanol: A mixture of 2,6-dichloropyrazine (233 mg, 1.56 mmol), (lR,2R)-2- (6-(aminomethyl)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohex anol (400 mg, 1.3 mmol) and DIEA (336 mg, 2.6 mmol) in DMA (5 mL) was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x20 mL). The combined organic exacts were washed with brine, dried and concentrated. The residue was purified via silica gel chromatography (50% to 90% EtOAc in hexanes) to give the title compound (250 mg, 45%) as a yellow oil. MS (ES+) C1 ₉ H22CIN5O2S, requires: 419, found: 420[M+H] ⁺ .

(lR,2R)-2-(4-Methoxy-6-((6-phenylpyrazin-2-ylamino)methyl)be nzo[d]thiazol-2- ylamino)cyclohexanol TFA salt: A mixture of phenylboronic acid (25 mg, 0.2 mmol), (lR,2R)-2-(6-((6-chloropyrazin-2-ylamino)methyl)-4-methoxybe nzo[d]thiazol-2- ylamino)cyclohexanol (42 mg, 0.1 mmol), Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol) and aq. K2CO ₃ (2M, 0.15 mL, 0.3 mmol) in 1,4-dioxane (1 mL) was irradiated in the microwave at 150 °C for 1 hr. The reaction mixture was concentrated, dissolved in MeCN and purified by preparative-HPLC (TFA) to afford the title compound (28 mg, 60%) as a yellow solid. MS (ES+) C25H27N5O2S requires: 461, found: 462[M+H]+; ^l H NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 8.03 - 7.95 (m, 2H), 7.88 (s, 1H), 7.50 - 7.39 (m, 4H), 7.27 (s, 1H), 4.76 (s, 2H), 3.99 (s, 3H), 3.74 - 3.64 (m, 1H), 3.56 - 3.46 (m, 1H), 2.15 - 2.02 (m, 2H), 1.86 - 1.76 (m, 2H), 1.52 - 1.34 (m, 4H).

The following examples in Table 6 were prepared analogously to Example 77.

Table 6:

Examples 82 to 180 - Chemical synthesis

The following examples in Table 8 were prepared analogously to Example 48. Table 8:

The following examples in Table 9 were prepared analogously to Example Table 9:

(lR,2R)-2-((6-(((6-(5-chloro-2- methoxyphenyl)pyrazin-2-

151 525 526 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

(lR,2R)-2-((6-(((6-(4- chlorophenyl)pyrazin-2-

152 495 496 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

(lR,2R)-2-((6-(((6-(2- chlorophenyl)pyrazin-2-

153 495 496 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

(lR,2R)-2-((6-(((6-(2,4- diclilorophenyl)pyrazin-2-

154 529 530 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

(lR,2R)-2-((6-(((6-(2,5- diclilorophenyl)pyrazin-2-

155 529 530 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

( lR,2R)-2-((4-methoxy-6-(((6- (2-

(trifluoromethoxy)phenyl)pyra

156 545 546

zin-2- yl)amino)methyl)benzo [d]thiaz ol-2-yl)amino)cyclohexan-l-ol (lR,2R)-2-((6-(((6-(2- ethylphenyl)pyrazin-2-

157 489 490 yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

6-(((6-chloropyrazin-2- yl)amino)methyl)-4-methoxy-

160 419 420 N-((tetrahydro-2H-pyran-4- yl)methyl)benzo[d]tliiazol-2- amine

4-methoxy-6-(((6- phenylpyrazin-2- yl)amino)methyl)-N-

161 461 462

((tetrahydro-2H-pyran-4- yl)methyl)benzo[d]thiazol-2- amine

4-methoxy-6-(((6- 1 r ^{H F} phenylpyrazin-2- yl)amino)methyl)-N-((6-

162 522 523

(trifluoromethyl)pyridin-3 - yl)methyl)benzo[d]thiazol-2- amine

(R)-2-((6-(((6-cMoropyrazin-2- yl)amino)methyl)-4-

165 421 422

methoxybenzo [d]thiazol-2- yl)amino)-4-methylpentan- l-ol

(R)-2-((4-methoxy-6-(((6- phenylpyrazin-2-

168 463 464 yl)amino)methyl)benzo [d]thiaz ol-2-yl)amino)-4- methylpentan- 1 -ol (lR,2R)-2-((6-(((6-(2- (difluoromethoxy)phenyl)pyraz

169 527 528 in-2-yl)amino)methyl)-4- methoxybenzo [d]thiazol-2- y l)amino)cyclohexan- 1 -ol

(3S,4S)-3-((6-(((6- chloropyrazin-2- yl)amino)methyl)-4-

177 421 422

methoxybenzo [d]thiazol-2- yl)amino)tetrahydro-2H-pyran- 4-ol

(3S*,4R*)-4-((4-methoxy-6- (((6-phenylpyrazin-2-

178 463 464 yl)amino)methyl)benzo [d]thiaz ol-2-yl)amino)tetrahydro-2H- pyran-3-ol

(3S,4S)-3-((4-methoxy-6-(((6- phenylpyrazin-2-

179 463 464 yl)amino)methyl)benzo [d]thiaz ol-2-yl)amino)tetrahydro-2H- pyran-4-ol

The following example in Table 10 was prepared analogously to Example 1.

Table 10:

Example 86: ( 1R, 2R)-2-( ⁽ 6-( ( ⁽ 6-ethynylpyrazin-2-yl)amino)methyl)benzo[d]thiazol-2-yl) amino) cyclohexan-l-ol

(lR,2R)-2-((6-(((6-((trimethylsilyl)ethynyl)pyrazin-2-yl)ami no)methyl)benzo[d]thiazol- 2-yl)amino)cyclohexan-l-ol: To a solution of (lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino) methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.11 mmol) in DMF (384 μΐ) were added triethylamine (176 μΐ, 1.27 mmol), ethynyltrimethylsilane (48 μΐ, 0.34 mmol), bis(triphenylphosphine)palladium(II) chloride (8.1 mg, 0.012 mmol) and Cul (1.1 mg, 5.8 μηιοΐ). The mixture was degassed for 2 min and the resulting mixture was stirred at 80 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM) to give the title compound (64 mg, 92%) as a brown amorphous material. MS (ES+) C2 ₃ H2 ₉ N5OSS1 requires: 451, found: 452 [M+H] ⁺ .

(lR,2R)-2-((6-(((6-ethynylpyrazin-2-yl)amino)methyl)benzo [d]thiazol-2-yl)amino) cyclohexan-l-ol: A vial was charged with (lR,2R)-2-((6-(((6-((trimethylsilyl) ethynyl)pyrazin-2-yl)amino)methyl)benzo[d]thiazol-2-yl)amino )cyclohexanol (52 mg, 0.12 mmol) and TBAF (230 μΐ, 0.230 mmol, 1.0 M in THF) and the resulting mixture was stirred at 0 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM w/ 0.5% NH ₄ OH) to give the title compound (16 mg, 37%) as a tan solid. MS (ES+) C ₂ oH ₂ iN ₅ OS requires: 379, found: 380 [M+H] ⁺ . ^X H NMR (600 MHz, DMSO-c¾) δ 7.96 (s, 1H), 7.88 (d, J = 6.5 Hz, 1H), 7.81 (s, 1H), 7.73 (t, J = 5.7 Hz, 1H), 7.59 (s, OH), 7.30 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.74 (s, 1H), 4.45 (d, J = 5.6 Hz, 2H), 4.35 (s, 1H), 3.62 - 3.45 (m, 1H), 3.38 - 3.34 (m, 1H), 2.15 - 1.99 (m, 1H), 1.95 - 1.81 (m, 1H), 1.69 - 1.51 (m, 2H), 1.33 - 1.10 (m, 4H).

