WO2018119387A1

WO2018119387A1 - Small molecule inhibitors of colony stimulating factor-1 receptor (csf-1r) and uses thereof

Info

Publication number: WO2018119387A1
Application number: PCT/US2017/068168
Authority: WO
Inventors: Philip Jones; Barbara Czako; Jason P. BURKE; Jason Cross; Paul Graham LEONARD; Martin Tremblay; Pijus MANDAL
Original assignee: Tesaro, Inc.
Priority date: 2016-12-23
Filing date: 2017-12-22
Publication date: 2018-06-28
Also published as: TW201829402A

Abstract

Compounds of formula (I), which are useful as CSF-1R inhibitors, are provided. Also provided are pharmaceutical compositions and kits comprising said compounds, as well as methods and uses pertaining to said compounds.

Description

SMALL MOLECULE INHIBITORS OF COLONY STIMULATING FACTOR-1 RECEPTOR (CSF-IR) AND USES THEREOF

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.

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-IR needs to be modulated. In a first 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, 3 or 4;

m is 0, 1 or 2;

X¹ is selected from NH, O, S, -CH=N-, and -N=CH-;

L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which:

p is 1, 2 or 3, and

each R⁶ and each R⁷ 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, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl;

R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4.acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4.acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;

R² in each case is independently selected from halogen, hydroxyl, carbonitrile, C_halky 1, and -0(Ci_-4-alkyl),

wherein each said alkyl is optionally substituted;

R³ is selected from Ci-g-alkyl, C₂-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; and

R⁴ and R⁵ are independently selected from H and Ci-3-alkyl,

or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6- membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In embodiments:

R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C₂-8-alkenyl, C₂-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C₂-4.acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C₂-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; and/or

R² 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

R³ 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^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments, A is a 6-membered monocyclic heteroaryl.

In embodiments, n is 1 or 2.

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C₂-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸, R⁹ and R¹⁰ are each independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen. In embodiments, R¹ in each case is independently selected from halogen, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -0(Ci_-4-alkyl), C_M-alk l, aryl, and heteroaryl,

wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, and heteroaryl, R¹⁰ and R^10b are independently selected from H, and Ci-4-alkyl, and

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

In embodiments, R¹ in each case is independently selected from CI, Br, and amino, or from methylamino, -NHC(0)OCH_3, -NHC(0)CH₃, -NHC(0)NHCH₃, methyl, methoxy, -NH- pyrazolyl, phenyl and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl).

In embodiments, m is 1 or 2, and R² 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, R³ is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, aminosulfonyl, sulfonylamino, and -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen.

In embodiments, R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl, and heteroaryl.

In embodiments, R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, and -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl.

In embodiments, R⁴ and R⁵ are both hydrogen.

In embodiments, L is -(CR⁶R⁷)_P- in which p is 1 or 2 and in which each R⁶ and each R⁷ 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, all R⁶ and R⁷ groups present are hydrogen.

In embodiments, L denotes a direct bond.

In embodiments, X¹ is selected from NH, O and S.

In embodiments, X¹ is S.

In other aspects and embodiments the invention provides a compound characterized by formula (II),

(II)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

Q\ Q², Q³ and Q⁴ are independently selected from N, CH and CiR¹), wherein no fewer than one and no more than two of said Q¹, Q², Q³ and Q⁴ may denote N; and

n, m, X¹, L and R¹ to R⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (III),

(III)

larmaceutically acceptable salt or prodrug thereof, wherein

X² is selected from N, CH or C(R^X);

R¹¹ and R¹² are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R"R¹⁴), -N(R^1JR¹⁴), -NHC(0)NR"R , -NHC(0)OR , -NHC(0 )R^15b, -C(0)R^15b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^15B is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; and

m, X¹, L, and R² to R⁵ are as defined hereinbefore.

In embodiments, R¹¹ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹²R¹³), 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, R¹² is selected from halogen, C(0)N(R¹ R¹⁴), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, 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^hR') in which R^h and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^J in which R^J is selected from hydroxyl and amino and halogen.

In embodiments, X² is N.

In other aspects and embodiments the invention provides a compound characterized by formula (IV),

(IV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X³ is selected from N, CH, and CR¹;

n is 0, 1, 2 or 3; and

m, X¹, L, and R¹ to R⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (V),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R¹⁶ and R¹⁷ are independently 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; and

wherein n, X¹, X³, L, R¹ and R³ are as defined hereinbefore.

In embodiments, R¹⁶ and R¹⁷ are independently selected from hydrogen, halogen, hydroxyl, carbonitrile and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile.

In other aspects and embodiments the invention provides a compound characterized by formula (VI),

(VI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

18 19 20 d 21

R , R , R an R are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, - C(0)R^24b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R²² and R²³ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

R^24b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

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^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; and

wherein m, X¹, L, and R² to R⁵ are as defined hereinbefore.

In embodiments, R¹⁸ is selected from hydrogen, halogen, NR²²R²³, -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, C₂-4-acylamino, -0(C_M-alk l) and Ci-4-alkyl, wherein R²² and R²³ are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R²⁴ and R^24b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In embodiments, R²⁰ is selected from hydrogen, halogen, -0(Ci-4-alkyl), Ci-4-alkyl, aryl and heteroaryl,

wherein each said alkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In embodiments, R¹⁹ and R²¹ are each independently hydrogen.

In other aspects and embodiments the invention provides a compound characterized by formula (VII),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

q is 0, 1, 2 or 3;

R²⁵ is independently selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and

m, X¹, R², R⁴, R⁵, R¹⁸ and R²⁰ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (VII_a) or (V

or a pharmaceutically acceptable salt or prodrug thereof, wherein

m, q, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁵ are as defined hereinbefore. In other aspects and embodiments the invention provides a compound characterized by formula (VIII),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

r is 0, 1, 2 or 3;

R²⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^qR^r) in which R^q and R^r 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^qR^r) in which R^q and R^r are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and

m, X¹, R², R⁴, R⁵, R¹⁸ and R²⁰ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (VIII_a) or (VIII_b),

(Villa)

(VIIIb)

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁶ are as defined hereinbefore. In other aspects and embodiments the invention provides a compound characterized by formula (IX),

(IX)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n is 0, 1 or 2;

X⁴ is NH, O or S; and

m, X¹, L and R¹ to R⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized formula (X),

(X)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n is 0, 1 or 2;

X⁵ is NH, O or S; and

m, X¹, L and R¹ to R⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (XI),

(XI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein n, m, X¹, L and R¹ to R⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (XII),

(XII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

30 31

, R , and 32

R R^Ji are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, - C(0)R ^5b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R³⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; and

wherein m, X¹, L, and R² to R⁵ are as defined hereinbefore.

In embodiments, R³⁰ is selected from hydrogen, halogen, NR R³⁴, -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, C₂-4-acylamino, -0(C_M-alk l) and Ci-4-alkyl, wherein R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R³⁵ and R ^5b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen.

In embodiments, R³¹ and R³² are each independently hydrogen.

In other aspects and embodiments the invention provides a compound characterized by formula (XIV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

s is 0, 1, 2 or 3;

R³⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and

m, X¹, R², R⁴, R⁵ and R³⁰ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (XV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein s, R⁴, R⁵, R¹⁶, R¹⁷, R^: R³⁶ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (XV a) or formula (XVb),

In other aspects and embodiments the invention provides a compound characterized by formula (XVI),

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, R and R²⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound characterized by formula (XIV a) or formula (XlVb),

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, R²⁰ and R²⁵ are as defined hereinbefore.

In other aspects and embodiments the invention provides a compound selected from the group consisting of:

Compound 1 : (lR,2R)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)benzo[d]thiazol-2- y l)amino)cy clohexan- 1 -ol Compound 2: (lS,2S)-2-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 3: (lR,2R)-2-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol

Compound 4: (lR,2R)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 5: (lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 6: (lS,2S)-2-[(6-{[2-(methylamino)pyridin-4-yl]methoxy}-l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol

Compound 7: N-cyclohexyl-6-(pyridin-4-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 8: N-cyclohexyl-6-(pyridin-3-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 9: N-cyclohexyl-6-(l,3-thiazol-4-ylmethoxy)-l,3-benzothiazol-2-amine Compound 10: N-cyclohexyl-6-(pyridin-2-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 11 : N-cyclohexyl-6-(pyrazin-2-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 12: N-cyclohexyl-6-(pyrimidin-4-ylmethoxy)-l,3-benzothiazol-2-amine Compound 13: N-cyclohexyl-6-(l,3-thiazol-2-ylmethoxy)-l,3-benzothiazol-2-amine Compound 14: N-cyclohexyl-6-(l,3-thiazol-5-ylmethoxy)-l,3-benzothiazol-2-amine Compound 15: 6-[(2-aminopyridin-4-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 16: 6-[(6-chloropyrazin-2-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 17: 6-[(5-chloropyridin-3-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 18: N-cyclohexyl-6-[(2-methylpyridin-4-yl)methoxy]-l,3-benzothiazol-2-amine Compound 19 : 4-( { [2-(cy clohexylamino)- 1 ,3 -benzothiazol-6-y 1] oxy } methy 1)-N- methylpyridine-2-carboxamide

Compound 20: N-cyclohexyl-6-[(3-methylpyridin-4-yl)methoxy]-l,3-benzothiazol-2-amine Compound 21 : 5-({[2-(cyclohexylamino)-l,3-benzothiazol-6-yl]oxy}methyl)-N- methylpyridine-2-carboxamide

Compound 22: (lR,2R)-2-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 23: 6-[(3-chloropyridin-4-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 24: (lR,2R)-2-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 25: (lS,2S)-2-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol Compound 26: N-cyclohexyl-6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-benzothiazol-2- amine

Compound 27: (lS,2S)-2-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol

Compound 28: (lR,2S)-l-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol

Compound 29: (lR,2S)-l-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol

Compound 30: (lS,2S)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 31 : 6-[(3-bromopyridin-4-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 32:N-cyclohexyl-6-{[3-(l-methyl-lH-pyrazol-4-yl)pyridin-4-yl]methoxy}-l,3- benzothiazol-2-amine

Compound 33: N-cyclohexyl-6-[(3-phenylpyridin-4-yl)methoxy]-l,3-benzothiazol-2-amine Compound 34: (lR,2R)-2-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 35: (lS,2S)-2-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 36: (lR,2S)-l-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol

Compound 37: (lR,2R)-2-{[6-({3-chloro-lH-pyrrolo[2,3-b]pyridin-4-yl}methoxy)-l,3- benzothiazol-2-y 1] ainino } cy clohexan- 1 -ol

Compound 38: (lR,2S)-l-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-benzothiazol-2- yl)amino]-2,3-dihydro-lH-inden-2-ol

Compound 39: 6-[(2-amino-3-chloropyridin-4-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol- 2-amine

Compound 40: (lR,2S)-l-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol

Compound 41 : (lR,2S)-l-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol

Compound 42: N-cy clohexyl-6- { [2-(methylamino)pyridin-4-yl]methoxy } - 1 ,3-benzothiazol- 2-amine

Compound 43: (lR,2R)-2-[(6-{[2-(methylamino)pyridin-4-yl]methoxy}-l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol Compound 44: (lR,2R)-2-[(6-{[2-amino-3-(trifluoromethoxy)pyridin-4-yl]methoxy}-l,3- benzothiazol-2-yl)amino] cy clohexan- 1 -ol

Compound 45: (lS,2S)-2-[(6-{[2-amino-3-(trifluoromethoxy)pyridin-4-yl]methoxy}-l,3- benzothiazol-2-yl)amino] cy clohexan- 1 -ol

Compound 46: (lR,2R)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4- yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 47: (lS,2S)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4- yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 48: (lR,2R)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

Compound 49: (1 S,2S)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

Compound 50: (lR,2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-methoxy-l,3- benzothiazol-2-yl} amino)cy clohexan- 1 -ol

Compound 51 : (lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-methoxy-l,3- benzothiazol-2-yl} amino)cy clohexan- 1 -ol

Compound 52: N-[(lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-methoxy-l,3- benzothiazol-2-yl}amino)cyclohexyl]methanesulfonamide

Compound 53: (2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-methoxy-l,3- benzothiazol-2-yl}amino)-4-methylpentan-l-ol

Compound 54: (lS,2S)-2-((6-((2-amino-3-fluoropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

Compound 55: (lS,2S)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol-4-ylamino)pyrimidin- 4yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Compound 56: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-yl)amino]pyrimidin- 4-yl}methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

Compound 57: (lS,2S)-2-{[6-({2-[(2-hydroxyethyl)amino]pyrimidin-4-yl}methoxy)-4- methoxy- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

Compound 58: (lS,2S)-2-{[4-methoxy-6-({2-[(l,2-oxazol-4-yl)amino]pyrimidin-4- y 1 } methoxy )- 1 ,3 -benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 59: (lS,2S)-2-{[4-methoxy-6-({2-[(lH-pyrazol-4-yl)amino]pyrimidin-4- y 1 } methoxy)- 1 ,3 -benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 60: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-l,2,3-triazol-4- y l)amino] py rimidin-4-y 1 } methoxy)- 1 ,3-benzothiazol-2-y 1] amino } cy clohexan- 1 -ol Compound 61 : 6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

Compound 62: 6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

Compound 63 : 6-((2-aminopyrimidin-4-yl)methoxy)-N-(4,4-difluorocy clohexyl)-4- methoxybenzo [d]thiazol-2-amine

Compound 64: N-(3,3-difluorocyclohexyl)-4-methoxy-6-((2-(l-methyl-lH-pyrazol-4- ylamino)pyrimidin-4-yl)methoxy)benzo[d]thiazol-2-amine

Compound 65: (lS,2S)-2-(6-((2-amino-3-chloropyridin-4-yl)methoxy)-4- fluorobenzo[d]thiazol-2-ylamino)cyclohexanol

Compound 66: (1 S,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-4-methoxybenzo[d]thiazol- 2-yl)amino)cy clohexan- 1 -ol

Compound 67: 6-((2-amino-3-chloropyridin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

Compound 68: l-{4-[({2-[(3,3-difluorocyclohexyl)amino]-4-methoxy-l,3-benzothiazol-6- yl}oxy)methyl]pyridin-2-yl}-3-methylurea

Compound 69: (1 S,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

Compound 70: (1 S,2S)-2-(6-((2-aminopyrimidin-4-yl)methoxy)-7-fluoro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

Compound 71 : N-(4-((2-((l S,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-yl)acetamide

Compound 72: N-(4- {[(2- { [(lR,2R)-2-hydroxycyclohexyl]amino} -4-methoxy-l ,3- benzothiazol-6-yl)oxy] methyl }pyridin-2-yl)acetamide

Compound 73: (lS,2S)-2-(6-((2-aminopyrimidin-4-yl)methoxy)-4-methoxy-7- methylbenzo[d]thiazol-2-ylamino)cyclohexanol

Compound 74: (1 S,2S)-2-(6-((2-amino-3-fluoropyridin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

Compound 75: (lS,2S)-2-({6-[(2-aminopyridin-4-yl)methoxy]-7-chloro-4-methoxy-l,3- benzothiazol-2-yl} amino)cy clohexan- 1 -ol

Compound 76: (lS,2S)-2-(7-chloro-4-methoxy-6-((2-(l-methyl-lH-pyrazol-4- ylamino)pyrimidin-4-yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Compound 77: (lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-l,2,3-triazol-4- y l)amino] py rimidin-4-y 1 } methoxy)- 1 ,3-benzothiazol-2-y 1] amino } cy clohexan- 1 -ol Compound 78: (lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3- y l)amino] py rimidin-4-y 1 } methoxy)- 1 ,3-benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 79: Methyl 4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d] thiazol-6-yloxy)methyl)pyridin-2-ylcarbamate

Compound 80: l-(4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-yl)-3-methylurea

Compound 81 : (lS,2S)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol-4-ylamino)pyridin-4- yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol

Compound 82: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-yl)amino]pyridin-4- y 1 } methoxy)- 1 ,3 -benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 83: (lS,2S)-2-{[4-methoxy-6-({2-[(2-methylpyrimidin-4-yl)amino]pyridin-4- y 1 } methoxy)- 1 ,3 -benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 84: 6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-N-(3,3-difluorocyclohexyl)-4- methoxybenzo [d]thiazol-2-amine

Compound 85: (lR,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

and

Compound 86: (lS,2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

and the pharmaceutically acceptable salts and prodrugs thereof.

In embodiments, the compound has an inhibitory activity (measured as IC5₀ value) against CSF-IR of less than 200 nM.

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

A further aspect provides a pharmaceutical composition comprising a compound of the invention, 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. A further aspect provides a compound of the invention, or a pharmaceutical composition of the invention, for use in therapy.

A further aspect 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 of the invention.

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 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 such as HIV encephalitis, Alzheimer's disease and ALS.

In 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.

A further aspect provides a compound of the invention for use in a method as defined hereinbefore. A further aspect provides the use of a compound according to the invention manufacture of a medicament for use in a method as defined hereinbefore.

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",

etc. , have equivalent meanings, i.e. a saturated linear or branched free radical consisting essentially of 1 to 3 (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 term "C2-6-alkenyl" has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 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 term "C2-6-alkynyl" has an equivalent meaning, i.e. an unsaturated linear or branched free radical consisting essentially of 2 to 6 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 bicyclo[3.1.0]hexanyl, 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. The term "cycloalkenyl" has an equivalent meaning in relation to unsaturated carbocyclic groups. The term "aryl" has an equivalent meaning in relation to aromatic carbocyclic 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. Exemplary heterocycloalkyl groups include pyrrolidinyl, morpholinyl, piperidinyl, and piperzinyl. The term "heterocycloalkenyl" has an equivalent meaning in relation to unsaturated heterocyclic groups. Exemplary heterocycloalkenyl groups include 2,5-dihydro-lH-pyrrolyl, 2H-pyranyl, tetrahydro-2H-thiopyran-l,l-dioxidyl (thiane dioxidyl), tetrahydro-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 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 carbonitrile radical is attached via its carbon 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. Exemplary sulfonyl groups include sulfonic esters, e.g. -S(0)₂0R where R is a carbon radical, and alkylsufonyls, e.g. -S(0)₂R where R is an alkyl radical. The term "aminosulfonyl" means a sulfonyl group which is directly bonded to an amino group as defined herein, e.g. -S(0)₂NH₂. The term "sulfonylamino" means an amino group which is directly bonded to a sulfonyl group as defined herein, e.g. -NHS(0)₂CH₃.

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

ACN = acetonitrile

AcOH = acetic acid

β-Me = 2-mercaptoethanol

BSA = bovine serum albumin

BSTFA = N,0-Bis(trimethylsilyl)trifluoroacetamide

c¾-MeOD = deuterated methanol

<¾-DMSO = deuterated dimethyl sulfoxide

DBU = l,8-diazabicycloundec-7-ene

DCM = dichloromethane

DIBAL = diisobutylaluminum hydride

DIEA = Ν,Ν-diisopropylethylamine

DMA = dimethyl acetamide

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

DPPA = diphenylphosphoryl azide DTT = dithiothreitol

ES⁺ = electrospray positive ionization

EGTA = ethylene gly col-bis( -aminoethyl ether)-N,N,N',N'-tetraacetic acid

ELISA = enzyme-linked immunosorbent assay

Et₂0 = diethyl ether

EtOAc = ethyl acetate

FRET = fluorescence resonance energy transfer

h = hour

HATU = l -[bis(dimethylamino)methylene]-lH-1.2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

HEPES = 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid

HI FBS = heat inactivated fetal bovine serum

HPLC = high pressure liquid chromatography

HRP = horseradish peroxidase

Hz = hertz

IPA = isopropanol

M = molar

mCPBA = 3-chloroperbenzoic acid

MeCN = acetonitrile

MHz = megahertz;

min = minute

mL = milliliter

MS = mass spectrometry

MW = microwave

PBS = phosphate buffer saline

PMB = p-methoxybenzyl

qPCR = quantitative polymerase chain reaction

RPMI medium = Roswell Park Memorial Institute medium

rt / RT = room temperature

Selectfluor = l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane

bis(tetrafluoroborate)

tBuONO = tert-butyl nitrite

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:

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2;

X¹ is selected from NH, O, S, -CH=N-, and -N=CH-;

L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which:

p is 1, 2 or 3, and

R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4.acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4.acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted;

wherein each said alkyl is optionally substituted;

R⁴ and R⁵ are independently selected from H and Ci-3-alkyl,

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4.acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and

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

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

and

In embodiments:

R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and

R³ 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^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, 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 and a 9-membered bicyclic heteroaryl. In one embodiment, A is selected from the group consisting of thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and pyrrolopyridinyl. In another embodiment, A is selected from the group consisting of thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyrrolopyridinyl. In another embodiment, A is selected from the group consisting of pyridinyl and pyrimidinyl. In one embodiment, A is selected from the group consisting of pyridin-4-yl and pyrimidin-4-yl.

In embodiments, A is a 6-membered monocyclic heteroaryl, e.g. pyridinyl, pyrimidinyl or pyrazinyl. In one embodiment, A is pyridinyl. In another embodiment, A is pyrimidinyl. In other embodiments, A is a 9-membered bicyclic heteroaryl, e.g. pyrrolopyridinyl. In one embodiment, A is lH-pyrrolo[2,3-b]pyridinyl. In other embodiments, A is a 5 membered monocyclic heteroaryl, e.g. thiazolyl.

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

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen.

In embodiments, R⁸ and R⁹ are each independently selected from H, and an optionally substituted group selected from C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In other embodiments, neither R⁸ nor R⁹ is methyl. In other embodiments, where one of R⁸ and R⁹ is hydrogen, the other is not methyl. In other embodiments, R¹ is not -C(0)NH(CH₃).

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸, R⁹ and R¹⁰ are each independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen. In embodiments, R⁸ and R⁹ are each independently selected from H, and an optionally substituted group selected from C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In other embodiments, neither R⁸ nor R⁹ is methyl. In other embodiments, where one of R⁸ and R⁹ is hydrogen, the other is not methyl. In other embodiments, R¹ is not -C(0)NH(CH₃).

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸, R⁹ and R¹⁰ are each independently selected from H, C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R⁸, R⁹ and R¹⁰ are each independently selected from H, C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C₂-₄-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

and

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

and

wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen.

In embodiments, R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-4-acylamino, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-6-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In other embodiments, R¹ in each case is independently selected from halogen, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b,

C2-4-acylamino, -0(Ci-4-alkyl), Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁰ and R^10b are independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

and

wherein each said acylamino, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen.

In other embodiments, R¹ in each case is independently selected from halogen, -N(R⁸R⁹), C2-4-acylamino, -0(Ci-4-alkyl), Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In other embodiments, R¹ in each case is independently selected from halogen, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -0(Ci_-4-alkyl), Ci_-4-alkyl, aryl, and heteroaryl,

wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, and heteroaryl,

R¹⁰ and R^10b are independently selected from H, and Ci-4-alkyl,

and

In other embodiments, R¹ in each case is independently selected from halogen, -N(R⁸R⁹), -0(Ci-4-alkyl), Ci-4-alkyl, aryl, and heteroaryl,

wherein R⁸ and R⁹ are independently selected from H and Ci-4-alkyl, and

In other embodiments, R¹ in each case is independently selected from CI, Br, and amino, or from methylamino, -NHC(0)OCH_3, -NHC(0)CH₃, -NHC(0)NHCH₃, methyl, methoxy, -NH- pyrazolyl, phenyl and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl).