The following examples in Table 11 were prepared analogously to Example 86. Table 11:

Example 114: ( 1R, 2R)-2-( ( 4-methoxy-6-( ( ⁽ 6-(prop-l-yn-l-yl)pyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

A suspension of bis(triphenylphosphine) palladium(II) chloride (1.51 mg, 2.15 μηιοΐ), copper(I) iodide (0.41 mg, 2.2 μηιοΐ) and (lR,2R)-2-((6-(((6-bromopyrazin-2- yl)amino)methyl)-4-methoxybenzo[d]thiazol-2-yl) amino)cyclohexanol (20 mg, 0.043 mmol) in DMF (144 μΐ) was degassed with N2 for 1 min. Triethylamine (66 μΐ, 0.47 mmol) was added and prop-l-yne was then bubbled through the mixture for 5 min. The reaction mixture was sealed and heated to 90 °C and stirred for 3 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM w/ 0.5% NH4OH) to give the title compound (13 mg, 57%) as a tan solid. MS (ES+) C22H25N5O2S requires: 423, found: 424 [M+H] ⁺ . ^l H NMR (600 MHz, DMSO-c¾) δ 7.93 (s, 1H), 7.79 (d, J= 7.7 Hz, 1H), 7.73 (s, 1H), 7.62 (t, J= 5.8 Hz, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 4.78 (d, J = 5.1 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H), 3.56 - 3.45 (m, 1H), 3.32 - 3.29 (m, 1H), 2.07 - 2.01 (m, 4H), 1.91 - 1.82 (m, 1H), 1.67 - 1.55 (m, 2H), 1.30 - 1.16 (m, 4H).

The following examples in Table 12 were prepared analogously to Example 114.

Table 12:

Example 118: ( IS, 2S)-2-( (5-fluoro-6-( ( ⁽ 6-phenylpyrazin-2-yl)amino)methyl)benzo[ djthiazol- 2-yl)amino)cyclohexan-l-ol

5-Fluoro-6-methylbenzo[d]thiazol-2-amine: 3-Fluoro-4-methylaniline (5.0 g, 40 mmol) and KSCN (15.5 g, 160 mmol) in AcOH (50 mL) was cooled to 0 °C and Br ₂ (6.7 g, 42 mmol) in AcOH (20 mL) was added slowly. The mixture was then stirred at rt for 3 h. The reaction mixture was quenched with ice-cold NH ₄ OH (100 mL). The resulting solid was filtered, washed with water, and dried under vacuum to give the title compound (6.0 g, 99%) as a yellow solid. MS (ES+) C ₈ H ₇ FN ₂ S requires: 182, found: 183 [M+H] ⁺ .

2-Bromo-5-fluoro-6-methylbenzo[d]thiazole: 5-Fluoro-6-methylbenzo[d]thiazol-2-amine (5.5 g, 30 mmol) and CuBr ₂ (10 g, 45 mmol) in CH ₃ CN (80 mL) was cooled to 0 °C before adding t-BuONO (3.4 g, 33 mmol) slowly and stirring at rt for 4 h. The reaction mixture was quenched with water (500 mL), extracted with EtOAc (3 ^χ 100 mL), dried and concentrated to give the title compound (4.2 g, 50%) as a dark red solid. MS (ES+) C ₈ H ₅ BrFNS requires: 245, found: 246 [M+H] ⁺ .

2-Bromo-6-(bromomethyl)-5-fluorobenzo[d]thiazole: To a suspension of 2-bromo-5- fluoro-6-methylbenzo[d]thiazole (1.0 g, 4.1 mmol) and NBS (0.80 g, 4.5 mmol) in CC1 ₄ (20 mL) was added benzoic peroxyanhydride (97 mg, 0.40 mmol). The resulting mixture was stirred at 80 °C overnight. The reaction mixture was filtered, and the volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 3 % EtOAc in petroleum ether) to give the title compound (450 mg, 34%) as a white solid. MS (ES+) C ₈ H ₄ Br ₂ FNS requires: 323, found: 324 [M+H] ⁺ .

6-(azidomethyl)-2-bromo-5-fluorobenzo[d]thiazole: To a solution of 2-bromo-6- (bromomethyl)-5-fluorobenzo[d]thiazole (450 mg, 1.38 mmol) in DMF (5 mL) at -30 °C was added NaN3 (107 mg, 1.6 mmol). The reaction mixture was stirred at -20 °C for 2 h. The reaction was then quenched with ice water (50 mL), and the solid was filtered, washed with water, and dried to give the title compound (380 mg, 95%) as a light yellow solid. MS (ES+) C ₈ H ₄ BrFN ₄ S requires: 286, found: 287 [M+H] ⁺ .

(lS,2S)-2-((6-(azidomethyl)-5-fluorobenzo[d]thiazol-2-yl)ami no)cyclohexan-l-ol: A sealed tube was charged with 6-(azidomethyl)-2-bromo-5-fluorobenzo[d]thiazole (380 mg, 1.3 mmol) and (l S,2S)-2-aminocyclohexan-l-ol (460 mg, 4.0 mmol). The mixture was heated at 100 °C with stirring for 3 h. The mixture was then quenched with water (60 mL), extracted with EtOAc (3 ^χ 30 mL), dried and concentrated. The residue was purified via silica gel chromatography (5 - 50 % EtOAc in petroleum ether) to give the title compound (210 mg, 50%) as a light yellow solid. MS (ES+) Ci ₄ Hi ₆ FN ₅ OS requires: 321, found: 322 [M+H] ⁺ .

(lS,2S)-2-((6-(Aminomethyl)-5-fluorobenzo[d]thiazol-2-yl)ami no)cyclohexan-l-ol:

(l S,2S)-2-((6-(Azidomethyl)-5-fluorobenzo[d]thiazol-2-yl)amino )cyclohexan-l-ol (200 mg, 0.60 mmol) and Pd/C (50 mg, 10 wt. %) were suspended in MeOH (10 mL). Then the mixture was stirred at 50 °C under an atomsphere of H ₂ for 48 h. The reaction mixture was filtered through Celite and concentrated to give the title compound (180 mg, 99%) as a light yellow solid. MS (ES+) Ci ₄ Hi ₈ FN ₃ OS requires: 295, found: 296 [M+H] ⁺ .

(lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-5-flu orobenzo[d]thiazol-2-yl) amino)cyclohexan-l-ol: A mixture of (lS,2S)-2-((6-(aminomethyl)-5-fluorobenzo[d]thiazol- 2-yl)amino)cyclohexan-l-ol (180 mg, 0.60 mmol), 2,6-dichloropyrazine (136 mg, 0.90 mmol) and DIPEA (0.8 mL) in DMA (2 mL) was heated at 100 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (60 mg, 24%) as a tan solid. MS (ES+) Ci ₈ Hi ₉ ClFN ₅ OS requires: 407, found: 408 [M+H] ⁺ .

(lS,2S)-2-((5-Fluoro-6-(((6-phenylpyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl) amino)cyclohexan-l-ol: A mixture of (lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)- 5-fluorobenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol (40 mg, 0.10 mmol), phenylboronic acid (60 mg, 0.50 mmol), Pd(dppf) ₂ Cl ₂ (40 mg, 0.050 mmol) and aqueous K ₂ C0 ₃ (2M, 0.5 mL) in dioxane (1 mL) was irradiated in the microwave at 150 °C for 2 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (10 mg, 22%) as a tan solid. MS (ES+) C ₂₄ H ₂ 4FN ₅ OS requires: 449, found: 450 [M+H] ⁺ ; ^X H NMR (500 MHz, MeOD) δ 8.17 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.66 (d, J= 7.2 Hz, 1H), 7.55 - 7.39 (m, 3H), 7.14 (d, J = 11.2 Hz, 1H), 4.72 (s, 2H), 3.62 - 3.41 (m, 2H), 2.13 (dd, J = 28.8, 21.8 Hz, 1H), 2.04 (s, 1H), 1.83 - 1.62 (m, 2H), 1.44 - 1.25 (m, 4H).

The following examples in Table 13 were prepared analogously to Example 118.

Table 13:

Example 124: ( 1R, 2R)-2-( ⁽ 6-( ( ( 6-bromopyrazin-2-yl)amino)methyl-d2)benzo[ dJthiazol-2- yl) amino) cyclohexan-l-ol

(2-bromobenzo[d]thiazol-6-yl)methan-d2-ol: To a solution of ethyl 2- bromobenzo[d]thiazole-6-carboxylate (200 mg, 0.699 mmol) in CH ₂ C1 ₂ (3.5 mL) at -78 °C was added DIBAL-D in toluene (2.15 mL, 1.50 mmol, 0.7 M) slowly over 5 min and the resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched at -78 °C with 1 M Rochelles salt (5 mL) and allowed to warm to rt over 30 min. The aqueous layer was extracted with 1 :5 IPA/DCM (3 x 5 mL) and the combined organics were concentrated. The volatiles were removed under reduced pressure. The crude title compound (188 mg, 98%) was isolated as an off-white solid. MS (ES+) C ₈ H ₄ D ₂ BrNOS requires: 245, found: 246 [M+H] ⁺ . ^X H NMR (500 MHz, Chloroform-i ) δ 7.96 (d, J = 8.4 Hz, OH), 7.85 (dd, J= 1.7, 0.6 Hz, 1H), 7.45 (dd, J= 8.4, 1.7 Hz, 1H), 1.76 (s, 1H).

6-(azidomethyl-d2)-2-bromobenzo[d]thiazole: To a solution of (2-bromobenzo[d]thiazol-6- yl)methan-d2-ol (180 mg, 0.731 mmol) in THF (2.4 mL) at 0 °C were added diphenyl phosphorazidate (189 μΐ, 0.878 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (132 μΐ, 0.878 mmol) and the resulting mixture was stirred at rt for 15 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (148 mg, 75%) as a pale yellow liquid that slowly solidified. MS (ES+) requires: 270, found: 271 [M+H] ⁺ .

(lR,2R)-2-((6-(azidomethyl-d2)benzo[d]thiazol-2-yl)amino)cyc lohexan-l-ol: To a solution of 6-(azidomethyl-d2)-2-bromobenzo[d]thiazole (148 mg, 0.546 mmol) and (lR,2R)-2-aminocyclohexanol (189 mg, 1.64 mmol) in DMA (2.2 mL) was added DIPEA (105 μΐ, 0.600 mmol) and the resulting mixture was stirred at 90 °C for 3 h and at 50 °C for 12 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (135 mg, 81%) as a tan amorphous material. MS (ES+) Ci ₄ Hi ₅ D ₂ BrN ₅ OS requires: 305, found: 306 [M+H] ⁺ .

(lR,2R)-2-((6-(aminomethyl-d2)benzo[d]thiazol-2-yl)amino) cyclohexan-l-ol: A reaction vessel was charged with (lR,2R)-2-((6-(azidomethyl-d2)benzo[d]thiazol-2- yl)amino)cyclohexan-l-ol (135 mg, 0.442 mmol), Lindlar catalyst (47 mg, 0.022 mmol) and Ethanol (4.4 mL) under an atmosphere of N ₂ . The suspension was degassed with N ₂ for 5 min and purged with H ₂ for 5 min. The reaction mixture was stirred under an atmosphere of H ₂ at 1 atm for 2 h. The reaction mixture was purged with N ₂ , filtered through Celite, and concentrated under reduced pressure. Isolated the crude title compound (130 mg, 95%) as a tan amorphous material. MS (ES+) CwHnDjBrNsOS requires: 279, found: 280 [M+H] ⁺ .

(lR,2R)-2-((6-(((6-bromopyrazin-2-yl)amino)methyl-d2)benz o[d]thiazol-2- yl)amino)cyclohexan-l-ol: To a solution of 2,6-dibromopyrazine (0.221 g, 0.931 mmol) and (lR,2R)-2-((6-(aminomethyl-d2)benzo[d]thiazol-2-yl)amino)cyc lohexan-l-ol (0.13 g, 0.46 mmol) in dioxane (1.5 mL) was added potassium carbonate (0.129 g, 0.931 mmol) and the resulting mixture was stirred at 90 °C for 15 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 10 % MeOH in DCM w/ 0.5% NH ₄ OH) to give the title compound (110 mg, 49%) as a tan foam solid. MS (ES+) Ci ₈ Hi ₈ D ₂ BrN ₅ OS requires: 435, found: 280 [M+H]+. ¾ NMR (600 MHz, DMSO-c 6) δ 7.95 (s, 1H), 7.93 (s, 1H), 7.92 - 7.87 (m, 1H), 7.77 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 4.75 (s, 1H), 3.57 - 3.47 (m, 1H), 3.43 - 3.35 (m, 1H), 2.10 - 1.99 (m, 1H), 1.93 - 1.81 (m, 1H), 1.70 - 1.53 (m, 2H), 1.31 - 1.13 (m, 4H).

Example 125: ( 1R, 2R)-2-( ( 6-( ⁽ ( 6-(prop-l-yn-l-yl)pyrazin-2-yl)amino)methyl-d2) benzo[ d]thiazol-2-yl)amino)cyclohexan-l-ol

Using a procedure analogous to example 86 the title compound was isolated as a tan solid (18 mg, 60%). MS (ES+) C21H21D2N5OS requires: 395, found: 396 [M+H]+. ^l NMR (600 MHz, DMSO-c e) δ 8.02 - 7.90 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.75 (dt, J = 23.9, 12.2 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 4.74 (d, J = 5.1 Hz, 1H), 3.57 - 3.48 (m, 1H), 3.38 - 3.34 (m, 1H), 2.09 - 2.01 (m, 4H), 1.93 - 1.84 (m, 1H), 1.69 - 1.55 (m, 2H), 1.34 - 1.12 (m, 4H). Example 126: ( 1R, 2R)-2-( ( 6-( ( ( 6-phenylpyrazin-2-yl)amino)methyl-d2)benzo[ d]thiazol-2- yl) amino) cyclohexan-l-ol

Using a procedure analogous to example 48 the title compound was isolated as an off-white solid (20 mg, 81%). MS (ES+) C24H2 ₃ D2N5OS requires: 433, found: 434 [M+H]+. ^l NMR (600 MHz, DMSO-c¾) δ 8.27 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.62 (s, 1H), 7.49 - 7.44 (m, 2H), 7.44 - 7.40 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.73 (d, J = 5.1 Hz, 1H), 3.38 - 3.33 (m, 1H), 2.09 - 1.98 (m, 1H), 1.92 - 1.83 (m, 1H), 1.72 - 1.52 (m, 2H), 1.35 - 1.01 (m, 4H).

Example 135: ( IS, 2S)-2-((4-fluoro-6-( ( ⁽ 6-phenylpyrazin-2-yl)amino)methyl)benzo[ djthiazol- 2-yl)amino)cyclohexan-l-ol

Methyl 4-amino-3-fluorobenzoate: A mixture of methyl 3-fluoro-4-nitrobenzoate (2.50 g, 12.5 mmol) and Pd/C (300 mg, 10 wt%) in 1 : 1 EtOAc/EtOH (40 mL) was stirred at rt for 16 h under 1 atm of H ₂ . The mixture was filtered through Celite and concentrated to give the title compound (2.1 g, 99%) as a beige solid. MS (ES+) C ₈ H ₈ FN0 ₂ requires: 169, found: 170 [M+H] ⁺ .

Methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate: KSCN (4.82 g, 49.7 mmol) was added to a solution of methyl 4-amino-3-fluorobenzoate (2.1 g, 12 mmol) in AcOH (15 mL). The mixture was stirred at rt until it became a clear solution. Then a solution of Br2 (2.19 g, 13.7 mmol) in AcOH (5 mL) was added dropwise and the resulting mixture stirred at rt for 48 h. At that time an additional amount of Br ₂ (600 mg, 3.73 mmol) in AcOH (2 mL) was added dropwise. The mixture was heated at 50 °C for 2 h. The reaction mixture was filtered and H ₂ 0 was added to the filtrate. Aqueous NH ₄ OH was then added to adjust the pH to 8. The resulting mixture was filtered and the solid collected to give the title compound (1.8 g, 64%) as a yellow solid. MS (ES+) C ₉ H ₇ FN ₂ 0 ₂ S requires: 226, found: 227 [M+H] ⁺ .

Methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate: To a solution of CuBr ₂ (2.7 g, 12 mmol) in CH ₃ CN (30 mL) at 0 °C was added t-BuONO (1.65 g, 16.0 mmol) dropwise, followed by the addition of methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (1.8 g, 8.0 mmol) in one portion. The reaction was stirred for 4 h at rt before diluting with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound (2.0 g, 86%) as a yellow solid. MS (ES+) Ci ₀ H ₈ BrNO ₃ S requires: 289, found: 290 [M+H] ⁺ .

(2-Bromo-4-fluorobenzo[d]thiazol-6-yl)methanol: DIBAL-H (17 3 mL, 17 3 mmol, 1M in THF) was added to a mixture of methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (2.0 g, 6.9 mmol) in THF (20 mL) at 0°C. The resulting mixture was stirred at rt for 16 h. An additional portion of DIBAL-H (13.8 mL, 13.8 mmol, l.OM in THF) was added. After stirring at rt for 3 h, the reaction was diluted with water, the solid filtered, and the filtrate was extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound (1.2 g, 66%) as a yellow oil. MS (ES+) C ₈ H ₅ BrFNOS requires: 261, found: 262 [M+H] ⁺ .

6-(Azidomethyl)-2-bromo-4-fluorobenzo[d]thiazole: DPPA (1.51 g, 5.50 mmol) and DBU (835 mg, 5.50 mmol) were added to a solution of (2-bromo-4-fluorobenzo[d]thiazol-6- yl)methanol (1.2 g, 4.58 mmol) in dry THF (20 mL) at 0 °C. The resulting mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (20 - 40% EtOAc in petroleum ether) to give the title compound (660 mg, 50%) as a yellow oil. MS (ES+) C ₈ H ₄ BrFN ₄ S requires: 286, found: 287 [M+H] ⁺ .

(lS,2S)-2-(6-(azidomethyl)-4-fluorobenzo[d]thiazol-2-ylam ino)cyclohexanol: A mixture of 6-(azidomethyl)-2-bromo-4-fluorobenzo[d]thiazole (330 mg, 1.15 mmol), (lS,2S)-2- aminocyclohexanol (198 mg, 1.72 mmol) and DIPEA (297 mg, 2.3 mmol) in DMA (4 mL) was stirred at 90 °C for 16 h. The mixture was then cooled to rt, diluted with water, and extracted with EtOAc (3 ^χ 20 mL). The combined organic exacts were washed with brine, dried and concentrated. The residue was purified via silica gel chromatography (30 - 50% EtOAc in petroleum ether) to give the title compound (140 mg, 39%) as a yellow solid. MS (ES+) Ci ₄ Hi ₆ FN ₅ OS, requires: 321, found: 322 [M+H] ⁺ . (lS,2S)-2-(6-(aminomethyl)-4-fluorobenzo[d]thiazol-2-ylamino )cyclohexanol: A mixture of (lS,2S)-2-(6-(azidomethyl)-4-fluorobenzo[d]thiazol-2-ylamino )cyclohexanol (140 mg, 0.44 mmol) and Pd/C (50 mg, 10 wt%) in MeOH (3 mL) was stirred at rt for 16 h under 1 atm of H ₂ . The reaction mixture was then filtered through Celite and concentrated to give the title compound (120 mg, 92%) as a yellow oil. MS (ES+) Ci ₄ Hi ₈ FN ₃ OS requires: 295, found: 296 [M+H]+.

(lS,2S)-2-(6-((6-chloropyrazin-2-ylamino)methyl)-4-fluoroben zo[d]thiazol-2-ylamino) cyclohexanol: A mixture of 2,6-dichloropyrazine (73 mg, 0.49 mmol), (l S,2S)-2-(6- (aminomethyl)-4-fluorobenzo[d]thiazol-2-ylamino)cyclohexanol (120 mg, 0.41 mmol) and DIPEA (105 mg, 0.81 mmol) in DMA (2 mL) was stirred at rt overnight. The reaction was then diluted with water, extracted with EtOAc (3 ^χ 20 mL) and the combined organic exacts were washed with brine, dried and concentrated. The residue was purified via silica gel chromatography (50 - 100% EtOAc in petroleum ether) to give the title compound (20 mg, 12%) as a yellow solid. MS (ES+) Ci ₈ Hi ₉ ClFN ₅ OS, requires: 407, found: 408 [M+H] ⁺ .

(lS,2S)-2-(4-fluoro-6-((6-phenylpyrazin-2-ylamino)methyl) benzo[d]thiazol-2-ylamino) cyclohexanol: A mixture of phenylboronic acid (13 mg, 0.10 mmol), (lS,2S)-2-(6-((6- chloropyrazin-2-ylamino)methyl)-4-fluorobenzo[d]thiazol-2-yl amino)cyclohexanol (20 mg, 0.050 mmol), Pd(PPh ₃ ) ₄ (6 mg, 0.005 mmol) and aq. K ₂ C0 ₃ (2M, 0.075 mL, 0.15 mmol) in

I, 4-dioxane (1 mL) was irradiated in the microwave at 150 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC

(MeCN/H ₂ 0/TFA) to give the title compound (2 mg, 9%) as a yellow solid. MS (ES+) C24H24FN5OS requires: 449, found: 450 [M+H] ⁺ ; Ti NMR (500 MHz, MeOD) δ 8.23 (s, 1H), 7.99 (dd, J = 8.0, 1.4 Hz, 2H), 7.88 (s, 1H), 7.56 (s, 1H), 7.50 - 7.42 (m, 3H), 7.23 (dd, J =

I I .6, 0.8 Hz, 1H), 4.72 (s, 2H), 3.72 - 3.63 (m, 1H), 3.49 - 3.44 (m, 1H), 2.16 - 2.06 (m, 2H), 1.82 - 1.74 (m, 2H), 1.49 - 1.31 (m, 4H).

The following examples in Table 14 were prepared analogously to Example 135. Table 14:

Example 149: Rel-( 1R, 2R 3R 5R)-3-( ⁽ 6-( ( ( 6-phenylpyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)bicyclo[3.1.0]hexan-2-ol

2-((lR*,2R*)-2-hydroxycyclopent-3-enyl)isoindoline-l,3-dione : A solution of 2- (cyclopent-3-enyl)isoindoline-l,3-dione (500 mg, 2.3 mmol) in dioxane/H ₂ 0/Pyridine (45/1/0.1 mL) was treated with SeC>2 (600 mg, 5.4 mmol). The resulting mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (33% EtOAc in petroleum ether) to give the title compound (400 mg, 74%) as a white solid. MS (ES ⁺ ) Ci ₃ HnN0 ₃ requires: 229, found: 230 [M+H] ⁺ .