In other embodiments, R¹ in each case is independently selected from CI, Br and amino, or from methylamino, methyl, methoxy, phenyl and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl).

In embodiments, at least one R¹ group is present which is selected from halogen. In one embodiment said halogen is selected from F, CI and Br. In another embodiment, said halogen is selected from CI and Br. In another embodiment, said halogen is CI. In another embodiment, said halogen is Br. In another embodiment, said halogen is F. In embodiments, at least one R¹ group is present which is selected from -N(R⁸R⁹), e.g. NH₂ or -NH-pyrazolyl optionally substituted by 1 to 3 groups independently selected from Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen.

In embodiments, n is 1 and R¹ is -N(R⁸R⁹), e.g. NH₂ In embodiments, n is 1 and R¹ is -N(R⁸R⁹), e.g. -NH-pyrazolyl optionally substituted by 1 to 3 groups independently selected from Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen. In embodiments, n is 1 and R¹ is -NH-pyrazol-3-yl or -NH-pyrazol-4-yl optionally substituted by 1 to 3 groups independently selected from Ci-4-alkyl. In embodiments, n is 1 and R¹ is CI. In embodiments, n is 1 and R¹ is Br. In embodiments, n is 1 and R¹ is -NHC(0)OCH_3. In embodiments, n is 1 and R¹ is -NHC(0)CH_3. In embodiments, n is 1 and R¹ is -NHC(0)NHCH₃ In embodiments, n is 1 and R¹ is methyl, optionally substituted by 1 to 3 halogen. In embodiments, n is 1 and R¹ is pyrazolyl optionally substituted by methyl. In embodiments, n is 1 and R¹ is methoxy optionally substituted byl to 3 halogen. In embodiments, n is 1 and R¹ is phenyl optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, -N(R^aR^b) in which R^a and R^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen.

In embodiments, n is 2, a first R¹ is -N(R⁸R⁹), e.g. NH₂, and a second R¹ is selected from halogen, -0(Ci-8-alkyl) and Ci-3-alkyl, wherein said alkyl is optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl).

In embodiments, n is 2, a first R¹ is -N(R⁸R⁹), e.g. NH₂, and a second R¹ is CI. In embodiments, n is 2, a first R¹ is -N(R⁸R⁹), e.g. NH₂, and a second R¹ is -CF₃. In embodiments, n is 2, a first R¹ is -N(R⁸R⁹), e.g. NH₂, and a second R¹ is -OCF3. In embodiments, n is 2, a first R¹ is -N(R⁸R⁹), e.g. NH₂, and a second R¹ is -OCHF₂. In one embodiment, n is 2, a first R¹ is NH₂, and a second R¹ is CI.

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

In embodiments, R² 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 and hydroxyl. In other embodiments, R² in each case is independently selected from halogen, carbonitrile, and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen. In other embodiments, R² in each case is independently selected from halogen and carbonitrile. In other embodiments, R² in each case is independently 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. In other embodiments, R² in each case is independently selected from halogen and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen.

In embodiments, m is 1 or 2, and R² 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 other embodiments, m is 1 or 2, and R² is selected from halogen, carbonitrile, and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen. In embodiments, m is 1 and R² is -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen. In other embodiments, m is 2, and R² is selected from halogen, and -0(Ci-4-alkyl). In other embodiments, m is 2, and R² is selected from 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, R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl, and heteroaryl

In other embodiments, each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R³ is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, aminosulfonyl, sulfonylamino, and -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen. In other embodiments, R³ is Ci-6-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen, hydroxyl, -N(R^dR^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, aminosulfonyl, and sulfonylamino. In other embodiments, R³ is Ci-5-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen, hydroxyl and NH₂. In other embodiments, R³ is Ci-5-alkyl, optionally substituted with 1 to 3 groups independently selected from halogen and hydroxyl. In one embodiment, R³ is 4-methylpentan-l-ol.

In other embodiments, R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl, wherein each cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl is optionally substituted with 1 to 5 groups independently selected from selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl, or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R³ is selected from cycloalkyl, and heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 5 groups independently selected from selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl, or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In other embodiments, R³ is selected from cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro-2H-thiopyranyl-l,l-dioxidyl, pyridinyl, piperidinyl or indanyl (2,3-dihydro-lH-indenyl), optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R 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 R³ is C3-8-cycloalkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In one embodiment, R³ 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 CONH₂. In another embodiment, R³ is cyclohexyl substituted with hydroxyl. In another embodiment, R³ is cyclohexyl substituted with hydroxymethyl. In another embodiment, R³ is cyclohexyl substituted with two F.

In one embodiment, R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen. In another embodiment, R³ is cyclohexyl substituted with hydroxyl and with fluorine. In another embodiment, R³ is cyclohexyl substituted with hydroxyl and with two F. In one embodiment, the two F atoms are attached to the same carbon atom of the cyclohexyl group.

In other embodiments, R³ is selected from aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl, or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In one embodiment, R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, and -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl. In another embodiment, R³ is indanyl substituted with hydroxyl. In another embodiment, R³ is indanyl substituted with hydroxymethyl.

In one embodiment, R³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6- membered cycloalkyl group, e.g. a cyclopropyl group. In other embodiments, R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered heterocycloalkyl group, e.g. a 3- to 6-membered cycloalkoxy group, such as an oxetanyl group. In other embodiments, one of R⁴ and R⁵ is hydrogen and the other is selected from Ci-3-alkyl (e.g. methyl). In other embodiments, R⁴ and R⁵ are both independently selected from Ci-3-alkyl (e.g. they are both methyl). In a preferred embodiment, R⁴ and R⁵ are both hydrogen.

In embodiments, L is -(CR⁶R⁷)_P- in which p is preferably 1 or 2 (especially in which p is 1) and in which each R⁶ and each R⁷ 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), hydroxyl, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl.

In embodiments, L is -(CR⁶R⁷)_P- in which p is preferably 1 or 2 (especially in which p is 1) and in which each R⁶ and each R⁷ 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 R⁶ and R⁷ 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 R⁶ and R⁷ attached to the same carbon atom is hydrogen and the other is methyl. In still other embodiments, one of an R⁶ and R⁷ attached to the same carbon atom is hydrogen and the other is hydroxymethyl. In yet other embodiments, all R⁶ and R⁷ groups present are hydrogen.

In embodiments, L denotes a direct bond.

In embodiments, X¹ is selected from NH, O and S. In other embodiments, X¹ is selected from O and S. In one embodiment, X¹ is O. In another embodiment, X¹ is S. In embodiments, X¹ is selected from -CH=N- and -N=CH-. In one embodiment, X¹ is -CH=N-. In another embodiment, X¹ is -C=NH-.

In one embodiment: A is a 6-membered monocyclic heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; X¹ is selected from NH, O or S; L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which p is 1 or 2 and each R⁶ and each R⁷ 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, hydroxyl, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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; R³ is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and C_1-3- alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In one embodiment: A is a 9-membered bicyclic heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; X¹ is selected from NH, O or S; L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which p is 1 or 2 and each R⁶ and each R⁷ 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, hydroxyl, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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; R³ is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and C_1-3- alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In another embodiment: A is a 6-membered monocyclic heteroaryl; n is 1 or 2; m is 0, 1 or 2; X¹ is S; L denotes a direct bond; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, C₂-₄-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, and heteroaryl, wherein R¹⁰ and R^10b are independently selected from H and Ci-4-alkyl, and wherein each said acyl, acylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^b) in which R^a and R^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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 and hydroxyl; R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and C1-3- alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms. In another embodiment: A is a 9-membered bicyclic heteroaryl; n is 1 or 2; m is 0, 1 or 2; X¹ is S; L denotes a direct bond; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, C₂-₄-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, and heteroaryl, wherein R¹⁰ and R^10b are independently selected from H and Ci-4-alkyl, and wherein each said acyl, acylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^b) in which R^a and R^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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 and hydroxyl; R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and C_halky 1, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In one embodiment: A is a 6-membered monocyclic heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; X¹ is selected from NH, O or S; L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which p is 1 or 2 and each R⁶ and each R⁷ 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, hydroxyl, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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; R³ is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and Ci-3-alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In one embodiment: A is a 9-membered bicyclic heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; X¹ is selected from NH, O or S; L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which p is 1 or 2 and each R⁶ and each R⁷ 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, hydroxyl, Ci-4-alkyl optionally substituted by 1 to 3 halogen, -0(Ci-4-alkyl) optionally substituted by 1 to 3 halogen, aminoacyl, acylamino, sulfonyl, aminosulfonyl, sulfonylamino, and -N(R'R ) in which R and R are independently selected from hydrogen and Ci-3-alkyl; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² 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; R³ is selected from Ci-g-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and Ci-3-alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In another embodiment: A is a 6-membered monocyclic heteroaryl; n is 1 or 2; m is 0, 1 or 2; X¹ is S; L denotes a direct bond; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H and Ci-4-alkyl, and wherein each said acyl, acylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^b) in which R^a and R^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² in each case is independently selected from halogen, hydroxyl, carbonitrile, C_halky 1, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl; R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and Ci-3-alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

In another embodiment: A is a 9-membered bicyclic heteroaryl; n is 1 or 2; m is 0, 1 or 2; X¹ is S; L denotes a direct bond; R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H and Ci-4-alkyl, and wherein each said acyl, acylamino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^aR^b) in which R^a and R^b are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, Ci-4-alkyl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; R² in each case is independently selected from halogen, hydroxyl, carbonitrile, C_halky 1, and -0(Ci-4-alkyl), wherein each said alkyl is optionally substituted by 1 to 3 groups independently selected from halogen and hydroxyl; R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and R⁴ and R⁵ are independently selected from H and Ci-3-alkyl, or R⁴ and R⁵ taken together with the intervening carbon atom form a 3- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with one or more halogen atoms.

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

(Π)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

Q\ Q², Q³ and Q⁴ are independently selected from N, CH and C(R^X), wherein no fewer than one and no more than two of said Q¹, Q², Q³ and Q⁴ may denote N; and

n, m, X¹, L and R¹ to R⁵ are as defined herein.

In embodiments, Q¹ is N and Q², Q³ and Q⁴ are CH or CiR¹). In other embodiments, Q¹ and Q³ are both N and Q² and Q⁴ are both CH or CiR¹). In other embodiments, Q¹ and Q⁴ are both N and Q² and Q³ are both CH or C(R^l). In other embodiments, Q² and Q⁴ are both N and Q¹ and Q³ are both CH or CiR¹). In preferred embodiments, Q² is N. In preferred embodiments, Q² is N, and Q¹, Q³ and Q⁴ are CH or CiR¹). In other preferred embodiments, Q² and Q⁴ are N, and Q¹ and Q³ are CH or CiR¹).

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

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

X^Z is selected from N, CH or C(R^X);

R¹¹ and are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹ R¹⁴), -N(R¹ R¹⁴), -NHC(0)NR¹ R¹⁴, -NHC(0)OR¹⁵, -NHC(0)R^15b, - C(0)R^15b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R and R are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

R^15b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; and

m, X¹, L, and R² to R⁵ are as defined herein.

In embodiments, R¹¹ and R¹² are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹ R¹⁴), -N(R¹ R¹⁴), C₂-₄-acyl, C₂-4-acylamino, hydroxy 1, -0(Ci-8-alkyl), -C(0)OR¹⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and

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

R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, 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^hR') in which R^h and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^J in which R^J is selected from hydroxyl and amino and halogen.

In embodiments, R¹¹ is selected from hydrogen, halogen, C(0)N(R¹ R¹⁴), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, 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^hR') in which R^h and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^J in which R^J is selected from hydroxyl and amino and halogen. In embodiments, R¹¹ is not hydrogen.

In other embodiments, R¹¹ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹²R¹³), 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 R¹¹ is hydrogen.

In embodiments, R¹² is selected from hydrogen, halogen, carbonitrile, -N(R¹ R¹⁴), -C(0)N(R¹ R¹⁴), Ci_-4-alkyl, C₂-₄-alkynyl, C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-4-alkyl), -C(0)OR¹⁵, sulfonyl, and aminosulfonyl, wherein

R¹³ and R¹⁴ are independently selected from H and Ci-3-alkyl,

R¹⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said alkyl, alkynyl, acyl, acylamino, sulfonyl, aminosulfonyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 3 groups independently selected from halogen and Ci-3-alkyl. In embodiments, R is selected from halogen, C(0)N(R R ), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, 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^hR') in which R^h and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^J in which R^J is selected from hydroxyl and amino and halogen.

In other embodiments, R¹² is hydrogen.

In embodiments, X² is N. In other embodiments, X² is CH or CiR¹). In other embodiments, X² is CH.

In embodiments: L is -(CR⁶R⁷)_P-, in which p is 1 and one of R⁶ and R⁷ is hydrogen and the other is Ci-4-alkyl optionally substituted by hydroxyl; and R³ 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), NH₂, NHSO2CH₃, S0₂CH₃ and CONH₂

In other embodiments, L denotes a direct bond and R³ 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), NH₂, NHSO2CH3, SO2CH3 and CONH₂.

In one embodiment, L denotes a direct bond; and R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci_-4-alkyl), and CONH₂.

In another embodiment, L denotes a direct bond; and R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci_ 3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl), and CONH₂. In one embodiment, L denotes a direct bond; and R³ is (2-hydroxy)cyclohexanyl.

In another embodiment, L denotes a direct bond; and R³ 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 CONH₂. In one embodiment, L denotes a direct bond; and R³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl) and CONH₂. In one embodiment, L denotes a direct bond; and R³ is (1- hydroxy)indanyl or (2-hydroxy)indanyl.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X³ is selected from N, CH, and CR¹;

n is 0, 1, 2 or 3; and

X¹, L, and R¹ to R⁵ are as defined herein.

In embodiments, X³ is N. In other embodiments, X³ is CH or CR¹. In preferred embodiments, X³ is CH.

In embodiments: X³ is N; n is 0, 1 or 2; and R¹ in each case is independently selected from halogen,

carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In embodiments: X³ is N; n is 0, 1 or 2; and R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In other embodiments: X³ is CH; n is 0, 1, 2 or 3; and R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, and heterocycloalkyl, aryl, and heteroaryl,

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

In other embodiments: X³ is CH; n is 0, 1, 2 or 3; and R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C_2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In other embodiments: X³ is N; n is 1 or 2; and R¹ is in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹),

NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸ and R⁹ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen

In other embodiments: X³ is N; n is 1 or 2; and R¹ is in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In other embodiments: X³ is CH; n is 1 or 2; and R¹ is in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C₂-₄-acyl, C₂-4-acylamino, hydroxy 1, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In other embodiments: X³ is CH; n is 1 or 2; and R¹ is in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

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

(V)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n, X¹, X³, L, R¹ and R³ are as defined herein.

In embodiments, R¹⁶ and R¹⁷ are independently selected from hydrogen, halogen, hydroxyl, carbonitrile and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile. In other embodiments, R and R¹' are

16 independently selected from hydrogen, halogen, and carbonitrile. In other embodiments, R and R¹⁷ are independently selected from halogen and -0(Ci-4-alkyl).

In embodiments, one of R¹⁶ and R¹⁷ is hydrogen and the other is as defined herein. In embodiments, R¹⁶ is hydrogen and R¹⁷ is as defined herein. In one embodiment, R¹⁶ is hydrogen and R¹⁷ 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, hydroxyl and carbonitrile. In other embodiments, R¹⁷ is hydrogen and R¹⁶ is as defined herein. In one embodiment, R¹⁷ is hydrogen and R¹⁶ 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, hydroxyl and carbonitrile. In other embodiments, R¹⁶ and R¹⁷ are both hydrogen.

In embodiments, R¹⁶ is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently

16

selected from halogen and R is hydrogen. In embodiments, R¹⁰ is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen and R is halog embodiments, R is methoxyl and R is hydrogen. In other embodiments, R is ethoxyl and

IV 16 IV 16

R is hydrogen. In embodiments, R is methoxyl and R is CI. In embodiments, R is methoxyl and R¹⁷ is methyl. In embodiments, R¹⁶ is -OCF₃ and R¹⁷ is methyl.

In embodiments: X³ is CH; n is 1 or 2; and R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; X¹ is selected from NH, O or S; L either denotes a direct bond; R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci_ 3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl) and CONH₂.

In embodiments: X³ is CH; n is 1 or 2; and R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; X¹ is selected from NH, O or S; L either denotes a direct bond; R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci_-4-alkyl) and CONH₂.

In embodiments: X³ is CH; n is 1 or 2; and R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; X¹ is selected from NH, O or S; L either denotes a direct bond; R³ is indanyl, optionally substituted by 1 to 4 groups independently selected from hydroxyl, C1-3- alkyl optionally substituted by halogen or hydroxyl, F, CI, -0(Ci-4-alkyl) and CONH₂.

In embodiments: X³ is CH; n is 1 or 2; and R¹ in each case is independently selected from halogen, carbonitrile, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O)R^10b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR¹⁰, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R⁸, R⁹ and R¹⁰ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^10b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; X¹ is selected from NH, O or S; L either denotes a direct bond; R³ 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 CONH₂.

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

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

R , R , R and R are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, - C(0)R^24b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R²² and R²³ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R²⁴ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and

wherein m, X¹, L, and R² to R⁵ are as defined herein. In embodiments, R , R , R and R are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R²²R²³), -N(R²²R²³), C₂-₄-acyl, C₂-4-acylamino, hydroxy 1, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

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^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen

In embodiments, R¹⁸ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, - C(0)R^24b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R^24b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

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^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In embodiments, R¹⁸ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R²²R²³), -N(R²²R²³), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In other embodiments, R¹⁸ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b,C_2-4-ac yl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R^24b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,

18 22 23

In other embodiments, R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

18 -C(0)N(R 22 R 23 22 23

In other embodiments, R is ) wherein R and R are independently selected from H, C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

In embodiments, R¹⁸ is selected from hydrogen, halogen, C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein

R²⁴ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

R^24b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl, and

wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In embodiments, R¹⁸ is selected from hydrogen, halogen, -C(0)N(R²²R²³), -N(R²²R²³), C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein

In other embodiments, R¹⁸ is selected from hydrogen, halogen, NR²²R²³, -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, C₂-4-acylamino, -0(C_M-alk l) and Ci-4-alkyl, wherein R²² and R²³ are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R²⁴ and R^24b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

18 22 23

In other embodiments, R is selected from hydrogen, halogen, -NR R , C2-4-acylamino, -0(Ci-4-alkyl) and Ci-4-alkyl, wherein R²² and R²³ are independently selected from H and Ci-4-alkyl, and

wherein each alkyl or acylamino is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In other embodiments, R¹⁸ is selected from NH₂, and from NH(CH₃), NH-pyrazolyl optionally substituted by methyl, NHC(0)NHCH_3, NHC(0)OCH_3, NHC(0)CH₃ and methyl, each optionally substituted by 1 to 3 halogen. In other embodiments, R¹⁸ is selected from NH₂, NH(CH₃), and methyl, optionally substituted by 1 to 3 halogen. In other embodiments, R¹⁸ is hydrogen. In one embodiment, R¹⁸ is selected from NH₂ and NHC(0)NHCH₃

In embodiments, R¹⁹ is selected from hydrogen, halogen, NR²²R²³, -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, C₂-4-acylamino, -0(C_M-alk l) and Ci-4-alkyl, wherein R²² and R²³ are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R²⁴ and R^24b are independently selected from H and Ci-4-alkyl and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci_-3-alkyl, -0(Ci_-3-alkyl), carbonitrile, C₃-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In embodiments, R is selected from hydrogen, halogen, -NR R , C_2-4-acylamino, -0(Ci-4-alkyl) and Ci-4-alkyl, wherein R²² and R²³ are independently selected from H and Ci-4-alkyl, and

wherein each alkyl or acylamino is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci_-3-alkyl, -0(Ci_-3-alkyl), carbonitrile, C₃-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In other embodiments, R¹⁹ is selected from NH₂, and from NH(CH₃), NH-pyrazolyl, optionally substituted by Ci_-4-alkyl, NHC(0)NHCH_3, NHC(0)OCH_3i NHC(0)CH₃ and methyl, each optionally substituted by 1 to 3 halogen. In other embodiments, R¹⁹ is selected from NH₂, NH(CH₃) and methyl, optionally substituted by 1 to 3 halogen. In other embodiments, R¹⁹ is hydrogen. In one embodiment, R¹⁸ is selected from NH₂ and NHC(0)NHCH₃

In embodiments, R¹⁹ is hydrogen and R¹⁸ is other than hydrogen. In embodiments, R is selected from hydrogen, halogen, carbonitrile, -C(0)NR²²R²³, -N(R²²R²³), C₂-4-acylamino, -0(Ci_-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, and heterocycloalkyl, aryl, and heteroaryl, and

wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

In other embodiments, R²⁰ is selected from hydrogen, halogen, -0(Ci-4-alkyl), Ci-4-alkyl, aryl and heteroaryl,

In other embodiments, R²⁰ is selected from CI, F, methyl, methoxy, phenyl, and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl). In other embodiments, R²⁰ is hydrogen.

In embodiments, R²¹ is selected from hydrogen, halogen, -0(Ci-8-alkyl), Ci-4-alkyl, aryl and heteroaryl,

In other embodiments, R²¹ is selected from CI, F, methyl, methoxy, phenyl, and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl). In other embodiments, R²¹ is hydrogen. In embodiments, R¹⁹ and R²¹ are each independently hydrogen (or deuterium).

In one embodiment, R¹⁸ is -N(R²²R²³), e.g. NH₂; R²⁰ is halogen, e.g. CI, F, or Br; and R¹⁹ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R is -N(R²²R²³), e.g. NH₂; R²⁰ is -0(C_1-3-alkyl), e.g. methoxy, optionally substituted by 1 to 3 halogen; and R¹⁹ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is -N(R²²R²³), e.g. NH₂; R²⁰ is C_1-3-alkyl, e.g. methyl, optionally substituted byl to 3 halogen; and R¹⁹ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NH₂; R²⁰ is CI; and R¹⁹ and R²¹ are each independently hydrogen

18 20 19 21

(or deuterium). In another embodiment, R is NH₂; R is F; and R and R are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NH₂; R²⁰ is Br; and R¹⁹ and R²¹ are each independently hydrogen (or deuterium).

20 18 19 21

In one embodiment, R is optionally substituted phenyl; and R , R and R are each independently hydrogen (or deuterium). In another embodiment, R²⁰ is optionally substituted pyrazolyl; R¹⁸, R¹⁹ and R²¹ are each independently hydrogen (or deuterium). In another

20 18 19 21

embodiment, R is halogen, e.g. CI or Br; and R , R and R are each independently hydrogen (or deuterium). In another embodiment, R²⁰ is Ci-3-alkyl, e.g. methyl, optionally substituted by 1 to 3 halogen; and R¹⁸, R¹⁹ and R²¹ are each independently hydrogen (or deuterium).