Rel-2-((lR,2R,3R,5R)-2-hydroxybicyclo[3.1.0]hexan-3-yl)isoin doline-l,3-dione: A solution of rel-(2-((lR,2R)-2-hydroxycyclopent-3-enyl)isoindoline-l,3-di one (400 mg, 1.7 mmol) in DCM (15 mL) was cooled in an ice bath and treated with diethylzinc (8.5 mL, 8.5 mmol, 1M in hexane) dropwise. After stirring at 0 °C for 20 min, diiodomethane (1.4 mL, 17 mmol) was added dropwise. The resulting cloudy solution was stirred at 0 °C for 20 min and allowed to warm up to rt. After 6 h, the reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified via silica gel chromatography (20 - 50% EtOAc in petroleum ether) to give the title compound (200 mg, 53%) as a white solid. MS (ES ⁺ ) d ₄ Hi ₃ N0 ₃ requires: 243, found: 244 [M+H] ⁺ .

Rel-(lR,2R,3R,5R)-3-aminobicyclo[3.1.0]hexan-2-ol: A mixture of rel-2-((lR,2R,3R,5R)- 2-hydroxybicyclo[3.1.0]hexan-3-yl)isoindoline-l,3-dione (600 mg, 2.5 mmol), N2H4 monohydrate (0.5 mL), and EtOH (20 mL) was stirred at rt overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 10% MeOH in DCM) to give the title compound (150 mg, 54%) as a white solid. MS (ES ⁺ ) CeHiiNO requires: 113, found: 114 [M+H] ⁺ ; ^l H NMR (500 MHz, CD ₃ OD) δ 4.02 (dd, J = 5.0, 4.5 Hz, 1H), 2.62 (m, 1H), 2.08 (dd, J = 7.0, 7 Hz, 1H), 1.66 (m, 1H), 1.47 (m, 1H), 1.31 (m, 2H), 0.60 (m, 1H), 0.46 (m, 1H).

Rel-(lR,2R,3R,5R)-3-(6-((6-chloropyrazin-2-ylamino)methyl)be nzo[d]thiazol-2- ylamino)bicyclo[3.1.0]hexan-2-ol: A mixture of 6-chloro-N-((2-(methylsulfinyl) benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine (40 mg, 0.12 mmol) and rel-(lR,2R,3R,5R)-3- aminobicyclo[3.1.0]hexan-2-ol (35 mg, 0.30 mmol) was stirred at 110 °C under Ar overnight. The residue was purified via silica gel chromatography (5 - 10% MeOH in DCM) to give the title compound (20 mg, 44%) as a white solid. MS (ES ⁺ ) Ci ₈ Hi ₈ ClN ₅ OS requires: 387, found: 388 [M+H] ⁺ ; ^X H NMR (500 MHz, CDC1 ₃ ) δ 11.94 (s, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.57 (s, H), 7.47 (t, 1H), 7.40 (dd, J = 1.0, 1.5 Hz, 1H), 5.35 (s, 1H), 4.67 (m, 1H), 4.63 (s, 2H), 3.20 (m, 1H), 2.36 (dd, J = 7.5, 7.5 Hz, 1H), 2.05 (m, 1H), 1.61 (m, 1H), 1.47 (m, 1H), 0.69 (m, 1H), 0.52 (m, 1H). Rel-(lR,2R,3R,5R)-3-(6-((6-phenylpyrazin-2-ylamino)methyl)be nzo[d]thiazol-2- ylamino)bicyclo[3.1.0]hexan-2-ol: A solution of rel-(lR,2R,3R,5R)-3-(6-((6-chloropyrazin- 2-ylamino)methyl)benzo[d]thiazol-2-ylamino)bicyclo[3.1.0]hex an-2-ol (20 mg, 0.050 mmol) in DMF (5 mL) was treated with phenylboronic acid (7 mg, 0.05 mmol), PdCl2(dppf) (5 mg, 0.007 mmol), and KOAc (17 mg, 0.12 mmol). The resulting mixture was stirred at 100 °C under nitrogen overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (30% EtOAc in petroleum ether) to give the title compound (15 mg, 68%) as a white solid. MS (ES ⁺ ) C24H2 ₃ N5OS requires: 429, found: 430 [M+H] ⁺ ; ^X H NMR (500 MHz, CD ₃ OD) 57.98 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 5.43 (s, 2H), 3.66 (m, 1H), 3.48 (m, 1H), 2.18 (d, J = 12.0 Hz, 1H), 2.08 (t, H), 1.79 (t, 2H), 1.40 (m, 4H).

Example 166: ( IS, 2S)-2-( (7-fluoro-6-( ( ⁽ 6-phenylpyrazin-2-yl)amino)methyl)benzo[ djthiazol- 2-yl)amino)cyclohexan-l-ol

2-Bromo-5-fluoro-4-methylaniline: To a suspension of 3-fluoro-4-methylaniline (6.0 g, 48 mmol) and K ₂ C0 ₃ (6.6 g, 48 mmol) in DCM (80 mL) at -15 °C was added Br ₂ (2.4 mL, 48 mmol) in DCM (20 mL) slowly. The reaction mixture was stirred at -15 °C for 1 h. The mixture was then quenched with ice water (30 mL), diluted with water (80 mL), and extracted with DCM (3 x 50 mL), dried and concentrated. The residue was purified via silica gel chromatography (0 - 10 % EtOAc in petroleum ether) to give the title compound (3.2 g, 33%) as a white solid. MS (ES+) C ₇ H ₇ BrFN requires: 203, found: 204 [M+H] ⁺ .

4-Bromo-7-fluoro-6-methylbenzo[d]thiazol-2-amine: To a suspension of 2-bromo-5- fluoro-4-methylaniline (3.0 g, 15 mmol) and KSCN (2.9 g, 30 mmol) in AcOH (50 mL) at 0 °C was added Br ₂ (0.80 mL, 15 mmol) in AcOH (10 mL) slowly. The reaction mixture was stirred at rt for 3 h and then quenched with ice-cold NH ₄ OH (80 mL). The mixture was diluted with water (80 mL), extracted with DCM (3 ^χ 50 mL), dried, and concentrated. The residue was purified via silica gel chromatography (10 - 25 % EtOAc in petroleum ether) to give the title compound (2.2 g, 57%) as a light yellow solid. MS (ES+) C ₈ H ₆ BrFN ₂ S requires: 260, found: 261 [M+H] ⁺ .

2,4-Dibromo-7-fluoro-6-methylbenzo[d]thiazole: To a suspension of 4-bromo-7-fluoro-6- methylbenzo[d]thiazol-2-amine (2.0 g, 7.7 mmol) and CuBr ₂ (2.5 g, 11 mmol) in CH ₃ CN (50 mL) at 0 °C was added t-BuONO (0.87 mL, 8.5 mmol) slowly. The reaction mixture was stirred at rt for 4 h. The reaction was then quenched with water (200 mL), extracted with EtOAc (3x50 mL), dried, and concentrated to give the title compound (2.2 g, 80%) as a tan solid. MS (ES+) C ₈ H ₄ Br ₂ FNS requires: 323, found: 324 [M+H] ⁺ .