In one embodiment, R¹⁸ is NH₂ NH(CH₃), NH-pyrazolyl, optionally substituted by C1-4- alkyl, NHC(0)NHCH_3, NHC(0)OCH_3, or NHC(0)CH₃; and R¹⁹, R²⁰ and R²¹ are each independently hydrogen (or deuterium). In one embodiment, R¹⁸ is NH₂ orNH(CH₃); and R¹⁹,

R ^u and R ¹ are each independently hydrogen (or deuterium). In another embodiment, R is

Ci-₃-alkyl, e.g. methyl, optionally substituted by 1 to 3 halogen; and R , R and R are each

18 20 19 independently hydrogen (or deuterium). In another embodiment, R is NH_2; and R , R and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NH-

20 19 21

pyrazolyl, optionally substituted by Ci-4-alkyl; and R , R and R are each independently

18 22 23 hydrogen (or deuterium). In another embodiment, R is NHC(0)NR R , e.g. NHC(0)NHCH₃; and R¹⁹, R²⁰ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NHC(0)OR²⁴, e.g. NHC(0)OCH₃; and R¹⁹, R²⁰ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NHC(0)R^24b, e.g.

19 20 21

NHC(0)CH₃; and R , R and R are each independently hydrogen (or deuterium). In embodiments: L is -(CR⁶R⁷)_P-, in which p is 1 and one of R⁶ and R⁷ is hydrogen and the other is Ci-4-alkyl optionally substituted by hydroxyl; and R³ 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), NH₂, NHSO₂CH₃, SO₂CH₃ and CONH₂

In other embodiments: L denotes a direct bond; and R³ 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), NH₂, NHSO2CH3, SO2CH3 and CONH2.

In one embodiment: L denotes a direct bond; and R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci_-4-alkyl) and CONH₂.

In another embodiment: L denotes a direct bond; and R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci_ 3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl) and CONH2. In one embodiment: L denotes a direct bond; and R³ is (2-hydroxy)cyclohexanyl.

In one embodiment: L denotes a direct bond; and R³ 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 CONH₂.

In another embodiment: L denotes a direct bond; and R³ is indanyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl) and CONH₂. In one embodiment: L denotes a direct bond; and R³ is (l-hydroxy)indanyl or (2-hydroxy)indanyl.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein q is 0, 1, 2 or 3;

m, X¹, R², R⁴, R⁵, R¹⁸ and R²⁰ are as defined herein.

In embodiments, q is 0, 1 or 2. In other embodiments, q is 1, 2 or 3. In other embodiments, q is 1 or 2. In other embodiments, q is 0. In other embodiments, q is 1. In other embodiments, q is 2.

In embodiments, each R²⁵ is independently selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(O)N(RⁿR⁰) in which Rⁿ and R° are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments, R²⁵ is independently selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(O)N(RⁿR⁰) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R²⁵ is attached to the carbon atom of the cyclohexane ring which is bonded to the oxygen atom of the hydroxyl group. In one embodiment, the R²⁵ group attached to the carbon atom of the cyclohexane ring which is bonded to the oxygen atom of the hydroxyl group is selected from Ci-3-alkyl, e.g. methyl.

In embodiments, q is 1 and R²⁵ is selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, q is 2 and each R²⁵ is independently selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, q is 2, a first R²⁵ is hydroxyl, and a second R²⁵ is selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

18 20 19 21

In another embodiment, R is NH₂; R is CI; and R and R are each independently

18 20 19 21 hydrogen (or deuterium). In another embodiment, R is NH₂; R is F; and R and R are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NH₂; R²⁰ is Br; and R¹⁹ and R²¹ are each independently hydrogen (or deuterium).

18 20 19 21

In another embodiment, R is NH₂ and R , R and R are each independently hydrogen (or

18 20 19 21 deuterium). In another embodiment R is NH(CH₃); and R , R and R are each independently hydrogen (or deuterium). In another embodiment R¹⁸ is NH-pyrazolyl,

20 19 21

optionally substituted by Ci-4-alkyl; and R , R and R are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NHC(0)NHCH₃; and R¹⁹, R²⁰ and R²¹ are each independently hydrogen (or deuterium). In another embodiment, R¹⁸ is NHC(0)OCH₃; and

19 20 21

R , R and R are each independently hydrogen (or deuterium). In another embodiment,

18 19 20 21

R is NHC(0)CH₃; and R , R and R are each independently hydrogen (or deuterium). In one embodiment, the compound is characterized by formula (VII_a),

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, q, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁵ are as defined herein.

Compounds characterized by formula (VII_a) may demonstrate inter alia a good selectivity for CSF-IR over other kinases, such as c-KIT, PDGFRa, PDGFR and/or FLT-3 as well as a good inhibitory activity towards CSF-IR.

In another embodiment, the compound is characterized by formula (ΥΙ¾),

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

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

Compounds characterized by formula (Vll_b), formula (VII_C) and formula (Vll_d) may demonstrate inter alia a good inhibitory activity towards CSF-1R.

In embodiments: R¹⁸ is selected from hydrogen, halogen, C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^24b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen;

20 22 23

R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R² 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; and X¹ is S, O or NH.

In embodiments: R¹⁸ is selected from hydrogen, halogen, -C(0)N(R²²R²³), -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S, O or NH.

In other embodiments: R¹⁸ is selected from hydrogen, halogen, -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^24b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R² 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; and X¹ is S, O or NH.

In other embodiments: R is selected from hydrogen, halogen, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S, O or NH. In other embodiments: R is selected from hydrogen, halogen, C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^24b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen;

20 22 23

R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² 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; and X¹ is S.

In other embodiments: R¹⁸ is selected from hydrogen, halogen, -C(0)N(R²²R²³), -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R and R are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S.

In other embodiments: R¹⁸ is selected from hydrogen, halogen, -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^24b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen;

20 22 23

R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² 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; and X¹ is S. In other embodiments: R is selected from hydrogen, halogen, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S.

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

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

r is 0, 1, 2 or 3;

m, X¹, R², R⁴, R⁵, R¹⁸ and R²⁰ are as defined herein.

In embodiments, r is 0, 1 or 2. In other embodiments, r is 1, 2 or 3. In other embodiments, r is 1 or 2. In other embodiments, r is 0. In other embodiments, r is 1. In other embodiments, r is 2.

In embodiments, each R²⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^qR^I) in which R^q and R^r 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^qR^r) in which R^q and R^r are independently selected from hydrogen and Ci-4-alkyl or in which R^q and R^r together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments, R²⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^qR^I) in which R^q and R^r 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^qR^I) in which R^q and R^r are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, each R²⁶ is attached to a saturated carbon atom within the indane moiety. In other embodiments each R²⁶ is attached to an unsaturated carbon atom within the indane moiety. In other embodiments at least one R²⁶ is attached to a saturated carbon atom within the indane moiety and at least one R²⁶ is attached to an unsaturated carbon atom within the indane moiety.

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

(Villa)

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁶ are as defined herein.

In one embodiment, the compound is characterized by formula (ΥΠ¾),

(Vlllb) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁶ are as defined herein.

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

18 22 23

In other embodiments: R is selected from hydrogen, halogen, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1 ; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S, O or NH.

In other embodiments: R¹⁸ is selected from hydrogen, halogen, -C(0)N(R²²R²³), -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S.

In other embodiments: R is selected from hydrogen, halogen, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen, halogen, carbonitrile, -N(R²²R²³), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1; R² is selected from halogen, hydroxyl, carbonitrile, Ci-4-alkyl, and -0(Ci-4-alkyl); and X¹ is S. embodiment, the compound is characterized by formula (IX),

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

n is 0, 1 or 2;

X⁴ is NH, O or S; and

m, X¹, L and R¹ to R⁵ are as defined herein.

In embodiments, X⁴ is O or S. In one embodiment, X⁴ is S.

In embodiments: n is 1 ; R¹ is selected from halogen, -C(0)N(R⁸R⁹) wherein R⁸ and R⁹ 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl and amino and halogen; R⁴ and R⁵ are independently selected from hydrogen; m is 0, 1 or 2; R² 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; X¹ is S; L denotes a direct bond; and R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments: n is 1; R¹ is selected from halogen, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl and amino and halogen; R⁴ and R⁵ are independently selected from hydrogen; m is 0, 1 or 2; R² 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; X¹ is S; L denotes a direct bond; and R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

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

(X)

armaceutically acceptable salt or prodrug thereof, wherein

is 0, 1 or 2;

X⁵ is NH, O or S; and m, X¹, L and R¹ to R⁵ are as defined herein.

In embodiments, X⁵ is O or S. In one embodiment, X⁵ is S.

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

(XI) or a pharmaceutically acceptable salt or prodrug thereof, wherein n, m, X¹, L and R¹ to R⁵ are as defined herein.

In embodiments: n is 1 or 2; R¹ is selected from halogen, -C(0)N(R⁸R⁹) wherein R⁸ and R⁹ 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl and amino and halogen; R⁴ and R⁵ are independently selected from hydrogen; m is 0, 1 or 2; R² 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; X¹ is S; L denotes a direct bond; and R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments: n is 1 or 2; R¹ is selected from halogen, 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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl and amino and halogen; R⁴ and R⁵ are independently selected from hydrogen; m is 0, 1 or 2; R² 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; X¹ is S; L denotes a direct bond; and R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

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

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

R , R , and R are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, - C(0)R ^5b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

wherein m, X¹, L, and R² to R⁵ are as defined herein.

In embodiments, R , R , and R are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), C₂-₄-acyl, C₂-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R³⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen

In embodiments, R³⁰ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b,- C(0)R ^5b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen.

In embodiments, R³⁰ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), C₂-₄-acyl, C₂-4-acylamino, hydroxy 1, -0(Ci-8-alkyl), -C(0)OR , sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

In other embodiments, R³⁰ is selected from hydrogen, halogen, carbonitrile, -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen. In other embodiments, R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

30 33 34 33 34

In other embodiments, R is -C(0)N(R R ) wherein R and R are independently selected from H, C2-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

In embodiments, R³⁰ is selected from hydrogen, halogen, C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein

wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen. In embodiments, R^3U is selected from hydrogen, halogen, -C(0)N(R³³R³⁴), -N(R³³R³⁴), C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein

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

In other embodiments, R³⁰ is selected from hydrogen, halogen, NR R³⁴, -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, C₂-4-acylamino, -0(C_M-alk l) and Ci-4-alkyl, wherein R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R³⁵ and R ^5b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen.

30 33 34

In other embodiments, R is selected from hydrogen, halogen, -NR R , C2-4-acylamino, -0(Ci-4-alkyl) and Ci-4-alkyl, wherein R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, and heteroaryl, and

wherein each alkyl, acylamino, or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen.

In other embodiments, R³⁰ is selected from NH₂, NH(CH₃), NHCH₂CH₂OH, NH-pyrazolyl optionally substituted by Ci-4-alkyl, NH-isoxazolyl optionally substituted by Ci-4-alkyl, NH- triazolyl optionally substituted by Ci-4-alkyl, and methyl, optionally substituted by 1 to 3 halogen. In other embodiments, R³⁰ is selected from NH₂, NH(CH₃), and methyl, optionally substituted by 1 to 3 halogen.

In embodiments, R³¹ is selected from hydrogen, halogen, carbonitrile, -C(0)NR R³⁴, -N(R R³⁴), C₂-4-acylamino, -0(Ci_-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

wherein R³³ and R³⁴ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, and heterocycloalkyl, aryl, and heteroaryl, and

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

In other embodiments, R³¹ is selected from hydrogen, halogen, -0(Ci-4-alkyl), Ci-4-alkyl, aryl and heteroaryl,

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

In other embodiments, R³¹ is selected from CI, F, methyl, methoxy, phenyl, and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl). In other embodiments, R³¹ is hydrogen.

In embodiments, R³² is selected from hydrogen, halogen, carbonitrile, -C(0)NR R³⁴, -N(R R³⁴), C₂-4-acylamino, -0(Ci_-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

In other embodiments, R³² is selected from hydrogen, halogen, -0(Ci-4-alkyl), Ci-4-alkyl, aryl and heteroaryl,

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

In other embodiments, R³² is selected from CI, F, methyl, methoxy, phenyl, and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci-3-alkyl). In other embodiments, R³¹ is hydrogen.

In embodiments, R³¹ and R³² are each independently hydrogen (or deuterium).

In one embodiment, R³⁰ is NH_2, NH(CH₃), NHCH₂CH₂OH, NH-pyrazolyl optionally substituted by Ci-4-alkyl, NH-isoxazolyl optionally substituted by Ci-4-alkyl, or NH-triazolyl optionally substituted by Ci-4-alkyl; and R³¹ and R³² are each independently hydrogen (or deuterium). In one embodiment, R³⁰ is NH₂ or NH-pyrazolyl optionally substituted by C1-4- alkyl; and R³¹ and R³² are each independently hydrogen (or deuterium). In one embodiment,

30 31 32

R is NH₂ orNH(CH₃); and R and R are each independently hydrogen (or deuterium).

30 31 32

In another embodiment, R is NH₂ and R and R are each independently hydrogen (or

30 31 32

deuterium). In another embodiment R is NH(CH₃); and R and R are each independently hydrogen (or deuterium). In another embodiment R³⁰ is NH-pyrazolyl, optionally substituted by Ci-4-alkyl; and R³¹ and R³² are each independently hydrogen (or deuterium). In another embodiment, R³⁰ is NHCH₂CH₂OH; and R³¹ and R³² are each independently hydrogen (or deuterium). In another embodiment R³⁰ is NH-triazolyl, optionally substituted by Ci-4-alkyl; and R and R are each independently hydrogen (or deuterium). In another embodiment R is NH-isoxazolyl, optionally substituted by Ci-4-alkyl; and R³¹ and R³² are each independently hydrogen (or deuterium).

In embodiments: L is -(CR⁶R⁷)_P-, in which p is 1 and one of R⁶ and R⁷ is hydrogen and the other is Ci-4-alkyl optionally substituted by hydroxyl; and R³ 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), NH₂, NHSO2CH3, SO2CH3 and CONH2

In other embodiments: L denotes a direct bond; and R³ 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), NH₂, NHSO2CH3, SO2CH3 and CONH₂.

In another embodiment: L denotes a direct bond; and R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from Ci_ 3-alkyl optionally substituted by hydroxyl, CI, -0(Ci-4-alkyl) and CONH₂. In one embodiment: L denotes a direct bond; and R³ is (2-hydroxy)cyclohexanyl.

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

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

X¹, L, R³, R⁴, R⁵, R¹⁶, R¹⁷ and R³⁰ are as defined herein. In embodiments: R is selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, - C(0)R ^5b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R³⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R ^5b is independently selected from H, Ci-4-alkyl, Ci_ 4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R¹⁶ is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen and R¹⁷ is hydrogen or halogen; X¹ is selected from NH, O or S; L denotes a direct bond; R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(Ci_-4-alkyl) and CONH₂.

In embodiments: R³⁰ is selected from halogen, carbonitrile, -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acyl, C2-4-acylamino, hydroxyl, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein R³³ and R³⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R³⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R ^5b is independently selected from H, Ci-4-alkyl, Ci_ 4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, 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^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R is -0(Ci-3-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen and R¹⁷ is hydrogen or halogen; X¹ is selected from NH, O or S; L denotes a direct bond; R³ is cyclohexyl optionally substituted by 1 to 4 groups independently selected from hydroxyl, Ci-3-alkyl optionally substituted by hydroxyl, CI, -0(C_M-alkyl) and CONH₂.

In another embodiment, R is methoxyl and R is hydrogen. In another embodiment, R is methoxyl and R¹⁷ is CI. In another embodiment, R¹⁶ is methoxyl and R¹⁷ is methyl.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein

s is 0, 1, 2 or 3;

m, X¹, R², R⁴, R⁵ and R³⁰ are as defined herein.

In embodiments, s is 0, 1 or 2. In other embodiments, s is 1, 2 or 3. In other embodiments, s is 1 or 2. In other embodiments, s is 0. In other embodiments, s is 1. In other embodiments, s is 2.

In embodiments, each R³⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-4-alkyl or in which R^y and R^w together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments, R³⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, R³⁶ is attached to the carbon atom of the cyclohexane ring which is bonded to the oxygen atom of the hydroxyl group. In one embodiment, the R³⁶ group attached to the carbon atom of the cyclohexane ring which is bonded to the oxygen atom of the hydroxyl group is selected from Ci-3-alkyl, e.g. methyl.

In embodiments, s is 1 and R³⁶ is selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, s is 2 and each R³⁶ is independently selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

In embodiments, s is 2, a first R³⁶ is hydroxyl, and a second R³⁶ is selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, sulfonyl, aminosulfonyl, sulfonylamino, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, s, X¹, R², R⁴, R⁵, R³⁰ and R³⁶ are as defined herein.

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

(xiv_b) or a pharmaceutically acceptable salt or prodrug thereof, wherein m, s, X¹, R², R⁴, R⁵, R³⁰ and R³⁶ are as defined herein.

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

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, s, X¹, R², R⁴, R⁵, R³⁰ and

R are as defined herein.

In embodiments: R is selected from hydrogen, halogen, C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R³³ to R³⁵ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are independently selected from H and Ci-3-alkyl; m is 0 or 1; R² 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; and X¹ is S, O or NH.

In other embodiments: R³⁰ is selected from hydrogen, halogen, -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R³³ to R³⁵ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; m is 0 or 1; R² 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; and X¹ is S, O or NH.

In other embodiments: R³⁰ is selected from hydrogen, halogen, C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R³³ to R³⁵ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1 ; R² 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; and X¹ is S.

In other embodiments: R³⁰ is selected from hydrogen, halogen, -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR , sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R³³ to R³⁵ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; m is 0 or 1 ; R² 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; and X¹ is S.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein s, R⁴, R⁵, R¹⁶, R¹⁷, R³⁰ and R³⁶ are as defined herein.

In embodiments, R³⁰ is selected from hydrogen, halogen, -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, -C(0)R ^5b, C2-4-acylamino, -0(Ci-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, and Ci-g-alkyl, wherein R³³ to R³⁵ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R ^5b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; R¹⁶ is -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen; R¹⁷ is selected from H, F, CI, and CH₃; s is 0 or 1; R³⁶ is selected from halogen, hydroxyl, carbonitrile, -N(R^yR^w) in which R^y and R^w 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^yR^w) in which R^y and R^w are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

30 33 34 33 34

In embodiments, R is -N(R R ), wherein R and R are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; R¹⁶ is methoxyl; R¹⁷ is H; and s is 0.

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

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

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

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein s, R⁴, R⁵, R¹⁶, R¹⁷, R³⁰ and R³⁶ are as defined herein. embodiment, the compound is characterized by formula (XVI),

20 or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, R and R are as defined herein.

In embodiments: R¹⁸ is selected from hydrogen, halogen,

C(0)N(R²²R²³), -N(R²²R²³), -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, -C(0)R^24b, C2-4-acylamino, -0(Ci-4-alkyl), -C(0)OR²⁴, sulfonyl, aminosulfonyl and Ci-4-alkyl, wherein R²² to R²⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R^24b is independently selected from H, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen;

20 22 23

R is selected from hydrogen, halogen, carbonitrile, -N(R R ), C2-4-acylamino, -0(Ci-4-alkyl), sulfonyl, aminosulfonyl, Ci-4-alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R²² and R²³ are independently selected from hydrogen, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R⁴ and R⁵ are each independently H; R¹⁶ is -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen; R¹⁷ is selected from H, F, CI, and CH₃; q is 0 or 1; and R²⁵ is selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl.

In embodiments: R¹⁸ is selected from -N(R²²R²³), and -NHC(0)NR²²R²³, wherein R²² and R²³ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein each said acyl, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen; R²⁰ is selected from hydrogen and halogen; R⁴ and R⁵ are each independently H; R¹⁶ is methoxyl; R¹⁷ is H; and q is 0.

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, R and R²⁵ are as defined herein.

In another embodiment, the compound is characterized by formula (XV¾),

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

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

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, and R²⁵ are as defined herein.

In one aspect, the compound is selected from the group consisting of Compounds 1 to 86:

(lR,2R)-2-((6-((2-amino-3-chloropyridin-4-

Compound 1

yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

(lS,2S)-2-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-

Compound 2

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lR,2R)-2-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-

Compound 3

benzothiazol-2-yl)amino]cyclohexan-l-ol

(lR,2R)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-

Compound 4

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-

Compound 5

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lS,2S)-2-[(6-{[2-(methylamino)pyridin-4-yl]methoxy}-l,3-

Compound 6

benzothiazol-2-yl)amino]cyclohexan-l-ol

N-cyclohexyl-6-(pyridin-4-ylmethoxy)-l,3-benzothiazol-2-

Compound 7

amine N-cyclohexyl-6-(pyridin-3-ylmethoxy)-l,3-benzothiazol-2-

Compound 8

amine

N-cyclohexyl-6-(l,3-thiazol-4-ylmethoxy)-l,3-benzothiazol-2-

Compound 9

amine

N-cyclohexyl-6-(pyridin-2-ylmethoxy)-l,3-benzothiazol-2-

Compound 10

amine

N-cyclohexyl-6-(pyrazin-2-ylmethoxy)-l,3-benzothiazol-2-

Compound 11

amine

N-cyclohexyl-6-(pyrimidin-4-ylmethoxy)-l,3-benzothiazol-2-

Compound 12

amine

N-cyclohexyl-6-(l,3-thiazol-2-ylmethoxy)-l,3-benzothiazol-2-

Compound 13

amine

N-cyclohexyl-6-(l,3-thiazol-5-ylmethoxy)-l,3-benzothiazol-2-

Compound 14

amine

6-[(2-aminopyridin-4-yl)methoxy] -N-cy clohexyl- 1 ,3-

Compound 15

benzothiazol-2-amine

6-[(6-chloropyrazin-2-yl)methoxy] -N-cy clohexyl- 1,3-

Compound 16

benzothiazol-2-amine

6-[(5-chloropyridin-3-yl)methoxy]-N-cyclohexyl-l,3-

Compound 17

benzothiazol-2-amine

N-cyclohexyl-6-[(2-methylpyridin-4-yl)methoxy]-l,3-

Compound 18

benzothiazol-2-amine

4-( { [2-(cy clohexy lamino)- 1 ,3 -benzothiazol-6-y 1] oxy } methy 1)-

Compound 19

N-methylpyridine-2-carboxamide

N-cyclohexyl-6-[(3-methylpyridin-4-yl)methoxy]-l,3-

Compound 20

benzothiazol-2-amine

5-( { [2-(cy clohexy lamino)- 1 ,3 -benzothiazol-6-y 1] oxy } methy 1)-

Compound 21

N-methylpyridine-2-carboxamide

(lR,2R)-2-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-

Compound 22

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

6-[(3-chloropyridin-4-yl)methoxy]-N-cyclohexyl-l,3-

Compound 23

benzothiazol-2-amine

(lR,2R)-2-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-

Compound 24

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lS,2S)-2-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-

Compound 25

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

N-cy clohexyl-6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy} -1,3-

Compound 26

benzothiazol-2-amine

(lS,2S)-2-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-

Compound 27

benzothiazol-2-yl)amino]cyclohexan-l-ol

(lR,2S)-l-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-

Compound 28

benzothiazol-2-y 1 } amino)-2,3 -dihy dro- 1 H-inden-2-ol

(lR,2S)-l-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-

Compound 29

benzothiazol-2-y 1 } amino)-2,3 -dihy dro- 1 H-inden-2-ol

(lS,2S)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-

Compound 30

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

6-[(3-bromopyridin-4-yl)methoxy]-N-cyclohexyl-l,3-

Compound 31

benzothiazol-2-amine N-cy clohexyl-6- {[3-(l-methyl-lH-pyrazol-4-yl)pyridin-4-

Compound 32

yljmethoxy } - 1 ,3-benzothiazol-2-amine

N-cyclohexyl-6-[(3-phenylpyridin-4-yl)methoxy]-l,3-

Compound 33

benzothiazol-2-amine

(lR,2R)-2-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-

Compound 34

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lS,2S)-2-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-

Compound 35

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lR,2S)-l-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-

Compound 36

benzothiazol-2-y 1 } amino)-2,3 -dihy dro- 1 H-inden-2-ol

(lR,2R)-2-{[6-({3-chloro-lH-pyrrolo[2,3-b]pyridin-4-

Compound 37

yl} methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

(lR,2S)-l-[(6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-

Compound 38

benzothiazol-2-yl)amino]-2,3-dihydro-lH-inden-2-ol

6-[(2-amino-3-chloropyridin-4-yl)methoxy]-N-cyclohexyl-l,3-

Compound 39

benzothiazol-2-amine

(lR,2S)-l-({6-[(3-phenylpyridin-4-yl)methoxy]-l,3-

Compound 40

benzothiazol-2-y 1 } amino)-2,3 -dihy dro- 1 H-inden-2-ol

(1 R,2S)- 1 -( { 6- [(2-amino-3 -chloropy ridin-4-y l)methoxy ] -1,3-

Compound 41

benzothiazol-2-y 1 } amino)-2,3 -dihy dro- 1 H-inden-2-ol

N-cy clohexyl-6- { [2-(methylamino)pyridin-4-yl]methoxy } - 1 ,3-

Compound 42

benzothiazol-2-amine

(1 R,2R)-2-[(6- { [2-(methylamino)pyridin-4-yl]methoxy } -1 ,3-

Compound 43

benzothiazol-2-yl)amino]cyclohexan-l-ol

(lR,2R)-2-[(6-{[2-amino-3-(trifluoromethoxy)pyridin-4-

Compound 44

yl]methoxy } - 1 ,3-benzothiazol-2-yl)amino] cy clohexan- 1 -ol

(lS,2S)-2-[(6-{[2-amino-3-(trifluoromethoxy)pyridin-4-

Compound 45

yl]methoxy } - 1 ,3-benzothiazol-2-yl)amino] cy clohexan- 1 -ol

(lR,2R)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4-

Compound 46

yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

(lS,2S)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4-

Compound 47

yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

(lR,2R)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4-

Compound 48

methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

(lS,2S)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4-

Compound 49

methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

(lR,2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-

Compound 50

methoxy- 1 ,3-benzothiazol-2-yl} amino)cy clohexan- 1 -ol

(lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-

Compound 51

methoxy- 1 ,3-benzothiazol-2-yl} amino)cy clohexan- 1 -ol

N-[(lS,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-

Compound 52 methoxy- 1 ,3-benzothiazol-2- y 1 } amino)cy clohexy 1] methanesulfonamide

(2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4-

Compound 53

methoxy-l,3-benzothiazol-2-yl}amino)-4-methylpentan-l-ol

(lS,2S)-2-((6-((2-amino-3-fluoropyridin-4-yl)methoxy)-4-

Compound 54

methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol (lS,2S)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol-4-

Compound 55 ylamino)pyrimidin-4yl)methoxy)benzo[d]thiazol-2- ylamino)cyclohexanol

(lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-

Compound 56 y l)amino] py rimidin-4-y 1 } methoxy )- 1 ,3 -benzothiazol-2- yljamino} cy clohexan- 1 -ol

(lS,2S)-2-{[6-({2-[(2-hydroxyethyl)amino]pyrimidin-4-

Compound 57 yl}methoxy)-4-methoxy-l,3-benzothiazol-2- yljamino} cy clohexan- 1 -ol

(lS,2S)-2-{[4-methoxy-6-({2-[(l,2-oxazol-4-

Compound 58 yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2- yljamino} cy clohexan- 1 -ol

(lS,2S)-2-{[4-methoxy-6-({2-[(lH-pyrazol-4-

Compound 59 yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2- yljamino} cy clohexan- 1 -ol

(lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-l,2,3-triazol-4-

Compound 60 yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2- yl]amino} cy clohexan- 1 -ol

6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-

Compound 61

difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine

6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-

Compound 62

difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine

6-((2-aminopyrimidin-4-yl)methoxy)-N-(4,4-

Compound 63

difluorocyclohexyl)-4-methoxybenzo [d]thiazol-2-amine

N-(3,3-difluorocyclohexyl)-4-methoxy-6-((2-(l-methyl-lH-

Compound 64 pyrazol-4-ylamino)pyrimidin-4-yl)methoxy)benzo[d]thiazol-2- amine

(lS,2S)-2-(6-((2-amino-3-chloropyridin-4-yl)methoxy)-4-

Compound 65

fluorobenzo[d]thiazol-2-ylamino)cyclohexanol

(lS,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-4-

Compound 66

methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

6-((2-amino-3-chloropyridin-4-yl)methoxy)-N-(3,3-

Compound 67

difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine

1 - {4- [( {2- [(3 ,3 -difluorocy clohexy l)amino] -4-methoxy- 1 ,3 -

Compound 68

benzothiazol-6-yl}oxy)methyl]pyridin-2-yl}-3-methylurea

(lS,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-4-

Compound 69

methoxybenzo[d]thiazol-2-yl)amino)cy clohexan- 1 -ol

(lS,2S)-2-(6-((2-aminopyrimidin-4-yl)methoxy)-7-fluoro-4-

Compound 70

methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

N-(4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-

Compound 71

methoxybenzo[d]thiazol-6-yloxy)methyl)pyridin-2-yl)acetamide

N-(4- { [(2- { [( 1 R,2R)-2-hy droxy cy clohexy 1] amino } -4-methoxy-

Compound 72

l,3-benzothiazol-6-yl)oxy]methyl}pyridin-2-yl)acetamide

(lS,2S)-2-(6-((2-aminopyrimidin-4-yl)methoxy)-4-methoxy-7-

Compound 73

methylbenzo[d]thiazol-2-ylamino)cyclohexanol

(lS,2S)-2-(6-((2-amino-3-fluoropyridin-4-yl)methoxy)-7-chloro-

Compound 74

4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

(lS,2S)-2-({6-[(2-aminopyridin-4-yl)methoxy]-7-chloro-4-

Compound 75

methoxy- 1 ,3-benzothiazol-2-yl} amino)cy clohexan- 1 -ol (lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-pyrazol-

Compound 76 4-yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2- yl]amino} cy clohexan- 1 -ol

(lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-l,2,3-

Compound 77 triazol-4-yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol- 2-yl]amino} cy clohexan- 1 -ol

(lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-pyrazol-

Compound 78 3-yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2- yl]amino} cy clohexan- 1 -ol

Methyl 4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-

Compound 79

methoxybenzo[d] thiazol-6-yloxy)methyl)pyridin-2-ylcarbamate l-(4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-

Compound 80 methoxybenzo[d]thiazol-6-yloxy)methyl)pyridin-2-yl)-3- methylurea

(lS,2S)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol-4-

Compound 81 ylamino)pyridin-4-yl)methoxy)benzo[d]thiazol-2- ylamino)cyclohexanol

(lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-

Compound 82 yl)amino]pyridin-4-yl}methoxy)-l,3-benzothiazol-2- yl] amino} cy clohexan- 1 -ol

(lS,2S)-2-{[4-methoxy-6-({2-[(2-methylpyrimidin-4-

Compound 83 yl)amino]pyridin-4-yl}methoxy)-l,3-benzothiazol-2- yl] amino} cy clohexan- 1 -ol

6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-N-(3,3-

Compound 84

difluorocyclohexyl)-4-methoxybenzo [d]thiazol-2-amine

(1 R,2S)-2-( { 6- [(2-amino-3 -chloropy ridin-4-y l)methoxy ] -1,3-

Compound 85

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

(lS,2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-

Compound 86

benzothiazol-2-y 1 } amino)cy clohexan- 1 -ol

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound is selected from the group consisting Compounds 1 to 49, 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, 6, 7, 12, 13, 15, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46; 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, 6, 15, 17, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45 and 46; 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, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 35, 36, 37, 38, 39, 41, 44, 45, and 46; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 3, 5, 25, 26, 27, 30, 36, 37, 38, 39, and 41; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 3, 5, 25, 26, 27, 30, 36, 37, 38, 39, 41, 50, 51, 53, 54, 55, 56, 58, 59, 60, 61, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, and 86; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 5, 37, 38, 41, 55, 58, 59, 64, 65, 69, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, and 86; 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, 6, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, and 45; 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, 24, 25, 26, 27, 28, 29, 30, 31, 35, 36, 37, 38, 39, 44, and 45; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 5, 27, 30, and 41; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 5, 27, 30, 38, 41, 54, 55, 56, 58, 59, 60, 61, 62, 64, 65, 66, 68, 69, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, and 86; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 5, 55, 58, 59, 60, 64, 65, 69, 74, 76, 77, 78, 79, 80, 81, 82, 83, and 84; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 59, 55, 76, 79, 64, 82, 71, 72, 60, 56, 69, 73, 58, 80, and 77; 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, 15, 20, 24, 25, 26, 30, 35, 36, and 38; 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, 15, 20, 24, 25, 35, and 36; 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, 24, 25, and 36; 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, 20, 24, 25, 26, 27, 30, 35, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 3, 4, 24, 25, 35, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 4, 24, 25, 35, and 36; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 4, 20, 24, 25, 30, 35, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 2, 4, 24, 25, 30, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 2, 4, 25, 36, and 38; 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, 20, 24, 25, 30, 35, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 1, 2, 4, 24, 25, 36, and 38; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 2, 24, 25, and 36; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compound is selected from the group consisting of: Compounds 2, 4, 24, 25, 36, 50, 54, 55, 56, 66, 69, 70, 72, 73, and 84; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 3, 4, 24, 25, 35, 36, 38, 50, 51, 54, 55, 56, 66, 69, 70, 72, 73, and 84; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 36, 54, 55, 66, 69, 70, 72, and 73; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 2, 36, 50, 54, 55, 56, 66, 69, 70, 72, 73, and 84; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 36, 54, 55, 66, 69, 70, 72, and 73; or a pharmaceutically acceptable salt or prodrug thereof. In another embodiment, the compound is selected from the group consisting of: Compounds 50, 51, 54, 55, 56, 66, 69, 70, 72, 73, and 84; 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 IC5₀ value (e.g. an inhibitory activity against CSF-1R in a cell-free assay), of less than 1.5 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 other embodiments, compounds of the invention have an IC5₀ value (e.g. an inhibitory activity against CSF-1R in a cell-free assay), of less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM.

In embodiments, compounds of the invention have an IC5₀ value (e.g. an inhibitory activity against CSF-1R in a cell-based assay), of less than 10 μΜ, less than 5 μΜ, 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, or less than 75 nM. In other embodiments, compounds of the invention have an IC5₀ value (e.g. an inhibitory activity against CSF-1R in a cell-based assay), of less than 65 nM, less than 40 nM, less than 30 nM, or less than 20 nM. The compounds of the invention may be selective for CSF-1R 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-1R over other kinases, e.g. c-KIT, PDGFRa, PDGFR and/or FLT3. Assays for determining the selectivity of a compound for CSF-1R over other kinases are known in the art. Examples of assays for determining the selectivity of a compound for CSF-1R 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-1R 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, at least 1500 times, at least 2000 times or at least 5000 times. By "selective" is meant that the concentration of compound which results in 50% maximal inhibition (IC5₀) 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 IC5₀ value of 10 nM against CSF-IR, and having an IC5₀ 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 times, 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, at least 30 times or at least 40 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, at least 100 times, at least 150 times, at least 200 times or at least 250 times.

In embodiments, the compounds of the invention are selective for CSF-IR over c-KIT by a value of at least 15 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times, at least 300 times, at least 400 times, at least 500 times, at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times or at least 5000 times.

In embodiments, the compounds of the invention are selective for CSF-IR over FLT3 by a value of at least 50 times, at least 100 times, at least 200 times, at least 500 times, at least 1000 times, at least 1500 times, at least 2000 times, at least 3000 times, at least 4000 times or at least 5000 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 carboxylic acid or 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 R³ 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 (VII_a) and (Vll_b), or pharmaceutically acceptable salts or prodrugs of one or more thereof. In other embodiments, the invention provides a mixture of compounds characterized by formulae (VIII_a) and (VHI_b), 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 ²H, H, ¹ C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0,

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 R⁴ and R⁵ are both hydrogen:

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 reacted with a substituted amine via nucleophilic aromatic substitution to give intermediate B. In step (ii), deprotection of the methoxy group, e.g. using BBr₃, yields intermediate C. In step (iii), cyclic group A (which may be protected if necessary, e.g. if substituted), which carries a carbon atom having a leaving group "LG" attached thereto, participates in a nucleophilic substitution or coupling reaction to yield the target compound D.

Scheme I may be varied to obtain other compounds as disclosed herein. For example, where the cyclic group A is substituted in target compound D with an alkyl, alkenyl, alkynyl or (hetero)aryl group {i.e. R¹), the target compound may be obtained using the substituted cyclic group R¹-A-C(R₄R₅)-LG in step (iii) of Scheme I. Alternatively, the target compound may be prepared using a cyclic group A-C(R₄R₅)-LG which is substituted by a halide or a pseudohalide {e.g. a triflate, or alkoxy group) at the position on the ring to be substituted by R¹. This yields a corresponding product, D' which may then be coupled with either (a) an organoboron species, e.g. R¹-B(OH)₂, in a Suzuki reaction; (b) an organozinc species, e.g. (R¾Zn, 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 II and III:

Scheme II In Scheme II, 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 D, in which R¹ is typically a group that contains at least one carbon-carbon double or triple bond. Unsaturated bonds in an R¹ group may be reduced, e.g. as illustrated in Scheme III in which a compound D is catalytically hydrogenated to yield the corresponding product.

D (reduced)

Scheme III

By way of a further example, an illustrative synthetic scheme (Scheme IV) is shown below for the preparation of benzothiazole compounds of formula (I) comprising an R² group such as -0(Ci-4-alkyl) or halogen, illustrated using -OMe as an exemplary R² group:

Scheme IV

In Scheme IV, an alkoxy nitrobenzene derivative E (which may be obtained from commercial sources or prepared from e.g. a corresponding halogenated precursor) is converted into a corresponding alkoxy aminobenzothiazole derivative F, e.g. by treatment with a reducing agent in step (iv) (such as Raney-Ni and hydrazine) followed by cyclisation in step (v) (e.g. using KSCN and CuSC^). Compound F may then be converted into the bromobenzothiazole intermediate G, e.g. by treatment with t-BuONO and CuBr₂. Reacting G with a group H₂N-L-R₃ (e.g. as described in step (i) of Scheme I) yields compound H which may then be deprotected to yield the corresponding aryl alcohol I (e.g. using TFA). The product, J, may be obtained by reacting I with the "ring A" containing group, e.g. as shown in step (iii) of Scheme I. It will be appreciated that the "ring A" addition may be carried out before the group NH2-L-R³ is added, in which case reactions (viii) and (ix) may be performed before reaction (vii). It will also be appreciated that intermediates, such as G, may be substituted on the benzothiazole ring by additional R² groups, so as to yield the corresponding substituted products. By way of example, treatment of G with selectfluor in acetonitrile can yields the 7-fluoro derivative, which may then be taken through the reaction scheme to provide 7-fluoro-4-methoxybenzothiazole products.

By way of a yet further example, an illustrative synthetic scheme (Scheme V) is shown below for the preparation of benzothiazole compounds of formula (I) comprising an R² group such as -0(Ci-4-alkyl) or halogen, illustrated using -OMe as an exemplary R² group:

O

Scheme V

In Scheme V, the "ring A" containing moiety is introduced before the benzothiazole ring is formed. In step (x), the "ring A" containing compound K is coupled with a substituted / nitrophenol, e.g. using CS2CO₃, to form intermediate L. This compound is then reduced to the corresponding aniline M (e.g. using hydrogen in the presence of a Pt-C catylist), and further reacted to form the substituted thiourea compound N (e.g. by reacting with di(lH- imidazol-l-yl)methanethione and then with NH₂-L-R³). Compound N is then cyclised to form the corresponding benzothiazole O (e.g. with BSTFA and benzyltrimethylammonium tribromide). It will be appreciated that the product O may be further elaborated, e.g. substituted or deprotected at R¹, to yield further compounds of formula (I). Typically in these reactions one or both of R⁴ and R⁵ is hydrogen. It will also be appreciated that halogenated derivatives of K other than the bromomethyl derivative may be used, e.g. chloromethyl derivatives. By way of a still further example, an illustrative synthetic scheme (Scheme VI) is shown below for the preparation of benzothiazole compounds of formula (I) comprising an R² group such as -0(Ci-4-alkyl) or halogen, illustrated using -OMe as an exemplary R² group:

Scheme VI

In Scheme VI, an optionally substituted o-methoxyaniline precursor, P, is brominated (e.g. using Br₂ in solution) to yield compound Q, which is then converted to the corresponding benzothiazole compound R and then S (e.g. as described in steps (v) and (vi) of Scheme IV). This intermediate may then be reacted with NH₂-L-R³ to yield compound T (e.g. as described in step (i) of Scheme I). Formation of the corresponding boronate U (e.g. using bis(pinacolato)diboron with PCy₃ and Pd₂(dba)3) and subsequent hydrolysis (e.g. using hydrogen peroxide) yields the hydroxybenzothiazole compound V. The product, O, may be obtained by reacting V with the "ring A" containing group, e.g. as shown in step (iii) of Scheme I.

Other methods for the preparation of compounds according to the present disclosure would be apparent to the skilled person on the basis of their common general knowledge and the content of this application, in particular the Examples which follow. 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.

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- IR 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-IR 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-IR 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-IR 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-IR 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 injectable 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-(isobutyl 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 nonbiodegradable, 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.

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

EXAMPLES

Examples 1 to 49 - Chemical synthesis

Example 1 : ( 1R, 2R)-2-( f6-(( 2-amino-3-chloropyridin-4-yl)methoxy)benzo[ dJthi zol-2- yl) amino) cyclohexan-l-ol

The title compound was synthesised according to the following synthetic scheme:

Step 1:

A mixture of 2,3-dichloroisonicotinic acid (960 mg, 5.00 mmol) and BH₃ ^»THF (1.0 M, 25 mL, 25 eq) was heated at 60 °C for 4 h. After cooling to RT, MeOH (5 mL) was added, and the volatiles were removed under reduced pressure. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated to give (2,3- dichloropyridin-4-yl)methanol (400 mg, 45%) as a white solid. MS (ES+) C₆H₅C1₂N0 requires: 178, found: 179 [M+H]⁺. ^XH NMR (500 MHz, i¾-DMSO) δ 8.38 (d, J = 5 Hz, 1H), 7.58 (d, J= 5 Hz, 1H), 5.85-5.75 (br s, 1 H), 4.61 (s, 2H).

Step 2:

A mixture of (2,3-dichloropyridin-4-yl)methanol (200 mg, 1.12 mmol) and (4- methoxyphenyl)methanamine (1.0 mL, 7.65 mmol, 6.8 eq) was heated at 150 °C for 4 h. The reaction mixture was concentrated. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA/H₂0, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 12 min; Column: CI 8) to give (3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methanol (200 mg, 64%) as a white solid. MS (ES+) C14H15CIN2O2 requires: 278, found: 279 [M+H]⁺. ^XH NMR (500 MHz, i¾-DMSO) δ 7.93 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 9 Hz, 2H), 6.85 (d, J = 9 Hz, 2H), 6.78 (d, J = 5.5 Hz, 1H), 4.53 (s, 2H), 4.50 (s, 2H), 3.70 (s, 3H).

Step 3:

A mixture of (3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methanol (50 mg, 0.18 mmol) and SOCl₂ (2.0 mL, 27 mmol) in DCM (2 mL) was stirred at RT for 2 h. The volatiles were removed under reduced pressure to give 3-chloro-4-(chloromethyl)-N-(4- methoxybenzyl)pyridin-2-amine (50 mg, 94%) as a yellow solid. MS (ES+) C14H14CI2N2O requires: 297, found: 298 [M+H]⁺. ^XH NMR (500 MHz, d₆-OMSO) δ 7.96 (d, J = 5.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 5.5 Hz, 1H), 4.76 (s, 2H), 4.60 (s, 2H), 3.71 (s, 3H).

Step 4:

A mixture of 2-bromo-6-methoxybenzo[d]thiazole (3.00 g, 12.3 mmol) and (lR,2R)-2- aminocyclohexanol (4.25 g, 36.9 mmol) was heated at 110 °C for 6 h. The reaction was cooled to RT, diluted with water (30 mL), and extracted with EtOAc (3 χ 30 mL). The combined organic exacts were dried over Na₂SC>4 and concentrated to give (lR,2R)-2-((6- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol (3.5 g, 88%) as a brown solid. MS (ES+) Ci4Hi₈N₂0₂S requires: 278, found: 279 [M+H]⁺. ^lH NMR (500 MHz, CDC1₃) δ 7.37 (d, J = 11 Hz, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.84 (dd, J = 11, 3.5 Hz, 1H), 6.27 (bs, 1H), 3.78 (s, 3H), 3.4-3.35 (m, 2H), 2.12-2.01 (m, 2H), 1.70-1.65 (m, 2H), 1.38-1.16 (m, 4H).

Step 5:

To a solution of 2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (3.00 g, 10.8 mmol) in DCM (30 mL) at 0 °C, was added boron tribromide (5.4 g, 21 mmol) slowly. The resulting mixture was stirred at RT for 3 h. The reaction mixture was then diluted slowly with ice- water (20 mL) followed by sat. NaHCC (10 mL). The resulting precipitate was filtered and collected to give 2-(((lR,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-ol (2.6 g, 90%) as a tan solid. MS (ES+) Ci₃Hi₆N₂0₂S requires: 264, found: 265 [M+H]⁺. ^l NMR (500 MHz, d₄-MeOO) δ 7.12 (d, J = 9 Hz, 1H), 6.89 (d, J = 2 Hz, 1H), 6.62 (dd, J = 9, 2 Hz, 1H), 3.50-3.41 (m, 1H), 3.31-3.36 (m, 1H), 2.10-2.03 (m, 1H), 1.98-1.93 (m, 1H), 1.70-1.59 (m, 2H), 1.36-1.17 (m, 4H).