2,4-Dibromo-6-(bromomethyl)-7-fluorobenzo[d]thiazole: To a suspension of 2,4-dibromo- 7-fluoro-6-methylbenzo[d]thiazole (2.0 g, 6.2 mmol) and NBS (1.2 g, 6.8 mmol) in CC1 ₄ (40 mL) was added benzoic peroxy anhydride (150 mg, 0.62 mmol). The mixture was stirred at 90 °C overnight. The mixture was then filtered, and the filtrate concentrated. The residue was purified via silica gel chromatography (0 - 2 % EtOAc in petroleum ether) to give the title compound (1.2 g, 48%) as a light yellow solid. MS (ES+) C ₈ H ₃ Br ₃ FNS requires: 401, found: 402 [M+H] ⁺ .

6-(Azidomethyl)-2,4-dibromo-7-fluorobenzo[d]thiazole: To a solution of 2,4-dibromo-6- (bromomethyl)-7-fluorobenzo[d]thiazole (1.0 g, 2.5 mmol) in DMF (10 mL) at -30 °C was added NaN ₃ (194 mg, 3.0 mmol). The mixture was stirred at -20 °C for 2 h. The reaction was then quenched with ice water (60 mL), and the solid filtered to give the title compound (0.90 g, 99%) as a light yellow solid. MS (ES+) C ₈ H ₃ Br ₂ FN ₄ S requires: 364, found: 365 [M+H] ⁺ .

(lS,2S)-2-((6-(Azidomethyl)-4-bromo-7-fluorobenzo[d]thiaz ol-2-yl)amino)cyclohexan-l- ol: A sealed tube was charged with 6-(azidomethyl)-2,4-dibromo-7-fluorobenzo[d]thiazole (300 mg, 0.80 mmol) and (l S,2S)-2-aminocyclohexan-l-ol (300 mg, 2.5 mmol) and the mixture was stirred at 100 °C for 3 h. The reaction was then quenched with water (60 mL), extracted with EtOAc (3 ^χ 30 mL), dried and concentrated. The residue was purified via silica gel chromatography (5 - 50 % EtOAc in petroleum ether) to give the title compound (190 mg, 58%) as a light yellow solid. MS (ES+) C14H15BrFN50S requires: 399, found: 400 [M+H] ⁺ .

(lS,2S)-2-((6-(Aminomethyl)-7-fluorobenzo[d]thiazol-2-yl)ami no)cyclohexan-l-ol: A suspension of (lS,2S)-2-((6-(azidomethyl)-4-bromo-7-fluorobenzo[d]thiazol- 2-yl)amino) cyclohexan-l-ol (190 mg, 0.47 mmol) and Pd/C (100 mg, 10 wt.%) in MeOH (20 mL) was stirred at 50 °C under an atmosphere of H ₂ for 48 h. The resulting mixture was then filtered through Celite and concentrated to give the title compound (140 mg, 99%) as a light yellow solid. MS (ES+) Ci ₄ Hi ₈ FN ₃ OS requires: 295, found: 296 [M+H] ⁺ .

(lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7-fluoro benzo[d]thiazol-2-yl) amino)cyclohexan-l-ol: A mixture of (lS,2S)-2-((6-(aminomethyl)-7-fluorobenzo[d]thiazol- 2-yl)amino) cyclohexan-l-ol (140 mg, 0.47 mmol), 2,6-dichloropyrazine (106 mg, 0.71 mmol), and DIPEA (0.5 mL) in DMA (2 mL) was heated at 100 °C overnight. The residue was purified by preparative HPLC (Mobile phase: MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (62 mg, 32%) as a tan solid. MS (ES+) Ci ₈ Hi ₉ ClFN ₅ OS requires: 407, found: 408 [M+H] ⁺ ; ^X H NMR (500 MHz, DMSO) δ 8.21 (s, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.79 (d, J = 5.3 Hz, 1H), 4.48 (d, J= 5.5 Hz, 2H), 3.53 (s, 1H), 2.04 (s, 1H), 1.89 (d, J = 11.7 Hz, 1H), 1.62 (d, J = 11.6 Hz, 2H), 1.37 - 1.07 (m, 5H).

(lS,2S)-2-((7-fluoro-6-(((6-phenylpyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino )cyclohexan-l-ol: A mixture of (lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7- fluorobenzo[d] thiazol-2-yl)amino)cyclohexan-l-ol (25 mg, 0.060 mmol), phenylboronic acid (37 mg, 0.31 mmol), Pd(dppf) ₂ Cl ₂ (25 mg, 0.030 mmol) and aqueous K ₂ C0 ₃ (2M, 0.3 mL) in dioxane (1 mL) was irradiated at 150 °C for 2 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (12 mg, 44%) as a tan solid. MS (ES+) C ₂₄ H ₂₄ FN ₅ OS requires: 449, found: 450 [M+H] ⁺ ; ^l H NMR (500 MHz, DMSO) δ 8.29 (s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 7.53 - 7.36 (m, 3H), 7.30 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.77 (d, J = 5.5 Hz, 1H), 4.63 (d, J = 5.3 Hz, 2H), 3.52 (s, 1H), 3.35 (s, 1H), 2.06 (s, 1H), 1.87 (s, 1H), 1.63 (s, 2H), 1.26 (t, J = 22.1 Hz, 4H).

The following examples in Table 15 were prepared analogously to Example 166.

Table 15:

Example 170: ( IS, 2S)-2-( (7-fluoro-6-( ( ( 5-(prop-l-yn-l-yl)pyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

A mixture of (lS,2S)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)-7-fluoro benzo [djthiazol- 2-yl)amino)cyclohexan-l-ol (40 mg, 0.10 mmol), trimethyl(prop-l-yn-l-yl)silane (0.3 mL), Pd(dppf) ₂ Cl ₂ (40 mg, 0.05 mmol), KF (29 mg, 0.5 mmol), PPh ₃ (52 mg, 0.20 mmol) and Cul (95 mg, 0.5 mmol), DIPEA (0.3 mL) in DMF (ImL) was heated in a sealed tube at 120°C overnight. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (MeCN/H ₂ 0/TFA) to give the title compound (12 mg, 30%) as a white solid. MS (ES+) C21H22FN5OS requires: 411, found: 412 [M+H] ⁺ ; ^l H NMR (500 MHz, MeOD) δ 7.83 (s, 1H), 7.71 (s, 1H), 7.45 (t, J= 7.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.64 (s, 2H), 3.63 - 3.56 (m, 1H), 3.52 - 3.43 (m, 1H), 2.20 (d, J = 21.0 Hz, 1H), 2.09 (s, 4H), 1.80 (s, 2H), 1.43 (dd, J = 25.6, 10.6 Hz, 4H).

The following examples in Table 16 were prepared analogously to Example 170.

Table 16:

Example 173: N-( ⁽ IS*, 2S*)-2-( ( 6-( ( ⁽ 6-chloropyrazin-2-yl)amino)methyl)-4-methoxy benzo[d]thiazol-2-yl)amino)cyclohexyl)methanesulfonamide

(lS*,2S*)-Nl-(6-((6-chloropyrazin-2-ylamino)methyl)-4-methox ybenzo[d]thiazol-2-yl) cyclohexane-l,2-diamine: A mixture of 6-chloro-N-((4-methoxy-2-(methylsulfinyl) benzo[d]thiazol-6-yl)methyl)pyrazin-2-amine (8.0 mg, 0.22 mmol) and trans-cyclohexane- 1,2-diamine (200 mg) was heated at 120 °C for 3 h. The crude title compound (-92 mg, 100%) was used directly in the next step. MS (ES+) Ci ₉ H ₂₃ ClN ₆ OS requires: 418, found: 419 [M+H] ⁺ .