Step 6: A mixture of 3-chloro-4-(chloromethyl)-N-(4-methoxybenzyl)pyridin-2-amine (50 mg, 0.17 mmol), 2-((lR,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (45 mg, 0.17 mmol) and Cs₂C0₃ (110 mg, 0.34 mmol) in DMF (2 mL) was stirred at 80 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A = 0.1% TFA/H₂0, B = 0.1% TFA/MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to give (lR,2R)-2-(6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy) benzo[d]thiazol-2-ylamino)cyclohexanol (30 mg, 34%) as a white solid. MS (ES+) C27H2₉CIN4O₃S requires: 524, found: 525 [M+H]⁺.

Step 7:

A mixture of (lR,2R)-2-(6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy) benzo[d]thiazol-2-ylamino)cyclohexanol (30 mg, 0.06 mmol) in TFA (2 mL) was stirred at RT for 8 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A = 0.1% NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: C18) to give (lR,2R)-2-(6-((2-amino-3-chloropyridin-4- yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol (5 mg, 21%) as a white solid. MS (ES+) C1₉H21CIN4O2S requires: 404, found: 405 [M+H]⁺. ^lH NMR (500 MHz, d₆-OMSO) δ 7.90 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.72 (d, J = 5.0 Hz, 1H), 6.31 (s, 2H), 5.07 (s, 2H), 4.73 (d, J = 5.5 Hz, 1H), 3.52-3.48 (m, 1H), 3.36-3.31 (m, 1H), 2.06-2.04 (m, 1H), 1.89-1.86 (m, 1H), 1.64 - 1.60 (m, 2H), 1.29 - 1.17 (m, 4H).

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

Table 1:

Calc. Mass

Ex # Structure Name

Mass [M+H]⁺

(lS,2S)-2-({6-[(2- aminopyridin-4-

2 370 371 yl)methoxy]-l,3- benzothiazol-2- y 1 }amino)cy clohexan- 1 -ol 1 -ol

1 -ol

1 -ol - 1 -ol

-

N-cyclohexyl-6-( 1,3 -

345 346 thiazol-4-ylmethoxy)- 1 ,3- benzothiazol-2 -amine

N-cyclohexyl-6-(pyridin-2-

I JL 339 340 ylmethoxy)-l,3- '>~^Nv^H benzothiazol-2 -amine

N-cyclohexyl-6-(pyrazin-

340 341 2-ylmethoxy)-l,3- benzothiazol-2 -amine

N-cyclohexyl-6-

340 341 (pyrimidin-4-ylmethoxy)- 1 ,3 -benzothiazol-2-amine

N-cyclohexyl-6-( 1,3 -

345 346 thiazol-2-ylmethoxy)- 1 ,3- benzothiazol-2 -amine

N-cyclohexyl-6-( 1,3 -

345 346 thiazol-5-ylmethoxy)-l,3- benzothiazol-2 -amine

6-[(2-aminopyridin-4- yl)methoxy]-N-

354 355

cyclohexyl-1,3- benzothiazol-2 -amine

" t>

1 -ol 1 -ol

1 -ol -

-

- 1 -ol

1 -ol

ridin-

1 -ol 1 -ol

Examples 50 to 86 - Chemical synthesis

Example 50: Synthesis of (lR,2R)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-4- methoxy-1, 3-benzothiazol-2-yl}amino)cyclohexan-l-ol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of phenylmethanol (41.0 g, 380 mmol) in DMF (500 ml) was added NaH (9.60 g, 399 mmol) at 0°C. The reaction mixture was stirred for 0.5 h then 4-fiuoro-2-methoxy-l- nitrobenzene (50.0 g, 292 mmol) was added. The mixture was stirred at RT for 1 h. The reaction was quenched with water (500 mL), filtered and concentrated under reduce pressure to give 4-(benzyloxy)-2-methoxy-l -nitrobenzene (75 g, 99%) as yellow solid. LC-MS (ES+) C14H13N04 requires: 259, found: 260 (M+H)⁺.

Step 2:

To a solution of 4-(benzyloxy)-2-methoxy-l -nitrobenzene (75.0 g, 290 mmol) in MeOH (800 mL) was added Raney-Ni (3.0 g) followed by the dropwise addition of N₂H₄.H₂0 (44.0 g, 870 mmol) at 0 °C. the mixture was stirred at RT overnight. The reaction mixture was quenched by sat. NH₄OH (200ml) and extracted with EtOAc (100 mL x 2). The organic layers were dried, filtered and concentrated under reduced pressure to give 4-(benzyloxy)-2- methoxybenzenamine (56 g, 84 %) as yellow liquid. LC-MS (ES+) C14H15N02 requires: 229, found: 230 (M+H)⁺.

Step 3:

To a solution of 4-(benzyloxy)-2-methoxybenzenamine (28.0 g, 0.122 mol) in methanol (600ml) was added KSCN (59.3g, 0.611 mol), followed by the addition of anhydrous CuS0₄ (195g, 1.22 mol). The mixture was stirred overnight at 90 °C and concentrated under reduced pressure. The residue was dissolved in DCM (500ml), the precipitate was filtered and the filter cake was washed with dichloromethane (100 mL x 2). The combined organic layer was washed with sat. NH₄OH (500 mL). The aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel silica gel chromatography (50%- 100% EtOAc in petroleum ether) to give 6-(benzyloxy)-4-methoxybenzo[d]thiazol-2-amine (13 g, 37%) as a black solid. LC-MS (ES+) C15H14N202S requires: 286, found: 287 (M+H)⁺.

Step 4:

To a suspension of 6-(benzyloxy)-4-methoxybenzo[d]thiazol-2-amine (22.0 g, 0.077 mol) in acetnitrile (100 mL) was added t-BuONO (11.8 g, 0.110 mol) at 0 °C. The mixture was stirred for 30 min, then CuBr₂ (10.3 g, 0.046 mol) was added. The reaction was stirred for an additional 2 h at room temperature. Water was added, the precipitate was filtered and the filtrate was extracted with EtOAc. The combined organic layers were washed with water, diluted sat. NH₄OH, brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in Petroleum ether) to give 6-(benzyloxy)-2- bromo-4-methoxybenzo[d]thiazole (8.0 g, 30%) as a grey-white solid. LC-MS (ES+) C15H12BrN02S requires: 349, found: 350 (M+H)⁺.

Step 5:

A mixture of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (3.50 g, 10.0 mmol), (1R, 2R)-2-aminocyclohexanol (3.45 g, 30.0 mmol) and DIPEA (5.16 g, 40.0 mmol) in DMF (10 mmol) was heated at 110 °C for 48 h. The reaction was cooled to RT, diluted with water (30 mL), and extracted with EtOAc (3 ^χ 30 mL). The combined organic exacts were washed by water (100 ml), brine (100 ml), dried over Na₂S0₄ and concentrated to give (lR,2R)-2-(6- (benzyloxy)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (3.8 g, 100%, crude) as a brown solid. MS (ES+) C21H24N2O₃S requires: 384, found: 385 [M+H]⁺.

Step 6:

A solution of (lR,2R)-2-(6-(benzyloxy)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1152 mg, 3.0 mmol) in TFA (10 mL) was heated at 65 °C for 48 h. The solvent was removed, the reaction mixture was diluted slowly by sat. NaHC0₃ and extracted with EtOAc (3 x 50 mL). The combined organic exacts were washed with water (100 ml) and brine (100 ml), dried over Na₂S0₄ and concentrated to give 2-((lR,2R)-2-hydroxycyclohexylamino)-4- methoxybenzo[d]thiazol-6-ol (882 mg, 100%, crude) as a brown solid. MS (ES+) Ci₄Hi₈N₂0₃S requires: 294, found: 295 [M+H]⁺. Step 7:

A mixture of 3-chloro-4-(chloromethyl)-N-(4-methoxybenzyl)pyridin-2-amine (Example 1, Step 3; 202 mg, 0.68 mmol), 2-((lR,2R)-2-hydroxycyclohexylamino)-4- methoxybenzo[d]thiazol-6-ol (200 mg, 0.68 mmol) and CS2CO₃ (443 mg, 1.36 mmol) in DMF (2 mL) was stirred at 80 °C for 3 h. The mixture was diluted by water (30 ml) and extracted with EtOAc (3 ^χ 30 mL). The combined organic phases were washed with water (100 ml) and brine (100 ml), dried over Na₂S0₄ and concentrated to give (lR,2R)-2-(6-((3- chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2- ylamino)cyclohexanol (300 mg, 79%, crude) as a brown solid. MS (ES+) C2₈H₃1CIN4O4S requires: 554, found: 555 [M+H]⁺.

Step 8:

A mixture of (lR,2R)-2-(6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (300 mg, 0.54 mmol) in TFA (2 mL) was stirred at RT for 8 h. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A = 0.1% NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to give (lR,2R)-2-(6-((2-amino-3- chloropyridin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (19 mg, 8%) as a white solid. MS (ES+) C2₀H2₃CIN4O₃S requires: 434, found: 435 [M+H]⁺. ^l NMR (500 MHz, DMSO) δ 8.50 (s, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.04 (s, 1H), 6.85 (d, J = 5.5 Hz, 1H), 6.69 (s, 1H), 5.14 (s, 2H), 3.88 (s, 3H), 3.60 (d, J = 11.0 Hz, 1H), 3.32 (dd, J = 17.5, 11.8 Hz, 1H), 2.01 (d, J = 13.0 Hz, 1H), 1.89 (d, J = 8.9 Hz, 1H), 1.70 - 1.56 (m, 2H), 1.42 - 0.92 (m, 4H).

The following examples in Table 2 were prepared analogously to Example 50.

Table 2:

Example 54: ( IS, 2S)-2-( (6-(( 2-amino-3-fluoropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

The title compound was synthesized according to the following synthetic scheme:

Step 1: To a solution of 2-chloro-3-fluoroisonicotinic acid (5.0 g, 28 mmol) and 4-methyl morpholine (3.8 mL, 7.0 mmol) in dry THF (150 mL) was added isobutyl chloroformate (4.5 mL, 34 mmol) dropwise at 0 °C and stirred for 1 h. The reaction mixture was diluted with THF (50 mL) and filtered through Celite. The filtrate was cooled to 0 °C, NaBH₄ (1.0 g, 28 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with 10 % KHSO4 (5 mL). The volatiles were removed under reduced pressure and the reaction mixture was diluted with EtOAc (200 mL). The layers were separated and the organic layer was washed with water (50 mL) followed by sat. NaHCCb (2 x 50 mL), dried over MgSC>4, filtered and concentrated under reduced pressure. The residue was triturated with 5: 1 hexane-ether (50 mL). The resulting solid was filtered and collected to give (2- chloro-3-fluoropyridin-4-yl)methanol (3.7 g, 80%). MS (ES+) C6H5C1FNO requires: 161, found: 162 [M+H]⁺.

Step 2:

To a solution of (2-chloro-3-fluoropyridin-4-yl)methanol (1.0 g, 6.2 mmol) in DCM (25 mL) was added phosphorus tribromide (0.70 mL, 7.4 mmol) dropwise and the resulting mixture was stirred at 0 °C for 2 h, then stirred at RT overnight. The reaction mixture was diluted with DCM (20 mL) and washed with 10% NaHCC (5 mL). The layers were separated, and the organic layer was washed with brine (5 mL), dried over MgSC^, filtered and concentrated under reduced pressure to give 4-(bromomethyl)-2-chloro-3-fluoropyridine (1.1 g, 79%) as a light yellow solid. MS (ES+) C6H4BrClFN requires: 223, found: 224, 226 [M+H]⁺.

Step 3:

To a solution of 3-methoxy-4-nitrophenol (0.750 g, 4.46 mmol) and 4-(bromomethyl)-2- chloro-3-fluoropyridine (1.0 g, 4.4 mmol) in 1 : 1 DMF/THF (10 mL) was added Cs₂C0₃ (2.2 g, 6.7 mmol) and the resulting mixture was stirred at RT for 20 h. Ice cold water (20 mL) was added to the reaction mixture, stirred for 10 min, and filtered on a Buchner funnel. The solid was washed with cold water (10 mL) and dried under vacuum for 2 h to afford 2-chloro-3- fluoro-4-((3-methoxy-4-nitrophenoxy)methyl)pyridine (1.34 g, 96%) as an off-white solid. MS (ES+) C13H10C1FN2O4 requires: 312, found: 313 [M+H]⁺.

Step 4:

A reaction vessel was charged with 2-chloro-3-fluoro-4-((3-methoxy-4- nitrophenoxy)methyl)pyridine (1.3 g, 15 mmol), 10% Pt-C (130 mg), and 5: 1 THF/MeOH (24 mL). The suspension was degassed with N₂ for 1 min and purged with H₂ for 1 min. The reaction mixture was stirred under an atmosphere of H₂ at 20 PSI for 1 h. The reaction mixture was purged with N₂, filtered through Celite, and concentrated under reduced pressure to give 4-((2-chloro-3-fluoropyridin-4-yl)methoxy)-2-methoxyaniline (1.1 g, 94%) as a light yellow powder. MS (ES+) C13H12C1FN202 requires: 282, found: 283 [M+H]⁺.

Step 5:

To a solution of 4-((2-chloro-3-fluoropyridin-4-yl)methoxy)-2-methoxyaniline (1.1 g, 3.9 mmol) in DCM (60 mL) was added di(lH-imidazol-l-yl)methanethione (0.97 g, 5.5 mmol) and the resulting mixture was stirred at RT for 3 h. To this solution (l S,2S)-2- aminocyclohexanol (0.9 g, 7.8 mmol) was added and the resulting mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (20 - 80% EtOAc in hexanes) to give l-(4-((2-chloro-3- fluoropyridin-4-yl)methoxy)-2-methoxyphenyl)-3-((l S,2S)-2-hydroxycyclohexyl)thiourea (1.59 g, 93%) as an off white powder. MS (ES+) C20H23C1FN3O3S requires: 439, found: 440 [M+H]⁺.

Step 6:

To a solution of l-(4-((2-chloro-3-fluoropyridin-4-yl)methoxy)-2-methoxyphenyl)-3- ((lS,2S)-2-hydroxycyclohexyl)thiourea (0.90 g, 2.1 mmol) in DCM (80 mL) was added BSTFA (1.1 mL, 4.1 mmol) and stirred for 10 min. Solid benzyltrimethylammonium tribromide (0.80 g, 2.1 mmol) was then added. After 10 min, sat. NaHCC (30 mL) was added into the reaction mixture and stirred for 5 min. The reaction mixture was diluted with DCM (20 mL), and the layers were separated. The organic layer was washed with sat. NaHC0₃ (30 mL), followed by 10% aq. Na₂S₂0₃ solution (20 mL), dried over MgS0₄, filtered and concentrated under reduced pressure. The residue was triturated with 1 :2 ether/hexanes (30 mL) and the resulting solid was filtered through a Buchner funnel, rinsed with 1 : 1 ether/hexanes (10 mL), dried under vacuum. (lS,2S)-2-((6-((2-Chloro-3- fluoropyridin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohexanol was isolated as an off-white powder (810 mg, 90%). MS (ES+) C19H21C1N403S requires: 437, found: 438 [M+H]⁺.

Step 7:

A suspension of acetamide (0.221 g, 3.73 mmol), (l S,2S)-2-((6-((2-chloro-3-fluoropyridin-4- yl)methoxy)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohexanol (1.09 g, 2.49 mmol) and CS2CO₃ (1.62 g, 4.98 mmol) in dioxane (12 mL) was degassed with N₂ for 2 min. Pd₂(dba)₃ (0.057 g, 0.062 mmol) and Xantphos (0.072 g, 0.12 mmol) were added and the mixture was degassed with N₂ for an additional 2 min. The reaction mixture was heated to 100 °C and stirred for 5 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 10 mL), dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes w/ 10% MeOH) to give N-(3-fluoro-4-(((2-(((l S,2S)-2-hydroxycyclohexyl)amino)-4-methoxybenzo[d]thiazol-6- yl)oxy)methyl)pyridin-2-yl)acetamide (320 mg, 28%) as a tan foam solid. MS (ES+) C22H25FN404S requires: 460, found: 461 [M+H]⁺.

Step 8:

To a solution of N-(3-fluoro-4-(((2-(((l S,2S)-2-hydroxycyclohexyl)amino)-4- methoxybenzo[d]thiazol-6-yl)oxy)methyl)pyridin-2-yl)acetamide (68 mg, 0.15 mmol) in MeOH (0.74 mL) was added HCl in dioxanes (185 μΐ, 0.738 mmol, 4M) and the resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated. The residue was triturated with Et₂0 (2 x 2 mL), the filtrate removed carefully, and the solid dried under vacuum to provide (l S,2S)-2-((6-((2-amino-3-fluoropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol (65 mg, 97%, HCl salt) as an off-white fluffy solid. MS (ES+) C20H23FN4O3S requires: 418, found: 419 [M+H]⁺; ^lH NMR (600 MHz, DMSO-c¾) δ 9.36 (br s, 1H), 8.00 (br s, 2H), 7.84 (d, J = 6.2 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.91 (t, J = 5.7 Hz, 1H), 6.79 (s, 1H), 5.26 (s, 2H), 3.92 (s, 3H), 3.76 - 3.67 (m, 1H), 3.37 - 3.31 (m, 1H), 2.02 - 1.95 (m, 1H), 1.95 - 1.86 (m, 1H), 1.68 - 1.64 (m, 2H), 1.33 - 1.20 (m, 4H).

Example 55: ( IS, 2S)-2-( 4-methoxy-6-( (2-(l -methyl- ΙΗ-pyr azol-4-ylamino)pyrimidin- 4yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

A mixture of (lS,2S)-2-((6-((2-chloropyrirnidin-4-yl)methoxy)-4-methoxybenzo[d] thiazol-2- yl)amino)cyclohexanol (Example 66, Step 5) (4.0 g, 9.5 mmol), 1 -methyl- lH-pyrazol-4- amine (1.84 g, 19 mmol), DIPEA (2.45 g, 19 mmol) in DMA (30 mL) was heated to 120 °C for 10 h. Water (100 ml) was added into the mixture and it was extracted with EtOAc (100 mL x 3). The combined EtOAc phase was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified via silica gel chromatography (0-10% MeOH in DCM) to give the crude product (2.45 g) as a brown oil. Then the crude product was purified by reverse phase HPLC (Mobile phase: A = 0.1% NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 0 - 100%; 20 min; Column: C18) to give (lS,2S)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol- 4-ylamino)pyrimidin-4-yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol (1.4 mg, 31%) as a brown solid. MS (ES+) C23H27N703S requires: 481, found: 482 [M+H] ^{+ 1}H NMR (500 MHz, MeOD) δ 8.37 (d, J = 5 Hz, 1H),7.94 (s, 1H),7.56 (s, 1 H), 6.86-6.91 (m, 2 H), 6.64 (d, J = 2 Hz, 1H), 5.08 (s, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.57-3.62 (m, 1H), 3.39-3.43 (m, 1H), 2.14-2.16 (m, 1H), 2.03-2.05 (m, 1H), 1.72-1.79(m, 2H), 1.24-1.43 (m, 4H).

The following examples in Table 3 were prepared analogously to Example 55.

Table 3:

Examples 61 and 62: 6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

The title compounds were synthesized according to the following synthetic scheme

Step 1:

A mixture of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (700 mg, 1.80 mmol) in TFA (10 mL) was stirred at 65°C for 16 h. The reaction mixture was concentrated, diluted by sat. NaHCC (50 ml) and extracted with EtOAc (50 ml ^χ 3). The combined organic layers were washed water (100 ml) and brine (100 ml), dried over Na2SC>4, filtered and concentrated to give 2-bromo-4-methoxybenzo[d]thiazol-6-ol (520 mg, 100%) as a yellow solid. MS (ES+) C₈H₆BrN0₂S requires: 259, 261, found: 262[M+H]+

Step 2:

To a solution of 2-bromo-4-methoxybenzo[d]thiazol-6-ol (520 mg, 2.00 mmol) and (2- aminopyrimidin-4-yl)methyl methanesulfonate (406 mg, 2.00 mmol) was added CS2CO₃ (1.9 g, 6.0 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml ^χ 3). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over Na2SC>4, filtered and concentrated to give 4-((2-bromo-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyrimidin-2-amine (400 mg, 54%) as a yellow solid. MS (ES+) Ci₃HiiBrN₄02S requires: 366, found: 367[M+H]⁺.

Step 3:

To a solution of 4-((2-bromo-4-methoxybenzo[d]thiazol-6-yloxy)methyl)pyrimidin-2-amine (367 mg, 1.00 mmol) and 3,3-difluorocyclohexanamine hydrochloride (516 mg, 3.00 mmol) was added DIPEA (774 mg, 6.00 mmol) in DMF (5 mL). The reaction mixture was stirred at 140°C for 16 h. The reaction mixture was purified by prep-HPLC (Mobile phase: A = 0.1% NH4HCO₃/H2O, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to give 6-((2- aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2- amine (48 mg, 11%) as a white solid. MS (ES+) C19H21F2N5O2S requires: 421, found: 422[M+H]⁺.

The final product was separated by chiral chromatography [Mobile phase: EtOH (l%Methanol Ammonia) Column: Cellulose-SC 4.6 ^χ 100 mm 5 um] to give two isomers. Isomer 1 (Compound 60) (5.9 mg) as a white solid. MS (ES+) C19H21F2N5O2S requires: 421, found: 422[M+H]+; ^XH NMR (500 MHz, MeOD) δ 8.25 (d, J = 5.1 Hz, 1H), 6.83 (dd, J = 6.2, 3.7 Hz, 2H), 6.62 (d, J = 2.2 Hz, 1H), 4.96 (s, 2H), 4.10 - 3.98 (m, 1H), 3.97 - 3.88 (m, 3H), 2.51 - 2.39 (m, 1H), 2.20 - 2.11 (m, 1H), 2.09 - 1.99 (m, 1H), 1.75 (ddd, J= 37.7, 24.5, 11.3 Hz, 3H), 1.38 - 1.24 (m, 2H); Isomer 2 (Compound 61) (6.8 mg) as a white solid. MS (ES+) C1₉H21F2N5O2S requires: 421 , found: 422[M+H]+; ^XH NMR (500 MHz, MeOD) δ 8.25 (d, J = 5.1 Hz, 1H), 6.83 (dd, J = 6.2, 3.7 Hz, 2H), 6.62 (d, J = 2.3 Hz, 1H), 4.96 (s, 2H), 4.09 - 3.97 (m, 1H), 3.95 - 3.89 (m, 3H), 2.46 (dd, J = 19.1, 10.9 Hz, 1H), 2.15 (dd, J = 10.9, 7.5 Hz, 1H), 2.05 (dd, J = 21.9, 11.1 Hz, 1H), 1.85.

The following example in Table 4 was prepared analogously to Examples 61 and 62.

Table 4:

Example 64: N-( 3, 3-difluorocyclohexyl)-4-methoxy-6-( ⁽ 2-( 1 -methyl- lH-pyrazol-4-ylamino) pyrimidin-4-yl)methoxy)benzo d]thiazol-2-amine

The title compounds were synthesized according to the following synthetic scheme:

Step 1:

A mixture of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (300 mg, 0.86 mmol), 3,3-difluorocyclohexanamine hydrochloride (296 mg, 1.72 mmol) and DIPEA (222 mg, 1.72 mmol) in NMP (1 ml) was heated to 180°C for 4 h. Saturated NH₄C1 solution (100 ml) was added, and the mixture was extracted with EtOAc (50 mL ^χ 3). The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated. The residue which was purified by silica gel chromatography (50% EtOAc in petroleum ether) to give 6-(benzyloxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine (130 mg, 37%) as a yellow solid. MS (ESI+) C21H22F2N2O2S requires: 404, found: 405[M+H]⁺.

Step 2:

A mixture of 6-(benzyloxy)-N-(3,3-difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine (130 mg, 0.32 mmol) in TFA (3 ml) was stirred at 55°C for 2 h. TFA was evaporated and the residue was taken up in EtOAc (100 mL). The organic layer was washed with sat. NaHCCb, dried over Na2SC>4, filtered and concentrated to give 2-(3,3-difluorocyclohexylamino)-4- methoxybenzo[d]thiazol-6-ol (90 mg, 89%) as a yellow oil. MS (ESI+)

requires:314, found: 315 [M+H]⁺.

Step 3:

A mixture of 2-(3,3-difluorocyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (90 mg, 0.29 mmol), 2-chloro-4-(chloromethyl)pyrimidine (57 mg, 0.35 mmol) and CS2CO₃ (189 mg, 0.58 mmol) in DMF (5 ml) was stirred at 80°C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in petroleum ether) to give 6-((2-chloropyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4-methoxy benzo[d]thiazol-2-amine (60 mg, 43%) as a yellow solid. MS (ESI+) C1₉H1₉CIF2N4O2S requires: 440 found: 441 [M+H]⁺.

Step 4:

A mixture of 6-((2-chloropyrirnidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine (60 mg, 0.14 mmol), 1 -methyl- lH-pyrazol-4-amine (23 mg, 0.17 mmol) and TsOH.H20 (12 mg, 0.07 mmol) in dioxane (2 ml) was stirred at 110°C for 16 h. The mixture was diluted with EtOAc, washed with sat. NaHCCb, and dried over Na₂SC>4. The combined organic layers were concentrated and the residue was purified by preparative HPLC (Mobile phase: A = 0.1% NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: C18) to give N-(3,3-difluorocyclohexyl)-4-methoxy-6-((2-(l-methyl- lH-pyrazol-4-ylamino) pyrimidin-4-yl)methoxy)benzo[d]thiazol-2-amine (3 mg, 5%) as a white solid. MS (ES+) C22H25N7O₃S requires: 501 found: 502 [M+H]⁺. ^XH NMR (500 MHz, d6-DMSO) δ 9.51 (s, 1H), 8.40 (d, J = 5 Hz, 1H), 7.78 - 7.88 (m, 2H),7.46 (s, 1 H), 6.98 (s, 1 H), 6.81 (d, J = 5 Hz, 1H), 6.61 (d, J = 2 Hz, 1H), 5.04 (s, 2H), 3.89 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.26 (s, 1H), 1.97 - 2.01 (m, 2H), 1.72 - 1.84 (m, 3H), 1.43 - 1.50 (m, 1H), 1.21 - 1.33 (m, 1H).

Example 65: ( IS, 2S)-2-( 6-((2-amino-3-chloropyridin-4-yl)methoxy)-4-fluorobenzo[ djthiazol- 2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 2-fluoro-4-methoxyaniline (3.0 g, 21 mmol) in HOAc (50 mL) was added KSCN (8.2 g, 85 mmol). The reaction mixture was cooled to 0°C and Br₂ (4.6 g, 25 mmol) was added dropwise. The reaction mixture was stirred for 4 h at room temperature. The pH of the reaction mixture was adjusted to pH = 7 with sat. NH₄OH. The mixture was extracted with EtOAc (3 ^χ 80 mL), the combined organic layers were dried over Na₂S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% EtOAc in PE) to give 4-fluoro-6-methoxybenzo[d]thiazol-2-amine (2.1 g, 50%) MS (ES+) C₈H₇FN₂OS requires: 198, found: 199 [M+H]⁺.

Step 2:

A solution of 4-fluoro-6-methoxybenzo[d]thiazol-2-amine (1.3 g, 5.8 mmol) in MeCN (40 mL), was cooled to -5°C. CuBr₂ (1.3 g, 5.8 mmol) and T3uONO (0.67 mg, 5.80 mmol) was slowly added dropwise. The reaction was stirred at 0-5°C for 30 min. The reaction mixture was heated to 40°C and stirred for 6 hours. The reaction mixture was filtered. The filtrate was washed with 1 N HC1 solution, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole (1.2 g, 70%). MS (ESI+) C₈H₅BrFNOS requires: 261, found: 262 [M+H]⁺.

Step 3:

A mixture of 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole (300 mg, 1.15 mmol), (l S,2S)-2- aminocyclohexanol (297 mg, 2.30 mmol) and DIPEA (397 mg, 3.45 mmol) in DMA (10 ml) was heated to 100°C for overnight. Sat. NH₄C1 solution (80 ml) was added, the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% EtOAc in PE) to give (lS,2S)-2-(4-fluoro-6-methoxybenzo[d]thiazol- 2-ylamino)cyclohexanol (236 mg, 43%) as a brown solid. MS (ESI+) C14H17FN2O2S requires: 296, found: 297 [M+H]⁺.

Step 4:

A solution of (lS,2S)-2-(4-fluoro-6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (490 mg, 1.64 mmol) in DCM (10 ml) was cooled to 0°C, and BBr₃ (4 ml, 17%) was added. The resulting solution was stirred overnight at RT. Sat. NH₄C1 solution was added, the suspension was filtered, and the solid was collected, to provide 4-fluoro-2-((lS,2S)-2- hydroxycyclohexylamino)benzo[d]thiazol-6-ol (360 mg, 77%). MS (ESI+) C1₃H15FN2O2S requires: 282, found: 283 [M+H]⁺.

Step 5:

A mixture of 4-fluoro-2-((lS,2S)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (80 mg, 0.28 mmol), 3-chloro-4-(chloromethyl)-N-(4-methoxybenzyl)pyridin-2-amine (Example 1, Step 3; 116 mg, 0.34 mmol) and CS2CO₃ (183 mg, 0.56 mmol) in DMF (5 ml) was stirred at 80 °C overnight. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (50% EtOAc in petroleum ether) to give (l S,2S)-2-(6- ((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-4-fluorobenzo[d]thiazol-2- ylamino)cyclohexanol (82 mg, 54%) as a yellow solid. MS (ESI+) C27H2₈CIFN4O₃S requires: 542, found: 543 [M+H]⁺.

Step 6:

A mixture of (l S,2S)-2-(6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-4- fluorobenzo[d]thiazol-2-ylamino)cyclohexanol (82 mg, 0.15 mmol) in TFA (3 mL) was stirred at room temperature overnight. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A = 0.1 % NH4HCO₃/H₂O, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to give (l S,2S)-2-(6-((2-amino-3- chloropyridin-4-yl)methoxy)-4-fluorobenzo[d]thiazol-2-ylamino)cyclohexanol (19.4 mg, 31%) as a white solid. MS (ES+) C1₉H2₀CIFN4O2S requires: 422, found: 423 [M+H]⁺. ^XH NMR (500 MHz, d6-DMSO) δ 7.9-7.95(m, 2H),7.24 (d, J = 2.5 Hz, 1H), 6.84-6.87 (m, 1H), 6.71 (d, J = 5 Hz, 1H), 6.34 (s, 2H), 5.08(s, 2H), 4.75 (d, J = 5 Hz, 1H), 3.49-3.52 (m, 1H), 2.03-2.07 (m, 1H), 1.86-1.89 (m, 1H), 1.61-1.65 (m, 2H), 1.17-1.30 (m, 4H). Example 66: ( IS, 2S)-2-( ( 6-((2-aminopyrimidin-4-yl)methoxy)-4-methoxybenzo[ dJthiazol-2- yl) amino) cyclohexan-l-ol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 2-chloro-4-methylpyrimidine (5.0 g, 39 mmol) in CC (100 ml) was added NCS (7.8 g, 58 mmol) and AIBN (0.64 g, 3.9 mmol) and the resulting mixture was heated at reflux for 18 h. The reaction mixture was allowed to cool to RT. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (10 - 40 % EtOAc in hexanes) to give 2- chloro-4-(chloromethyl)pyrimidine (3.1 g, 49%) as a clear oil. MS (ES+) C5H4C12N2 requires: 162, found: 163 [M+H]⁺.

Step 2:

To a solution of 3-methoxy-4-nitrophenol (2.83 g, 16.7 mmol) and 2-chloro-4- (chloromethyl)pyrimidine (3.0 g, 18 mmol) in DMF (16 ml) was added K₂C0₃ (2.8 g, 20 mmol) and the resulting mixture was stirred at RT for 20 h. Ice cold water (30 ml) was added and the mixture was stirred for 10 min before filtering on a Buchner funnel. The solid was washed with cold water (10 mL) and dried under vacuum for 2 h to give 2-chloro-4-((3- methoxy-4-nitrophenoxy)methyl)pyrimidine (4.6 g, 93%) as a light brown solid. MS (ES+) C12H10C1N3O4 requires: 295, found: 296 [M+H]⁺.

Step 3:

A reaction vessel was charged with 2-chloro-4-((3-methoxy-4- nitrophenoxy)methyl)pyrimidine (4.6 g, 15.6 mmol), 10% Pt-C (460 mg, 0.12 mmol), and THF-MeOH (5: 1, 60 ml). The suspension was degassed with N₂ for 3 min and purged with H₂ for 3 min. The reaction mixture was stirred under an atmosphere of H₂ at 1 atm for 2 h. The reaction mixture was purged with N₂, filtered through Celite, and concentrated under reduced pressure to give 4-((2-chloropyrimidin-4-yl)methoxy)-2-methoxy aniline (4.0 g, 97%) as a light yellow powder. MS (ES+) C12H12C1N302 requires: 265, found: 266 [M+H]⁺.

Step 4:

To a solution of 4-((2-chloropyrirnidin-4-yl)methoxy)-2-methoxyaniline (4.0 g, 15 mmol) in DCM (200 ml) was added di(lH-imidazol-l-yl)methanethione (3.2 g, 18 mmol) and the resulting mixture was stirred at RT for 4 h. (lS,2S)-2-Aminocyclohexanol (3.5 g, 30 mmol) was added and the resulting mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (25 - 100% EtOAc in hexanes) to give l-(4-((2-chloropyrimidin-4-yl)methoxy)-2-methoxyphenyl)-3- ((lS,2S)-2-hydroxycyclohexyl)thiourea (6.1 g, 96%) as a white. MS (ES+) C19H23C1N403S requires: 422, found: 423 [M+H]⁺.

Step 5:

To a solution of l-(4-((2-chloropyrirnidin-4-yl)methoxy)-2-methoxyphenyl)-3-((l S,2S)-2- hydroxycyclohexyl)thiourea (1.0 g, 2.3 mmol) in DCM (100 ml) was added BSTFA (1.3 ml, 4.7 mmol) and the resulting solution was stirred for 5 min. Solid benzyltrimethylammonium tribromide (0.92 g, 2.3 mmol) was added into the previous reaction mixture. After 20 min sat. NaHCC (30 ml) was added and the reaction mixture was stirred for 5 min. The biphasic mixture was transferred to a separatory funnel with an additional 20 ml of DCM, and the layers were separated. The organic layers were washed with saturated aq. NaHCC (30 ml), followed by 10% aq. Na₂S₂0₃ (1 x 20 ml), dried over MgSC , filtered, and concentrated under reduced pressure. The residue was triturated with 1 :2 Ether/Hexanes (30 ml) and the resulting solid was filtered through a Buchner funnel. After rinsing with 1 : 1 Ether/hexanes (10 ml), (1 S,2S)-2-((6-((2-chloropyrimidin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2- yl)amino)cyclohexan-l-ol (0.945 g, 95%) was collected as off white powder (945 mg, 95%). MS (ES+) C19H21C1N403S requires: 420, found: 421 [M+H]⁺.

Step 6:

A microwave vial was charged with (l S,2S)-2-((6-((2-chloropyrimidin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexanol (300 mg, 0.71 mmol) and ammonia (7 M in MeOH, 2.0 mL). The vial was sealed and the reaction mixture was heated to 120 °C in the microwave reactor for 4 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase preparative HPLC (Mobile phase: A = 0.1% TFA/H₂0, B = 0.1% TFA/MeCN; Gradient: B = 10 - 90%; 20 min; Column: C18) to give (l S,2S)-2-((6-((2- aminopyrinddin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol as a TFA salt (182 mg, 64%) as an off white powder. MS (ES+) C19H23N503S requires: 401, found: 402 [M+H]⁺; ^XH NMR (600 MHz, DMSO-c¾) δ 8.23 (d, J = 5.0 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.70 - 6.58 (m, 3H), 6.55 (d, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.75 (d, J = 4.9 Hz, 1H), 3.82 (s, 3H), 3.54 - 3.45 (m, 1H), 3.37 - 3.32 (m, 1H), 2.10 - 1.98 (m, 1H), 1.91 - 1.83 (m, 1H), 1.69 - 1.51 (m, 2H), 1.35 - 1.10 (m, 4H).

Example 67: 6-((2-amino-3-chloropyridin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (3.0 g, 8.5 mmol) in DMF (20 mL) was added NaSMe (1.2 g, 17 mmol). The reaction was stirred at RT for 16 h. The reaction mixture was diluted with water (100 ml) and extracted with Et^O (100 ml ^χ 3). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over Na₂SC>4, filtered and concentrated to give 6-(benzyloxy)-4- methoxy-2-(methylthio)benzo[d]thiazole (2.7 g, 100%) as a yellow oil. MS (ES+) C1₆H15NO2S2 requires: 317, found: 318 [M+H]+.

Step 2:

A mixture of 6-(benzyloxy)-4-methoxy-2-(methylthio)benzo[d]thiazole (2.7 g, 8.5 mmol) in TFA (20 ml) was stirred at 65°C for 16 h. The solvent was removed under reduced pressure. Sat. NaHCCb (50 ml) was added and the mixture was extracted with EtOAc (50 ml ^χ 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SC>4, filtered and concentrated to afford 4-methoxy-2-(methylthio)benzo[d]thiazol-6-ol (1.9 g, 100%) as a brown oil. MS (ES+) C₉H₉N0₂S₂ requires: 227, found: 228[M+H]+.

Step 3:

A mixture of 4-methoxy-2-(methylthio)benzo[d]thiazol-6-ol (1.8 g, 8.0 mmol), 3-chloro-4- (chloromethyl)-N-(4-methoxybenzyl)pyridin-2-amine (2.4 g, 8.0 mmol) and CS2CO₃ (7.8 g, 24 mmol) in DMF (20 mL) was stirred at 80°C for 2 h. The reaction mixture was diluted with water (100 ml), extracted with Et₂0 (100 ml) and EtOAc (50 ml χ 3). The combined organic phrases were washed with water (100 ml) and brine (100 ml), dried over Na₂SC>4, filtered and concentrated to give 3-chloro-4-((4-methoxy-2-(methylthio)benzo[d]thiazol-6-yloxy)methyl)- N-(4-methoxybenzyl)pyridin-2-amine (2.1 g, 53%) as a white solid. MS (ES+) C2₃H22CIN₃O₃S2 requires: 487, found: 488[M+H]+.

Step 4:

To a solution of 3-chloro-4-((4-methoxy-2-(methylthio)benzo[d]thiazol-6-yloxy)methyl)-N- (4-methoxybenzyl)pyridin-2-amine (2.0 g, 4.1 mmol) in DCM (100 mL) was added m-CPBA (834 mg, 4.1 mmol) at 0°C. The reaction mixture was stirred at RT for 2 h. The mixture was washed with sat. Na₂S₂0₃ (100 ml), sat. NaHC0₃ (100 ml) and brine (100 ml), dried over Na₂SC>4, filtered and concentrated to give 3-chloro-4-((4-methoxy-2- (methylsulfinyl)benzo[d]thiazol-6-yloxy)methyl)-N-(4-methoxybenzyl)pyridin-2-amine (2.1 g, 97%) as a white solid. MS (ES+) C23H22CIN3O4S2 requires: 503, found: 504[M+H]+.

Step 5:

A mixture of 3-chloro-4-((4-methoxy-2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)methyl)-N- (4-methoxybenzyl)pyridin-2-amine (50 mg, 0.1 mmol) and 3,3-difluorocyclohexanamine (135 mg, 1 mmol) was stirred at 140°C for 6 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml χ 3). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over Na₂SC>4, filtered and concentrated to give 6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)- 4-methoxybenzo[d]thiazol-2-amine (50 mg, 87%) as a yellow solid. MS (ES+) C28H29CIF2N4O3S requires: 574, found: 575[M+H]+.

Step 6:

A mixture of 6-((3-chloro-2-(4-methoxybenzylamino)pyridin-4-yl)methoxy)-N-(3,3- difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine (50 mg, 0.09 mmol) in TFA (5 mL) was stirred at RT for 8 h. The reaction mixture was purified by prep-HPLC Mobile phase: A = 10 mM ammonium bicarbonate/H20, B— acetonitrile; Gradient: B— 60%-95% in 18 min; Column: Welch Xtimate® C18, 10 urn, 21.2 mm x 250 mm) to give 6-((2-amino-3- chloropyridin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine (5.0 mg, 12%) as a white solid. MS (ES+) C2₀H21CIF2N4O2S requires: 454, found: 455[M+H]+; ^XH NMR (500 MHz, DMSO) δ 8.01 - 7.86 (m, 3H), 6.98 (d, J = 2.3 Hz, 1H), 6.75 (d, J = 5.0 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.33 (s, 2H), 5.07 (s, 2H), 3.94 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H), 2.61 (d, J = 4.6 Hz, 3H). Example 69: ( IS, 2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 3-methoxy-4-nitrophenol (1.0 g, 5.9 mmol) at 0 °C was added N- chlorosuccinimide (0.868 g, 6.50 mmol), and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 20 mL). The layers were separated, and the organic layer was washed with sat. NaCl (10 mL), dried over MgSC>4, filtered and concentrated under reduced pressure to provide 2-chloro-5- methoxy-4-nitrophenol (1.2 g, -100%) as a yellow solid. MS (ES+) C7H6C1N04 requires: 203, found: 204 [M+H]⁺.

Step 2:

To a suspension of K2CO₃ (0.758 g, 5.48 mmol) and 2-chloro-5-methoxy-4-nitrophenol (0.93 g, 4.5 mmol) in DMF (4.57 ml) was added 2-chloro-4-(chloromethyl)pyrimidine (0.89 g, 5.4 mmol) and the resulting mixture was stirred at 50 °C for 15 h. The reaction was diluted with water (15 mL), stirred for 5 min, and filtered on a Buchner funnel. The solid was washed with water (2 x 10 mL). After drying, 2-chloro-4-((2-chloro-5-methoxy-4- nitrophenoxy)methyl)pyrimidine (1.31 g, 83%) was isolated as a brown solid. MS (ES+) C12H9C12N304 requires: 329, found: 330 [M+H]+.

Step 3:

A reaction vessel was charged with 10% Pt-C (0.80 g, 0.20 mmol), 2-chloro-4-((2-chloro-5- methoxy-4-nitrophenoxy)methyl)pyrimidine (1.3 g, 4.1 mmol) and THF (41 ml) under an atmosphere of N₂. The suspension was degassed with N₂ for 2 min and purged with H₂ for 2 min. The reaction mixture was stirred under an atmosphere of H₂ at 1 atm for 2 h. The reaction mixture was purged with N₂, filtered through Celite, and concentrated under reduced pressure to provide 5-chloro-4-((2-chloropyrimidin-4-yl)methoxy)-2-methoxyaniline (1.2 g, 99%) as an orange-brown amorphous material. MS (ES+) C12H11C12N302 requires: 299, found: 300 [M+H]+.

Step 4:

To a solution of 5-chloro-4-((2-chloropyrimidin-4-yl)methoxy)-2-methoxyaniline (1.2 g, 4.0 mmol) in DCM (20 ml) was added di(lH-imidazol-l-yl)methanethione (0.78 g, 4.4 mmol) and the resulting mixture was stirred at RT for 1 h. (l S,2S)-2-Aminocyclohexanol (0.92 g, 8.0 mmol) was added and the yellow-brown mixture stirred at RT for an additional 1 h. The volatiles were removed under reduced pressure. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL). The layers were separated, and the organic layer was washed with sat. NaHCC (10 mL), dried over MgSC , filtered and concentrated under reduced pressure to give l-(5-chloro-4-((2-chloropyrimidin-4- yl)methoxy)-2-methoxyphenyl)-3-((lS,2S)-2-hydroxycyclohexyl)thiourea (1.8 g, 90%) as a fine tan solid. MS (ES+) C19H22C12N403S requires: 456, found: 457 [M+H]⁺.

Step 5:

To a solution of l-(5-chloro-4-((2-chloropyrimidin-4-yl)methoxy)-2-methoxyphenyl)-3- ((lS,2S)-2-hydroxycyclohexyl)thiourea (1.8 g, 3.5 mmol) in DCM (30 ml) was added (Z)- trimethylsilyl 2,2,2-trifluoro-N-(trimethylsilyl)acetimidate (1.88 ml, 7.08 mmol) and the resulting mixture was stirred at RT for 5 min. Benzyltrimethylammonium tribromide (1.38 g, 3.54 mmol) was then added as a solution in DCM (15 ml). After 15 min, the reaction mixture was diluted with sat. NaHCC (10 mL), water (20 mL), and sat. Na₂S₂0₄ (5 mL). The resulting mixture was stirred for 5 min, the layers were separated, and the organic layers were dried over MgSC , filtered and concentrated under reduced pressure. The residue was triturated with 1 : 1 Et^O/Hexanes (20 mL). The resulting solid was filtered through a Buchner funnel, rinsed with 1 : 1 Et^O/Hexanes (10 niL), and collected isolating (l S,2S)-2-((7-chloro- 6-((2-chloropyriniidin-4-yl)methoxy)-4-methoxybenzo[d]thiazol-2-yl)aniino)cyclohexan-l-ol (1.60 g, 94%) as a tan solid. MS (ES+) C19H20C12N4O3S requires: 454, found: 455 [M+H]⁺.