N-((lS*,2S*)-2-((6-(((6-chloropyrazin-2-yl)amino)methyl)- 4-methoxybenzo[d]thiazol-2- yl)amino)cyclohexyl)methanesulfonamide: MsCl (127 mg, 1.1 mmol) was added to a solution of (l S*,2S*)-Nl-(6-((6-chloropyrazin-2-ylamino)methyl)-4-methoxy benzo[d]thiazol-2-yl)cyclohexane-l,2-diamine (92 mg, 0.22 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at rt for 4 h. Additional MsCl (127 mg, 1.1 mmol) was added and the mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (15 mg, 14%) as a white solid. MS (ES+) C ₂ oH ₂₅ ClN ₆ 0 ₃ S ₂ requires: 496, found: 497 [M+H] ⁺ ; ^X H NMR (500 MHz, MeOD) δ 7.81 (s, 1H), 7.66 (s, 1H), 7.22 (d, J = 0.8 Hz, 1H), 6.96 (d, J = 1.0 Hz, 1H), 4.55 (s, 2H), 3.97 (s, 3H), 3.87 - 3.76 (m, 1H), 3.17 (td, J = 10.7, 4.1 Hz, 1H), 2.85 (s, 3H), 2.19 - 2.08 (m, 2H), 1.85 - 1.75 (m, 2H), 1.53 - 1.35 (m, 4H).

Example 175: N-( ( IS* 2S*)-2-( ( 4-methoxy-6-( ( ( 6-phenylpyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)cyclohexyl)methanesulfonamide

A mixture of phenylboronic acid (5 mg, 0.04 mmol), N-((l S*,2S*)-2-(6-((6-chloropyrazin-2- ylamino)methyl)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexy l)methanesulfonamide (10 mg, 0.02 mmol), Pd(PPh ₃ ) ₄ (3 mg, 0.002 mmol) and aq. K ₂ C0 ₃ (2M, 0.15 mL, 0.3 mmol) in 1,4-dioxane (1.5 mL) was irradiated in the microwave at 150 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (MeCN/H ₂ 0/NH ₄ HC0 ₃ ) to give the title compound (2 mg, 18%) as a beige solid. MS (ES+) C ₂ 6H3oN ₆ 0 ₃ S2 requires: 538, found: 539 [M+H]+; ^X H NMR (500 MHz, MeOD) δ 8.19 (s, 1H), 8.06 - 8.00 (m, 2H), 7.84 (s, 1H), 7.51 - 7.40 (m, 3H), 7.28 (d, J = 1.1 Hz, 1H), 7.03 (d, J = 0.9 Hz, 1H), 4.69 (s, 2H), 3.93 (s, 3H), 3.85 - 3.74 (m, 1H), 3.19 - 3.13 (m, 1H), 2.83 (s, 3H), 2.16 - 2.09 (m, 2H), 1.81 - 1.76 (m, 2H), 1.52 - 1.33 (m, 4H).

Example 176: Rel-(lS,2R, 3R,5S)-3-((6-(((6-phenylpyrazin-2-yl)amino)methyl) benzo[d]thiazol-2-yl)amino)bicyclo[3.1.0]hexan-2-ol

Rel-2-((lR,2R)-2-(tert-butyldimethylsilyloxy)cyclopent-3-eny l)isoindoline-l,3-dione: A solution of 2-((lR*,2R*)-2-hydroxycyclopent-3-enyl)isoindoline-l,3-dione (390 mg, 1.7 mmol) in DCM (20 mL) was treated with imidazole (174 mg, 2.6 mmol) and TBSC1 (308 mg, 2.0 mmol). The resulting mixture was stirred at rt under nitrogen overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (30% EtOAc in petroleum ether) to give the title compound (380 mg, 65%) as a white solid. MS (ES ⁺ ) requires: 343, found: 344 [M+H] ⁺ . Rel-2-((lS,2R,3R,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3 .1.0]hexan-3-yl)isoindoline- 1,3-dione: A solution of (2-((lR*,2R*)-2-(tert-butyldimethylsilyloxy)cyclopent-3- enyl)isoindoline-l,3-dione (380 mg, 1.1 mmol) in DCM (15 mL) was cooled in an ice bath and treated with IN diethylzinc (5.7 mL, 5.7 mmol, 1M in hexane) dropwise. After stirring at 0 °C for 20 min, diiodomethane (0.94 mL, 11 mmol) was added dropwise. The resulting cloudy solution was stirred at 0 °C for 20 min and allowed to warm up to rt. After 6 h, the reaction mixture was quenched with sat. aqueous NH ₄ C1 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ S0 ₄ , filtered, and concentrated. The residue was purified via silica gel chromatography (20 - 50% EtOAc in petroleum ether) to give the title compound (200 mg, 53%) as a white solid. MS (ES ⁺ ) C2 ₀ H27NO ₃ S1 requires: 357, found: 358 [M+H] ⁺ .

Rel-2-((lS,2R,3R,5S)-2-hydroxybicyclo[3.1.0]hexan-3-yl)isoin doline-l,3-dione: A solution of rel-2-((lS,2R,3R,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3 .1.0]hexan-3- yl)isoindoline-l,3-dione (790 mg, 2.2 mmol) in THF (15 mL) was treated with TBAF (1.7 g, 6.6 mmol). The resulting cloudy solution was stirred at rt overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (20 - 50% EtOAc in petroleum ether) to give the title compound (300 mg, 56%) as a white solid. MS (ES ⁺ ) C14H1 ₃ NO ₃ requires: 243, found: 244 [M+H] ⁺ .

Rel-(lS,2R,3R,5S)-3-aminobicyclo[3.1.0]hexan-2-ol: A mixture of rel-2-((lR,2R,3R,5R)-2- hydroxybicyclo[3.1.0]hexan-3-yl)isoindoline-l,3-dione (600 mg, 2.5 mmol), N2H4 monohydrate (0.5 mL), and EtOH (20 mL) was stirred at rt overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 10% MeOH in DCM) to give the title compound (150 mg, 54%) as a white solid. MS (ES ⁺ ) CeHiiNO requires: 113, found: 114 [M+H] ⁺ .

Rel-(lS,2R,3R,5S)-3-(6-((6-chloropyrazin-2-ylamino)methyl )benzo[d]thiazol-2-ylamino) bicyclo[3.1.0]hexan-2-ol: A mixture of 6-chloro-N-((2-(methylsulfinyl)benzo[d]thiazol-6- yl)methyl)pyrazin-2-amine (60 mg, 0.18 mmol) and rel-(lR,2R,3R,5R)-3- aminobicyclo[3.1.0]hexan-2-ol (34 mg, 0.30 mmol) was stirred at 110 °C under Ar overnight. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 10% MeOH in DCM) to give the title compound (60 mg, 88%) as a white solid. MS (ES ⁺ ) Ci ₈ Hi ₈ ClN ₅ OS requires: 387, found: 388 [M+H] ⁺ . Rel-(lS,2R,3R,5S)-3-(6-((6-phenylpyrazin-2-ylamino)methyl)be nzo[d]thiazol-2-ylamino) bicyclo[3.1.0]hexan-2-ol: A solution of rel-(lS,2R,3R,5S)-3-(6-((6-chloropyrazin-2- ylamino)methyl)benzo[d]thiazol-2-ylamino)bicyclo[3.1.0]hexan -2-ol (40 mg, 0.10 mmol) in DMF (5 mL) was treated with phenylboronic acid (14 mg, 0.11 mmol), PdC^dppf (10 mg, 0.015 mmol), and KOAc (34 mg, 0.24 mmol). The resulting mixture was stirred at 110 °C under nitrogen overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (30% EtOAc in petroleum ether) to give the title compound (20 mg, 45%) as a white solid. MS (ES ⁺ ) C24H2 ₃ N5OS requires: 429, found: 430 [M+H] ⁺ ; ^l NMR (500 MHz, d ₆ -DMSO) δ 8.28 (s, 1H), 7.99 (m, 3H), 7.83 (s, 1H), 7.67 (d, J = 4.5 Hz, 2H), 7.43 (m, 3H), 7.30 (m, 1H), 7.24 (m, 1H), 5.07 (d, J = 5.5 Hz, 1H), 4.57 (), 4.19 (d, J = 6.5 Hz, 1H), 2.20 (m, 1H), 1.65 (m, 1H), 1.40 (s, 1H), 1.26 (s, 1H), 0.57 (d, J = 3.5 Hz, 1H), 0.36 (dd, J = 8.0, 9.0 Hz, 1H).