Step 6:

A microwave vial was charged with (15',25 -2-((7-chloro-6-((2-chloropyrimidin-4- yl)methoxy)-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohexanol (0.90 g, 2.0 mmol) and NH₃ in MeOH (7.0 ml, 49 mmol, 7M). The vial was sealed and the reaction mixture was heated to 120 °C in the microwave reactor for 3 h. The volatiles were removed under reduced pressure. The residue was diluted with water (15 mL), stirred for 10 min at 50 °C, and the solid collected on a Buchner funnel. After drying, the residue was purified by reverse phase HPLC (Mobile phase: A = 0.1% NH40H/H20, B = 0.1% NH40H/ MeCN; Gradient: B = 0 - 100%; 20 min; Column: C18) to provide (lS,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-7- chloro-4-methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol (620 mg, 72%) as a tan solid. MS (ES+) C19H22C1N503S requires: 435, found: 436 [M+H]⁺; ^lH NMR (600 MHz, DMSO-c¾) δ 8.27 (d, J = 5.0 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 6.79 (s, 1H), 6.74 (d, J = 4.9 Hz, 1H), 6.67 (s, 2H), 5.04 (s, 2H), 4.75 (d, J = 5.1 Hz, 1H), 3.85 (s, 3H), 3.53 - 3.46 (m, 1H), 3.36 - 3.32 (m, 1H), 2.09 - 1.99 (m, 1H), 1.92 - 1.84 (m, 1H), 1.69 - 1.56 (m, 2H), 1.31 - 1.16 (m, 4H).

Example 70: ( IS, 2S)-2-( 6-( (2-aminopyrimidin-4-yl)methoxy)-7-fluoro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

A mixture of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (750 mg, 2.15 mmol), Selectfiuor (835 mg, 2.36 mmol) in CH₃CN (50 ml) was stirred at 80°C overnight. Sat. NaCl (100 mL) was added. The reaction mixture was extracted EtOAc (3 ^χ 50 mL), the combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in PE) to provide 6-(benzyloxy)-2-bromo-7-fluoro-4-methoxybenzo[d]thiazole (300 mg, 38%) as a yellow solid. MS (ESI+) Ci₅HnBrFN0₂S requires: 367, found: 368 [M+H]⁺.

Step 2:

A mixture 6-(benzyloxy)-2-bromo-7-fluoro-4-methoxybenzo[d]thiazole (300 mg, 0.810 mmol) and (lS,2S)-2-aminocyclohexanol (234 mg, 2.03 mmol) was stirred at 120°C for 6 h. The mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated. The residue was purified by silica gel silica gel chromatography (0 to 50 % EtOAc in PE) to afford (lS,2S)-2-(6-(benzyloxy)-7-fluoro-4-methoxybenzo[d]thiazol-2- ylamino)cyclohexanol as a solid (250 mg, 76%). MS (ES+) C21H23C1N203S requires: 402, found: 403[M+H]+.

Step 3:

A mixture of (lS,2S)-2-(6-(benzyloxy)-7-fluoro-4-methoxybenzo[d]thiazol-2-ylamino) cyclohexanol (90 mg, 0.22 mmol) in 5 mL of TFA was stirred at 55°C for 2 h. The solvent was removed, the reaction mixture was diluted by sat. NaHC0₃ (50 ml), extracted with EtOAc (50 ml ^χ 3). The combined organic layers was washed with water (100 ml), brine (100 ml), dried over Na₂S0₄, filtered and concentrated to give 7-fluoro-2-((lS,2S)-2- hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (70 mg, 100%) as a black solid. MS (ES+) C14H17FN203S requires: 312, found: 313[M+H]⁺. Step 4:

A mixture of 7-fluoro-2-((l S,2S)-2 -hydroxy cyclohexylamino)-4-methoxybenzo[d]thiazol-6- ol (70 mg, 0.22 mmol), 2-chloro-4-(chloromethyl)pyrimidine (37 mg, 0.22 mmol) and Cs₂C0₃ (216 mg, 0.66 mmol) in DMF (2 mL) was stirred at 80°C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over Na₂SC>4, filtered and concentrated to give (lS,2S)-2-(6-((2-chloropyrimidin-4-yl)methoxy)-7- fluoro-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (96 mg, 100%) as a yellow solid. MS (ES+) C19H20C1FN4O3S requires: 438, found: 439[M+H]⁺.

Step 5:

(l S,2S)-2-(6-((2-chloropyrimidin-4-yl)methoxy)-7-fluoro-4-methoxybenzo[d]thiazol-2- ylamino)cyclohexanol (60 mg, 0.14 mmol) in NH₄OH (2 ml) was stirred at 100°C for 1 h. The reaction mixture was purified by prep-HPLC (Mobile phase: A = 10 mM ammonium bicarbonate/H20, B = acetonitrile; Gradient: B = 60%-95% in 18 min; Column: Welch Xtimate® CI 8, 10 urn, 21.2 mm x 250 mm) to give (lS,2S)-2-(6-((2-aminopyrimidin-4- yl)methoxy)-7-fluoro-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (5.0 mg, 8%) as a white solid. MS (ES+) C19H22FN503S requires: 419, found: 420 [M+H]+; 1H NMR (500 MHz, MeOD) δ 8.35 (d, J = 5.9 Hz, 1H), 7.14 (d, J = 5.9 Hz, 1H), 6.87 (d, J = 6.8 Hz, 1H), 5.20 (s, 2H), 3.96 (s, 3H), 3.69 (dt, J = 11.7, 4.2 Hz, 1H), 3.46 (dt, J = 13.0, 4.8 Hz, 1H), 2.11 (dd, J = 47.6, 15.4 Hz, 2H), 1.84 - 1.73 (m, 2H), 1.41 (dt, J = 24.5, 15.1 Hz, 4H).

Example 71: N-(4-( (2-( ( IS, 2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-yl)acetamide

The title compound was synthesized according to the following synthetic scheme:

A mixture of 2-((lS,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (Prepared as described for Example 50, Steps 1 to 6) (20 mg, 0.068 mmol), N-(4- (chloromethyl)pyridin-2-yl)acetamide (15 mg, 0.082 mmol) and CS2CO₃ (44 mg, 0.136 mmol) in DMF (3 ml) was stirred at 80°C overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Mobile phase: A = 0.1% NH4HCO₃/H2O, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to give N-(4-((2- ((lS,2S)-2 -hydroxy cyclohexylamino)-4-methoxybenzo[d]thiazol-6-yloxy)methyl)pyridin-2- yl)acetamide (9 mg, 30%) as a white solid. MS (ES+) C22H2₆N4O4S requires: 442, found: 443 [M+H]⁺. ^XH NMR (500 MHz, d6-DMSO) δ 10.51 (s, 1H), 8.29 (d, J = 5 Hz, 1H), 8.16 (s, 1H),7.61 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 4 Hz, 1H), 6.93 (s, 1H), 6.55 (s, 1H), 5.12 (s, 2H), 4.76 (d, J = 5.5 Hz, 1H), 3.81 (s, 3H), 3.43 - 3.49 (m, 1H), 2.08 (s, 3H), 2.02 - 2.05 (m, 1H), 1.86 - 1.90 (m, 1H), 1.60 - 1.64 (m, 2H), 1.18 - 1.30 (m, 4H).

The following example in Table 5 was prepared analogously to Example 71.

Table S:

Example 73: ( IS, 2S)-2-( 6-( (2-aminopyrimidin-4-yl)methoxy)-4-methoxy-7- methylbenzo[d]thiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 4-bromo-2-methoxy-5-methylaniline (10 g, 73.0 mmol) in DCM (200 mL) was added the Br₂ (11.7 g, 73.0 mmol) dropwise over 10 min at 0°C. The reaction mixture was stirred at RT overnight. The reaction was quenched with aq. NaHCC (200 mL) at 0°C, the mixture was extracted with EtOAc (3 ^χ 200 mL) and washed with brine (200 mL). The mixture was dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0% to 20%, EtOAc in petroleum ether) to give 4-bromo-2-methoxy-5- methylaniline as a yellow solid (8.0 g, 50%). MS (ES+) C8H10BrNO, requires: 215, found: 216 [M+H]+.

Step 2:

To a solution of 4-bromo-2-methoxy-5-methylaniline (4.0 g, 18 mmol) in MeOH (200 mL) was added KSCN (3.6 g, 37 mmol) and CUSO4 (14.9 g, 93 mmol). The reaction mixture was stirred at 80°C overnight. The reaction mixture was quenched with aq. NH₃ (7M, 200 mL), extracted with EtOAc (3 ^χ 200 mL) and washed with brine (200 mL). It was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (0%) to 10%) MeOH in DCM) to give 6-bromo-4-methoxy-7-methylbenzo[d]thiazol-2-amine (2.0 g, 39.5%) as a yellow solid. MS (ES+) C9H9BrN20S, requires: 272, found: 274 [M+H]⁺.

Step 3:

Tert-Butyl nitrite (754 mg, 7.32 mmol) was added dropwise to a mixture of CuBr₂ (3.2 g, 14 mmol) and 6-bromo-4-methoxy-7-methylbenzo[d]thiazol-2-amine (2.0 g, 7.32 mmol) in CH3CN (20 mL) at 0°C. The mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to afford 2,6-dibromo-4-methoxy-7-methylbenzo[d]thiazole (2.1 g, 89.3%) as a beige solid. MS (ES+) C9H7Br2NOS requires: 335, found: 336, 338 [M+H]⁺.

Step 4:

A mixture of 2,6-dibromo-4-methoxy-7-methylbenzo[d]thiazole (1.5 g, 4.45 mmol) and (l S,2S)-2-aminocyclohexanol (768 mg, 6.67 mmol) was stirred at 130°C for lh. The mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated. The crude residue was purified by silica gel silica gel chromatography (10% to 50%, EtOAc in petroleum ether) to afford (lS,2S)-2-(6-bromo-4-methoxy-7-methylbenzo[d]thiazol-2- ylamino)cyclohexanol as a brown solid (800 mg, 48.4%). MS (ES+) C15H19BrN202S requires: 370, found: 370, 372 [M+H]⁺.

Step 5:

A mixture of (lS,2S)-2-(6-bromo-4-methoxy-7-methylbenzo[d]thiazol-2- ylamino)cyclohexanol (500 mg, 1.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (513 mg, 2.02 mmol), KOAc (265 mg, 2.70 mmol), PCy₃ (37 mg, 0.13 mmol) and Pd2(dba)3 (137 mg, 0.135 mmol) in 5 mL of 1,4-dioxane was stirred at 100°C for 16 h. The reaction mixture was filtered and purified by silica gel silica gel chromatography (10% to 50% EtOAc in petroleum ether) to afford (lS,2S)-2-(4-methoxy-7-methyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylamino) cyclohexanol (500 mg, 88.6%) as a brown solid. MS (ES+) C21H31BN204S requires: 418, found: 419 [M+H]⁺.

Step 6:

H2O2 (30 drops) was added dropwise to a solution of (lS,2S)-2-(4-methoxy-7-methyl-6- (4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylamino)cyclohexanol (500 mg, 1.20 mmol) in MeOH (12 mL) at 0°C. The reaction mixture was stirred at 0°C for 20 min, diluted with EtOAc, washed with water, brine, dried and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0% to 10%, MeOH in DCM) to give 2-((lS,2S)-2-hydroxycyclohexylamino)-4-methoxy-7-methylbenzo[d]thiazol- 6-0I (250 mg, 67%) as a brown solid. MS (ES+) C15H20N2O3S, requires: 308, found: 309 [M+H]⁺.

Step 7: A solution of 2-((l S,2S)-2 -hydroxy cyclohexylamino)-4-methoxy-7-methylbenzo[d]thiazol-6- ol (100 mg, 0.325 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (52 mg, 0.32 mmol) in DMF (1 mL) was added CS2CO₃ (211 mg, 0.650 mmol) at RT. Then the reaction was stirred at 80°C for 2 h. The reaction was quenched with water (5 mL), extracted with EtOAc (3 x 5 mL), washed with brine (5 mL), dried over Na₂SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 20% EtOAc in petroleum ether) to give (l S,2S)-2-(6-((2-chloropyrimidin-4-yl)methoxy)-4-methoxy-7-methylbenzo[d]thiazol-2- ylamino)cyclohexanol (20 mg, 14.3%) as a white solid. MS (ES+) C20H23C1N4O3S requires 434, found: 434, 436 [M+H]⁺.

Step 8:

A solution of (l S,2S)-2-(6-((2-chloropyrimidin-4-yl)methoxy)-4-methoxy-7-methylbenzo[d] thiazol-2-ylamino)cyclohexanol (20 mg, 0.046 mmol) in NH4OH (0.5 mL) was stirred at 100°C overnight. The reaction mixture was purified by prep-HPLC (Mobile phase: A = 10 mM ammonium bicarbonate/H20, B = acetonitrile; Gradient: B = 60%-95% in 18 min; Column: Welch Xtimate® C18, 10 urn, 21.2 mm x 250 mm) to afford ((l S,2S)-2-(6-((2- aminopyrinddin-4-yl)methoxy)-4-methoxy-7-methylbenzo[d]thiazol-2-ylamino)cyclohexanol (5 mg, 26%) as a white solid. MS (ES+) C21H26N403S requires: 415, found: 416 [M+H]+. 1H NMR (500 MHz, MeOD) δ 8.42 - 8.16 (m, 1H), 7.02 - 6.80 (m, 1H), 6.62 (s, 1H), 5.00 (s, 2H), 3.90 (s, 3H), 3.70 - 3.54 (m, 1H), 3.51 - 3.39 (m, 1H), 2.30 (s, 3H), 2.20 - 2.12 (m, 1H), 2.09 - 1.95 (m, 1H), 1.89 - 1.61 (m, 2H), 1.49 - 1.21 (m, 5H).

Example 74: ( IS, 2S)-2-(6-((2-amino-3-fluoropyridin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (0.5 g, 1.4 mmol) in NMP (5 mL), NCS (0.17 g, 2.8 mmol) was added at RT. The mixture was stirred at 50°C for 2 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 χ 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc in petroleum ether, 10-20%) to give 6- (benzyloxy)-2-bromo-7-chloro-4-methoxybenzo[d]thiazole as a white solid (0.4 g, 74%). MS (ES+) Ci₅HiiBrClN0₂S requires: 383, found: 384[M+H]⁺.

Step 2:

To a solution of 6-(benzyloxy)-2-bromo-7-chloro-4-methoxybenzo[d]thiazole (0.2 g , 0.5 mmol) in DMA (5 mL), (l S,2S)-2-aminocyclohexanol (0.12 g, 1 mmol) and DIPA (0.65 g, 5.0 mmol) were added at RT. The mixture was stirred at 90°C overnight. The resulting mixture was diluted with H₂0 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel silica gel chromatography (30- 50% EtOAc in petroleum ether) to give (l S,2S)-2-(6-(benzyloxy)-7-chloro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol as a yellow solid (0.2 g, 95%). MS (ES+) C21H2₃CIN2O₃S requires: 418, found: 419[M+H]⁺.

Step 3:

A solution of (lS,2S)-2-(6-(benzyloxy)-7-chloro-4-methoxybenzo[d]thiazol-2-ylamino)- cyclohexanol (0.20 g, 0.48 mmol) in TFA (2 mL) was heated at 50°C for 3 h. After cooled to RT, the mixture was neutralized with sat. NaHC0₃ and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford 7-chloro-2-((l S,2S)-2- hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol as a yellow solid (90 mg, 60%). MS (ES+) Ci₄Hi₇ClN₂0₃S requires: 328, found: 329 [M+H]⁺.

Step 4:

To a solution of 7-chloro-2-((l S,2S)-2 -hydroxy cyclohexylamino)-4-methoxybenzo[d]thiazol- 6-ol (90 mg, 0.27 mmol) in DMF (3 mL), 4-(chloromethyl)-3-fluoro-N-(4- methoxybenzyl)pyridin-2-amine (92 mg, 0.33 mmol) and CS2CO₃ (0.18 g, 0.54 mmol) were added at RT. The mixture was stirred at 100°C ovemight. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 ^χ 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford (lS,2S)-2-(7-chloro-6-((3-fluoro-2-(4-methoxybenzylamino)pyridin-4- yl)methoxy)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol as yellow solid (50 mg, 33%). MS (ES+) C2₈H₃₀CIFN4O4S requires: 572, found: 573 [M+H]⁺.

Step 5:

A solution of (lS,2S)-2-(7-chloro-6-((3-fluoro-2-(4-methoxybenzylamino)pyridin-4- yl)methoxy)-4-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (50 mg, 0.09 mmol) in TFA (2 mL) was stirred at RT overnight. The mixture was neutralized with aq. NaHCC and extracted with EtOAc (3 ^χ 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude product which was purified by pre-HPLC (Mobile phase: A = 0.01% TFA/H20, B = MeCN; Gradient: B = 5% - 95% in 8 min; Column: XBridge CI 8, 5 um, 30 mm 150 mm) to give (l S,2S)-2-(6-((2-amino-3-fluoropyridin-4-yl)methoxy)-7-chloro-4-methoxybenzo[d]thiazol- 2-ylamino)cyclohexanol as a white solid (17.3 mg, 44%). MS (ES+) C20H22C1FN4O3S requires: 452, found: 453 [M+H]+; 1H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.0 Hz, 1H), 7.75 (d, J= 4.0 Hz, 1H), 6.85 (s, 1H), 6.69 (t, J = 4.0 Hz, 1H), 6.24 (s, 2H), 5.21 (s, 2H), 4.75 (d, J = 4.0 Hz, 1H), 3.87 (s, 3H), 2.03 (d, J = 4.0 Hz, 1H), 1.87 (d, J = 4.0 Hz, 1H), 1.63 (t, J = 12.0 Hz, 2H), 1.24 (m, 6H).

The following example in Table 6 was prepared analogously to Example 74. Table 6:

Example 76: ( IS, 2S)-2-(7-chloro-4-methoxy-6-((2-(l-methyl-lH-pyrazol-4- ylamino)pyrimidin-4-yl)methoxy)benzo[dJthiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

A mixture of (lS,2S)-2-(7-chloro-6-((2-chloropyrimidin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (Example 74, step 5) (60 mg, 0.13 mmol), l-methyl-lH-pyrazol-4-amine (21 mg, 0.15 mmol) and TSOH.H2O (11 mg, 0.065 mmol) in dioxane (2 ml) was stirred at 110°C overnight. The mixture was diluted with EtOAc (5 mL), washed with sat. NaHCC , and dried over Na2S04_. The combined organic layers were concentrated. The residue was purified by preparative HPLC (Mobile phase: A = 0.1% NH4HCO₃/H2O, B = MeCN; Gradient: B = 5 - 95%; 12 min; Column: CI 8) to provide (lS,2S)-2-(7-chloro-4-methoxy-6-((2-(l -methyl- lH-pyrazol-4-ylamino)pyrirnidin-4- yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol (3.5 mg, 5%) as a white solid. MS (ES+) C2₃H2₆CIN7O₃S requires: 515 found: 516 [M+H]⁺. ^XH NMR (500 MHz, d6-DMSO) δ 9.51 (s, 1H), 8.44 (d, J = 4.5 Hz, 1H),7.89 (d, J = 9.5 Hz, 2H),7.48 (s, 1 H), 6.83 - 6.89 (m, 2H), 5.17 (s, 2H), 4.17 (d, J = 5.5 Hz, 1H), 3.77 (s, 3H), 3.49 (s, 3H), 2.02 - 2.08 (m, 1H), 1.86 - 1.89 (m, 1H), 1.60 - 1.65 (m, 2H), 1.19 - 1.30 (m, 4H).

The following examples in Table 7 were prepared analogously to Example

Table 7:

Example 79: Methyl 4-((2-((lS, 2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-ylcarbamate

The title compound was synthesized according to the following synthetic scheme: BocHN

Step 1:

The solution of fert-butyl 4-(chloromethyl)pyridin-2-ylcarbamate (700 mg, 2.88 mmol) in HCl-dioxane (4M, 5 mL) was stirred at 55 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-(chloromethyl)pyridin-2-amine, which was used in the next step without further purification. MS (ES+) C₆H₇C1N₂ requires: 142, found: 143[M+H]⁺.

Step 2:

To a solution of 4-(chloromethyl)pyridin-2-amine (300 mg, 2.1 mmol) in DCM (8 mL) were added Et₃N (637 mg, 6.3 mmol) and methyl carbonochloridate (199 mg, 2.1 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was washed with water (10 mL), extracted with DCM (15 mL χ 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 70 % EtOAc in PE) to give methyl 4-(chloromethyl)pyridin-2-ylcarbamate (120 mg, 28%) as a white solid. MS (ES+) C₈H₉C1N₂0₂ requires: 200, found: 201 [M+H]⁺.

Step 3:

To a solution of methyl 4-(chloromethyl)pyridin-2-ylcarbamate (100 mg, 0.5 mmol) and 2- ((15',25 -2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (Prepared as described in Example 50, steps 1 to 6) (138 mg, 0.47 mmol) in DMF (3 mL) was added K₂C0₃ (130 mg, 0.94 mmol). The reaction mixture was stirred at 90°C for 3 h. The mixture was filtered and purified by mass-triggered preparative HPLC (Mobile phase: A = 10M NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 40-70%; 8.5 min; Column: CI 8) to give methyl 4-((2-((lS 2S)-2- hydroxycyclohexylamino)-4-methoxybenzo[cf] thiazol-6-yloxy)methyl)pyridin-2-ylcarbamate (18 mg, 9%) as a white solid. MS (ES+) C₂₂H₂₆N₄O₅S requires: 458, found: 459 [M+H]⁺. ^l NMR (500MHz, DMSO) δ 10.23 (s, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.63 (d, J = 7.5 Ηζ,ΙΗ), 7.10 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 5.13 (s, 2H), 4.78 (d, J= 5.0 Hz, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 3.50 (s, 1H), 2.03 (d, J= 13.1 Hz, 1H), 1.86 (s, 1H), 1.63 (s, 2H),1.31 - 1.16 (m, 5H).

Example 80: l-(4-( (2-( ( lS,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-yl)-3-methylurea

The title compound was synthesized according to the following synthetic scheme:

O NT ^

I 1 .i A JL ,ci ^► CI

N N H H

Step 1:

The solution of fert-butyl 4-(chloromethyl)pyridin-2-ylcarbamate (400 mg, 1.65 mmol) in HCl-dioxane (4M, 3 mL) was stirred at 55°C for 2 h. The reaction mixture was concentrated to give 4-(chloromethyl)pyridin-2-amine. The residue was used in the next step without further purification. MS (ES+) C₆H₇C1N₂ requires: 142, found: 143[M+H]⁺.

Step 2:

To a solution of 4-(chloromethyl)pyridin-2-amine (300 mg, 2.1 mmol) in DCM (8 mL) were added Et₃N (4 mL) and methylcarbamic chloride (589 mg, 6.3 mmol). The resulting mixture was stirred at room temperature for overnight. The reaction mixture was washed with water (10 mL) and extracted with DCM (15 mL χ 3). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0-95% EtOAc in petroleum ether) to give l-(4-(chloromethyl)pyridin-2-yl)-3-methylurea (55 mg, 13%) as a white solid. MS (ES+) C₈Hi₀ClN₃O requires: 199, found: 200[M+H]⁺.