Example 181 - CSF-IR competitive binding assay

Compound binding to CSF-IR was measured by a FRET-based competitive binding assay (LanthaScreen® Eu Kinase Binding Assay; Invitrogen). Binding of the Alexa Fluor® conjugate tracer no. 236 (cat no. PV5592) to His-tagged hCSFIR (aa538-910) was detected by addition of a Eu-labeled anti-His antibody. Binding of the tracer and antibody to CSFIR results in a high degree of FRET, whereas displacement of the tracer with a kinase inhibitor results in a loss of FRET. His-CSFIR (5μ1) was incubated with 5μ1 of increasing compound concentrations for 20 min in reacting buffer (50 mM HEPES [pH 7.5], 10 mM MgCl ₂ , 1 mM EGTA, 0.003% Tween 20), then mixed with 5μ1 of antibody and incubated for 90 min at room temperature. Final concentration of CSFIR, tracer, and anti-His antibody were 3 nM, 10 nM and 2 nM respectively. The FRET signal was followed in a plate reader (excitation: 320 nm; emission: 615 nm). Dose-response curves were analysed using IC ₅₀ regression curve fitting (GeneData Screener).

Table 17 below summarises the results of the CSF-IR competitive binding assay, in which the IC5 ₀ values are indicated for each compound as: (A) less than 50 nM; (B) 50 nM to 200 nM; (C) 200 nM to 500 nM; (D) 500 nM to 1 μΜ; and (E) >1 μΜ. Table 17: CSF-IR competitive binding assay

Ex # ic ₅₀ Ex # ic ₅₀ Ex # ic ₅₀

124 A 143 A 162 B

125 A 144 A 163 A

126 A 145 A 164 A

127 A 146 A 165 A

128 A 147 A 166 A

129 A 148 A 167 A

130 A 149 A 168 A

131 A 150 A 169 A

132 A 151 A 170 A

133 A 152 A 171 A

134 A 153 A 172 A

135 A 154 B 173 A

136 A 155 A 174 A

137 A 156 A 175 A

138 A 157 A 176 A

139 A 158 A 177 A

140 A 159 A 178 A

141 A 160 A 179 A

142 A 161 A 180 A

Example 182 - mCSF dependent cell proliferation assay

M-NFS-60 cells (ATCC - CRL-1838) were resuspended in medium (RPMI-1640, GlutaMax Supplement, HEPES - Gibco 72400-047) containing 10 ng/mL of recombinant mouse m- CSF (R&D Systems - 416-ML-010). Cells were then plated onto 384-well plate (5000 cells/well, 35 L/well), and incubated at 37 °C, 5 % C0 ₂ overnight. DMSO (control) or increasing concentrations of compounds were diluted in medium, added to the 384-well plate (5 uL/well, final DMSO concentration of 0.5%), and cells incubated with compounds for 72 h at 37 °C, 5 % CO2. Cell viability was then measured by addition of 35 of CellTiter-Glo 2.0 (Promega, G9243) using manufacturer's recommendations. Cells were incubated with CellTiter-Glo 2.0 at room temperature for 10 min, and luminescence was then read by Envision plate reader. Dose-response curves were analyzed using IC50 regression curve fitting (GeneData Screener). Curves were normalized to a high controls without inhibitor, and low controls with 1 μΜ of staurosporine.

Table 18 below summarises the results of the mCSF dependent cell proliferation assay, in which the IC5 ₀ values are indicated for each compound as: (A) less than 1 μΜ; (B) 1 μΜ to 2 μΜ; (C) 2 μΜ to 3 μΜ; (D) 3 μΜ to 5 μΜ; (E) > 5 μΜ. Table 18: mCSF dependent cell proliferation assay

Ex # ic ₅₀ Ex # ic ₅₀ Ex # ic ₅₀

151 A 162 A 173 A

152 A 163 A 174 A

153 A 164 A 175 A

154 A 165 A 176 A

155 A 166 A 177 A

156 A 167 A 178 A

157 A 168 A 179 A

158 A 169 A 180 A

159 A 170 A

160 A 171 A

161 A 172 A

Example 183 - Selectivity of kinase inhibition

The selectivity of compounds of the invention for CSF-1R over the kinases c-Kit, FLT3, PDGFRa and PDGFR-β was assessed.

For the CSF-1R, FLT3, c-KIT, PDGFRa and PDGFR kinase assays, kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase, infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate affinity resins for kinase assays. The ligand-treated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, ligand-treated affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 IX stocks in 100% DMSO. Kd values were determined using an 11 -point, 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 h and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μΜ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 min. The kinase concentration in the eluates was measured by qPCR.

Compound Handling

An 11 -point 3-fold serial dilution of each test compound was prepared in 100% DMSO at lOOx final test concentration and subsequently diluted to lx in the assay (final DMSO concentration = 1%). Most Kd values were determined using a compound top concentration = 30,000 nM. If the initial Kd determined was < 0.5 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower top concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be >30,000 nM.

Binding Constants (Kd)

Binding constants were calculated with a standard dose-response curve using the Hill equation:

Response = Background +

Signal - Background

1 + (KdHill Slope / DoseHill Slope)

The Hill Slope was set to -1.

Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.

Table 19 below summarises the results of the selectivity assay, in which the IC5 ₀ values measured for c-Kit, FLT3, PDGFRa and PDGFR are given relative to the IC50 value for CSF-1R.

Selectivity of each compound for CSF-1R relative to c-Kit is given as: (A) > 50 times; (B) 10 to 50 times; (C) 5 to 10 times; and (D) less than 5 times more selective. Selectivity of each compound for CSF-1R relative to FLT3 is given as: (A) > 500 times; (B) 200 to 500 times; (C) 100 to 200 times; and (D) less than 100 times more selective. Selectivity of each compound for CSF-1R relative to PDGFRa is given as: (A) > 15 times; (B) 10 to 15 times; (C) 5 to 10 times; and (D) less than 5 times more selective. Selectivity of each compound for CSF-1R relative to PDGFR is given as: (A) > 10 times; (B) 2.5 to 10 times; (C) 1.5 to 2.5 times; and (D) less than 1.5 times more selective. Table 19: Kinase selectivity of compounds

Ex # c-KIT FLT3 PDGFRa PDGFRp

103 A A B A

105 B A C B

106 A A A A

107 B A B B

110 B A C B

111 A A A A

113 A A A A

114 A A A A

115 D D D D

116 B C C D

117 A B A A

118 D B D D

119 A A A A

127 A A A A

128 - - - C

129 - - - B

130 - - - D

131 - - - B

132 - - - D

133 A B A A

134 A A A A

136 - - - B

137 - - - C

138 - - - D

139 - - - D

143 D A D D

144 - - - A

146 A A A A

147 A A A A

148 A B A A

160 A A A A

163 A A B C

165 A A A A

166 B A D D

167 A A A C

170 D A D D

171 A A A A

173 A A A A

174 B A D D

180 A A A A

"- " indicates that no assay was run for the compound/kinase combination The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

While the present invention has particularly been shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the sprit and scope of the invention encompassed by the appended claims.