Step 3: To a solution of l-(4-(chloromethyl)pyridin-2-yl)-3 -methylurea (50 mg, 0.25 mmol) and 2- ((15',25 -2-hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (Prepared as described in Example 50, steps 1 to 6) (74 mg, 0.25 mmol) in DMF (1 mL) was added K2CO₃ (69 mg, 0.5 mmol). The reaction mixture was stirred at 90°C for 3 h. The mixture was filtered and purified by mass-triggered preparative HPLC (Mobile phase: A = 10M NH₄HC0₃/H₂0, B = MeCN; Gradient: B = 30-60%; 9.5min; Column: C18) to give l-(4-((2-((15,2S)-2- hydroxycyclohexylamino)-4-methoxybenzo[d]thiazol-6-yloxy)methyl)pyridin-2-yl)-3- methylurea (27 mg, 24%) as a white solid. MS (ES+) C22H27N5O4S requires: 457, found: 458 [M+H]⁺. ^XH NMR (500MHz, DMSO) δ 9.29 (s, 1H), 8.27 - 8.01 (m, 2H), 7.62 (d, J= 7.5 Hz, 1H), 7.39 (s, 1H), 6.95 (dd, J = 21.8, 3.5 Hz, 2H), 6.55 (d, J = 1.9 Hz, 1H), 5.07 (s, 2H), 4.77 (d, J = 4.9 Hz, 1H), 3.83 (s, 3H), 3.51 (s, 1H), 2.73 (d, J = 4.5 Hz, 3H), 2.02 (s, 1H), 1.86 (s, 1H), 1.63 (s, 2H), 1.32 - 1.12 (m, 5H).

The following example in Table 8 was prepared analogously to Example

Table 8:

Example 81: ( IS, 2S)-2-(4-methoxy-6-( (2-(l -methyl- ΙΗ-pyr azol-4-ylamino)pyridin-4- yl)methoxy)benzo[d]thiazol-2-ylamino)cyclohexanol

The title compound was synthesized according to the following synthetic scheme:

Step 1:

To a solution of (2-bromopyridin-4-yl)methanol (1.0 g, 5.3 mmol) and DIPEA (2.06 g, 15.9 mmol) in DCM (20 mL) was added MsCl (640 mg, 5.6 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with DCM (10 mL) and washed with saturated aqueous NH₄C1 (20 mL), saturated aqueous Na2CC>₃ (20 mL) and brine (10 mL). The mixture was dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography (0 to 50% EtOAc in PE) to give 2- bromopyridin-4-yl)methyl methanesulfonate (1.2 g, 85%) as a pale-red solid. MS (ES+) C₇H₈BrN0₃S requires: 265, found: 266 [M+H]⁺.

Step 2:

To a solution of (2-bromopyridin-4-yl)methyl methanesulfonate (300 mg, 1.13 mmol) and 2- ((l^,2^-2-hydroxycyclohexylamino)-4-methoxybenzo[cf]thiazol-6-ol (Prepared as described for Example 50, Steps 1 to 6) (332 mg, 1.13 mmol) in DMF (4 mL) was added Cs₂C0₃ (736 mg, 2.26 mmol). The resulting mixture was stirred at 80°C for 20 min. The reaction mixture was filtered and purified by mass-triggered preparative HPLC (Mobile phase: A = 10M NH4HCO₃/H2O, B = MeCN; Gradient: B = 40-70%; 10.85 min; Column: CI 8) to give (15',25)-2-(6-((2-bromopyridin-4-yl)methoxy)-4-methoxybenzo[ci]thiazol-2- ylamino)cyclohexanol (185 mg, 35%) as a white solid. MS (ES+) C2oH22BrN₃0₃S requires: 463, found: 464[M+H]⁺.

Step 3:

In a pressure tube, l-methylpyrazol-4-amine HCI (21 mg, 0.16 mmol), (\S,2S)-2-(6-((2- bromo pyridin-4-yl)methoxy)-4-methoxybenzo[cf|thiazol-2-ylamino) cyclohexanol (60 mg, 0.13 mmol), RuPhos Pd G4 (11 mg, 0.013 mmol), RuPhos (6 mg, 0.013 mmol) and Cs₂C0₃ (127 mg, 0.39 mmol) were dissolved in 1,4-dioxane (2 mL). The tube was sealed and purged with N₂. The reaction mixture was stirred at 85°C for 3h. LCMS monitored the reaction. The mixture was filtered and purified by mass-triggered preparative HPLC (Mobile phase: A = 10M NH4HCO₃/H2O, B = MeCN; Gradient: B = 30-60%; 10.0 min; Column: C18) to give (15',25)-2-(4-methoxy-6-((2-(l-methyl-lH-pyrazol-4-ylamino)pyridin-4-yl)

methoxy)benzo[cf|thiazol-2-ylamino)cyclohexanol (5 mg, 9%) as a white solid. MS (ES+) C24H₂8N₆0₃S requires: 480, found: 481 [M+H]⁺. ¾ NMR (500MHz, DMSO) δ 8.81 (s, 1H), 8.07 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.70 (s, 1H), 6.65 (d, J= 5.3 Hz, 1H), 6.54 (d, J = 2.2 Hz, 1H), 5.02 (s, 2H), 4.77 (d, J = 5.0 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.51 (s, 1H), 2.02 (s, 1H), 1.87 (d, J = 11.2 Hz, 1H), 1.63 (t, J= 10.8 Hz, 2H), 1.23 (s, 5H).

The following examples in Table 9 were prepared analogously to Example 81.

Table 9:

Example 84: 6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-N-(3, 3-difluorocyclohexyl)-4- methoxybenzo [dJthiazol-2-amine

The title compound was synthesized according to the following synthetic scheme:

Step 1:

A mixture of 6-(benzyloxy)-2-bromo-4-methoxybenzo[d]thiazole (Example 50, Step 4) (750 mg, 2.14 mmol) and NCS (570 mg, 4.29 mmol) in NMP (10 mL) was stirred at 50°C for 3 h under argon. Water was added and the mixture was extracted with EtOAc (3 x 5 mL). The organic layers were washed with brine, dried and concentrated under reduced pressure to afford 6-(benzyloxy)-2-bromo-7-chloro-4-methoxybenzo[d]thiazole as a brown solid. MS (ES+) C15H1 lBrClN02S requires: 383, found: 384, 386 [M+H¹⁺.

Step 2:

A mixture of 6-(benzyloxy)-2-bromo-7-chloro-4-methoxybenzo[d]thiazole (160 mg, 0.41 mmol) and 3,3-difluorocyclohexanamine hydrochloride salt (140 mg, 0.82 mmol) in DIPEA (20 drops) and NMP (20 drops) was stirred at 180°C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (3 χ 10 mL). The combined organic layers was dried over Na₂SC>4 and concentrated. The residue was purified via silica gel chromatography (0% to 10% EtOAc in petroleum ether) to give 6-(benzyloxy)-7-chloro-N-(3,3- difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine (100 mg, 54.9%) as a yellow oil. MS (ES+) C21H21C1F2N202S, requires:438, found: 439[M+H]⁺.

Step 3: A solution of 6-(benzyloxy)-7-chloro-N-(3,3-difluorocyclohexyl)-4-methoxybenzo[d]thiazol- 2-amine (100 mg, 0.23 mmol) in TFA (3 mL) was stirred at 65°C for 16 h. The TFA was evaporated, the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with sat. NaHCC solution, dried over Na₂SC>4 and concentrated to afford 7-chloro-2-(3,3-difluorocyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (100 mg, crude) as a brown oil. MS (ES+) C14H15C1F2N202S requires: 348, found: 349[M+H]⁺.

Step 4:

A mixture of (2-aminopyrimidin-4-yl)methyl methanesulfonate (52 mg, 0.26 mmol), 7- chloro-2-(3,3-difluorocyclohexylamino)-4-methoxybenzo[d]thiazol-6-ol (90 mg, 0.26 mmol) and Cs₂C0₃ (2168 mg, 0.52 mmol) in DMF (1 mL) was stirred at RT for 2 h. The reaction mixture was purified by prep-HPLC (Mobile phase: A = 0.01% TFA/H20, B = MeCN; Gradient: B = 60% - 95% in 18 min; Column: Venusil CBP C18 (L) C18, 10 urn, 21.2 mm x 250 mm, Cat. NO. :VX902520-L) to give 6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-N- (3,3-difluorocyclohexyl)-4-methoxybenzo[d]thiazol-2-amine (20 mg, 15%) as a white solid. MS (ES+) C19H20C1F2N5O2S, requires: 455, found: 456[M+H]+; 1H NMR (500 MHz, DMSO) δ 8.32 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.08 (s, 2H), 6.83 (s, 2H), 5.10 (s, 2H), 3.95 - 3.90 (m, 1H), 3.87 (s, 3H), 2.46 - 2.42 (m, 1H), 2.05 - 1.96 (m, 2H), 1.87 - 1.72 (m, 3H), 1.52 - 1.45 (m, 1H), 1.39 - 1.29 (m, 1H). Examples 85 and 86:

The following examples in Table 10 were prepared analogously to Example 1 :

Table 10:

Example 87 - 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 MgCl₂, 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 IC5₀ regression curve fitting (GeneData Screener).

Table 11 below summarises the results of the CSF-IR competitive binding assay, in which the IC5₀ 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 1.5 μΜ; and (E) >1.5 μΜ. Table 11: CSF-1R competitive binding assay

Example 88 - 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 % C0₂ 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 12 below summarises the results of the mCSF dependent cell proliferation assay, in which the IC5₀ values are indicated for each compound as: (A) less than 1 μΜ; (B) 1 μΜ to 2 μΜ; (C) 2 μΜ to 5 μΜ; (D) 5 μΜ to 10 μΜ; (E) greater than 10 μΜ.

Table 12: mCSF dependent cell proliferation assay

Ex.# ic₅₀ Ex.# ic₅₀

1 A 32 B

2 A 33 C

3 A 34 C

4 A 35 A

5 A 36 A

6 B 37 A

7 D 38 A

8 E 39 A

10 D 40 B

11 D 41 A

12 D 42 B

13 C 43 C

14 D 44 A

15 C 45 A

16 D 50 A

17 D 51 A

19 D 52 A

20 B 53 A

22 C 54 A

23 B 55 A

24 A 56 A

25 A 57 A

26 A 58 A

27 A 59 A

28 A 60 A

29 A 61 A

30 A 62 A

31 A 63 A Example 89 - 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 13 below summarises the results of the selectivity assay, in which the Kd values measured for c-Kit, FLT3, PDGFRa and PDGFR are given relative to the Kd 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 13: Kinase selectivity of compounds

Ex # c-KIT FLT3 PDGFRa PDGFRp

1 A B A A

2 A A A A

3 A C A A

4 A A A A

5 B D D D

15 B D A B

20 A B A B

24 A A A A

25 A A A A

26 A C B B Ex # c-KIT FLT3 PDGFRa PDGFRp

27 A D D D

30 A A B B

35 A B A B

36 A A A A

37 B D C D

38 A A A C

41 B B D D

50 A A A A

51 A C A A

54 A A A A

55 A A A A

56 A A A A

65 A A B B

66 A A A A

69 A A A A

70 A A A A

72 A A A A

73 A A A A

84 A A A A

Example 90 - CSF-IR cellular target engagement assay

THP-1 cells were resuspended in RPMI medium (without phenol red) containing 10% HI FBS and 0.1% β-Me, and then plated onto a 96-well TC plate (125 μΐ, 250K cells/well). The cells were incubated at 37°C, 5% C0₂ for 20 h, followed by the addition of 0.1% DMSO (control) or varying concentrations of CSF-IR inhibitors. After 30 minutes incubation at 37°C, the cells were treated with 50 ng/mL human MCSF (Sigma M6518) for 5 min, and then added to 125 μΐ lysis buffer (R&D Systems SAMPLE DILUENT CONC 2). After 45 minutes incubation at RT, the tyrosine-phosphorylated CSF-IR was evaluated by sandwich ELISA (R&D Systems DYC3268), following the manufacturer's protocol. Briefly, a Nunc- Immuno MaxiSorp plate (Sigma 9410) was coated with anti-human CSF-IR, blocked, and bound to 100 THP-1 lysate for 2h at RT. After being washed, HRP labeled anti-phospho- tyrosine was added to the plates and incubated for another 2h at RT. After washing, ELISA signal was induced and quenched by 1-Step Ultra TMB-ELISA Substrate Solution (Life Technologies 34028) and 2N sulfuric acid, respectively. Absorbance at 450 nm and 540 nm was measured on BioTek Neo plate reader, and ELISA signal was calculated as Ab450nm-

The standard dose response curves were fitted by Genedata Screener software using the variable-slope model:

Signal = Signal_ne ative control + (Signal_DMSO control - Signal_ne ative controi)/(l+(IC5o/Dose)^AHill slope) Only Signal and Dose in the equation were treated as known values.

Table 14 below summarises the results of the cellular target engagement assay, in which the IC5₀ values are indicated for each compound as: (A) less than 250 11M; (B) 250 11M to 500 nM; (C) 500 11M to 1 μΜ; (D) 1 μΜ to 2 μΜ; (E) greater than 2 μΜ.

Table 14: cellular target engagement assay

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.

Claims

1. A compound characterised by formula (I),

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2;

X¹ is selected from NH, O, S, -CH=N-, and -N=CH-;

L either denotes a direct bond, or it is a group -(CR⁶R⁷)_P- in which:

p is 1, 2 or 3, and

wherein each said alkyl is optionally substituted;

R⁴ and R⁵ are independently selected from H and Ci-3-alkyl,

2. The compound of claim 1, wherein:

R¹⁰ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^10b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

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^aR^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, aryl, heteroaryl, and (Ci-4-alkyl)-R^c in which R^c is selected from hydroxyl, amino and halogen; and/or

R³ is selected from Ci-8-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

3. The compound of claim 1 or claim 2, wherein A is a 6-membered monocyclic heteroaryl.

4. The compound of any one of the preceding claims, wherein n is 1 or 2.

5. The compound of any one of the preceding claims, wherein R¹ in each case is independently selected from halogen, carbonitrile, -C(0)N(R⁸R⁹), -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -C(O) R , C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR^lu, sulfonyl, aminosulfonyl, Ci-g-alkyl, C₂-8-alkenyl, C₂-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

R⁸, R⁹ and R¹⁰ are each independently selected from H, Ci-4-alkyl, C₂-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

6. The compound of any one of the preceding claims, wherein R¹ in each case is independently selected from halogen, -N(R⁸R⁹), -NHC(0)NR⁸R⁹, -NHC(0)OR¹⁰, -NHC(O)R^10b, -0(Ci_-4-alkyl), Ci_-4-alkyl, aryl, and heteroaryl,

7. The compound of any one of the preceding claims, wherein R¹ in each case is independently selected from CI, Br, and amino, or from methylamino, -NHC(0)OCH_3i - NHC(0)CH₃, -NHC(0)NHCH₃, methyl, methoxy, -NH-pyrazolyl, phenyl and pyrazolyl, each optionally substituted by 1 to 3 groups selected independently from halogen, Ci-3-alkyl and -0(Ci_-3-alkyl).

8. The compound of any one of the preceding claims, wherein m is 1 or 2, and R² 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.

9. The compound of any one of the preceding claims, wherein R³ is Ci-g-alkyl, optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, aminosulfonyl, sulfonylamino, and -0(Ci-4-alkyl) optionally substituted by hydroxyl or by 1 to 3 halogen.

10. The compound of any one of claims 1 to 8, wherein R³ is selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein each said cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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^fR ) in which R^f and R are independently selected from hydrogen and Ci-4-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7- membered heterocyclic group, C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl, and heteroaryl.

11. The compound of claim 10, wherein R³ is cyclohexyl substituted by hydroxyl and further optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl, carbonitrile, -N(R^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl or in which R^f and R together with the intervening nitrogen atom form a 4- to 7-membered heterocyclic group, and Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen.

12. The compound of claim 10, wherein R³ 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^dR^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, sulfonyl, aminosulfonyl, sulfonylamino, and -C(0)N(R^fR ) in which R^f and R are independently selected from hydrogen and Ci-3-alkyl.

13. The compound of any one of the preceding claims, wherein R⁴ and R⁵ are both hydrogen.

14. The compound of any one of the preceding claims, wherein L is -(CR⁶R⁷)_P- in which p is 1 or 2 and in which each R⁶ and each R⁷ 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.

15. The compound of any one of the preceding claims, wherein all R⁶ and R⁷ groups present are hydrogen.

16. The compound of any one of claims 1 to 13, wherein L denotes a direct bond.

17. The compound of any one of the preceding claims, wherein X¹ is selected from NH, O and S.

18. The compound of claim 25, wherein X¹ is S.

19. The compound of claim 1 characterised by formula (II),

(Π)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n, m, X¹, L and R¹ to R⁵ are as defined in any one of the preceding claims.

20. The com ound of claim 1 characterized by formula (III),

(III)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X² is selected from N, CH or C(R^X);

R¹¹ and R¹² are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹ R¹⁴), -N(R¹ R¹⁴), -NHC(0)NR¹ R¹⁴, -NHC(0)OR¹⁵, -NHC(0 )R^15b, -C(0)R^15b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR¹⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl,

wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R¹⁵ is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, C2-4-acyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, R^15b is independently selected from H, Ci-4-alkyl, Ci-4-alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, and wherein each said acyl, acylamino, sulfonyl, aminosulfonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted; and

m, X¹, L, and R² to R⁵ are as defined in any of claims 1 to 18.

21. The compound of claim 20, wherein R¹¹ is selected from hydrogen, halogen, carbonitrile, -C(0)N(R¹²R¹³), 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.

22. The compound of claim 20 or 21, wherein R¹² is selected from halogen, C(0)N(R¹ R¹⁴), sulfonyl, Ci-4-alkyl, C2-4-alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein R¹³ and R¹⁴ are independently selected from H, Ci-4-alkyl, C2-4-acyl, 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^hR') in which R^h and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^J in which R^J is selected from hydroxyl and amino and halogen.

23. The compound of any one of claims 20 to 22, wherein X² is N.

24. The compound of claim 1 characterized by formula (IV),

(IV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X³ is selected from N, CH, and CR¹;

n is 0, 1, 2 or 3; and

m, X¹, L, and R¹ to R⁵ are as defined in any one of claims 1 to 26.

The compound of claim 1 characterized by formula (V),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

wherein n, X¹, X³, L, R¹ and R³ are as defined in any one of the preceding claims.

26. The compound of claim 25, wherein R¹⁶ and R¹⁷ are independently selected from hydrogen, halogen, hydroxyl, carbonitrile and -0(Ci-4-alkyl) optionally substituted by 1 to 3 groups independently selected from halogen, hydroxyl and carbonitrile.

27. The compound of claim 1 characterized by formula (VI),

(VI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

18 19 20 21

wherein m, X¹, L, and R² to R⁵ are as defined in any one of claims 1 to 18.

28. The compound of claim 27, wherein R¹⁸ is selected from hydrogen, halogen, - NR²²R²³, -NHC(0)NR²²R²³, -NHC(0)OR²⁴, -NHC(0)R^24b, C₂-4-acylamino, -0(Ci_-4-alkyl) and Ci-4-alkyl, wherein R and R are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R²⁴ and R^24b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^kR') in which R^k and R¹ are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^m in which R^m is selected from hydroxyl, amino and halogen.

29. The compound of claim 27 or 28, wherein R²⁰ is selected from hydrogen, halogen, - 0(Ci-4-alkyl), Ci-4-alkyl, aryl and heteroaryl,

30. The compound of any one of claims 27 to 29, wherein R¹⁹ and R²¹ are each independently hydrogen.

31. The compound of claim 1 characterized by formula (VII),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

q is 0, 1, 2 or 3;

R²⁵ is independently selected from halogen, hydroxyl, carbonitrile, -N(RⁿR°) in which Rⁿ and R° 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(RⁿR°) in which Rⁿ and R° are independently selected from hydrogen and Ci-3-alkyl,

C3-8-cycloalkenyl, sulfonyl, aminosulfonyl, sulfonylamino, Ci-4-alkyl optionally substituted by amino or hydroxyl or by 1 to 3 halogen, aryl and heteroaryl; and

m, X¹, R², R⁴, R⁵, R¹⁸ and R²⁰ are as defined in any one of the preceding claims.

32. The compound of claim 1 characterized by formula (VII_a) or (VI¾,),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

m, q, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁵ are as defined in any one of the preceding claims.

33. The compound of claim 1 characterized by formula (VIII),

(VIII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

r is 0, 1, 2 or 3;

1 2 4 5 18 20

m, X , R , R , R , R and R are as defined in any one of the preceding claims.

34. The compound of claim 1 characterized by formula (VIII_a) or (Vlll_b),

(Villa)

(Vlllb)

or a pharmaceutically acceptable salt or prodrug thereof, wherein m, r, X¹, R², R⁴, R⁵, R¹⁸, R²⁰ and R²⁶ are as defined in any one of the preceding claims.

35. The compound of claim 1 characterized by formula (IX),

(IX)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n is 0, 1 or 2;

X⁴ is NH, O or S; and

m, X¹, L and R¹ to R⁵ are as defined in any one of the preceding claims. 36. The compound of claim 1 characterized by formula (X),

(X)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

n is 0, 1 or 2;

X⁵ is NH, O or S; and

m, X¹, L and R¹ to R⁵ are as defined in any one of the preceding claims.

(XI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein n, m, X¹, L and R¹ to R⁵ are as defined in any one of the preceding claims.

38. The compound of claim 1 characterized by formula (XII),

(XII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

30 31 32

R , R , and R^Ji are independently selected from hydrogen, halogen, carbonitrile, -C(0)N(R R³⁴), -N(R R³⁴), -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, - C(0)R ^5b, C_2-4-acyl, C₂-4-acylamino, hydroxyl, -0(Ci_-8-alkyl), -C(0)OR³⁵, sulfonyl, aminosulfonyl, Ci-g-alkyl, C2-8-alkenyl, C2-8-alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl, wherein

wherein m, X¹, L, and R² to R⁵ are as defined in any one of the preceding claims.

39. The compound of claim 38, wherein R³⁰ is selected from hydrogen, halogen, - NR R³⁴, -NHC(0)NR R³⁴, -NHC(0)OR³⁵, -NHC(0)R ^5b, C₂-4-acylamino, -0(Ci_-4-alkyl) and Ci-4-alkyl, wherein R and R are independently selected from H, Ci-4-alkyl, and heteroaryl, and wherein R³⁵ and R ^5b are independently selected from H and Ci-4-alkyl, and wherein each alkyl, acylamino or heteroaryl is optionally substituted by 1 to 5 groups independently selected from halogen, hydroxyl, -N(R^sR^l) in which R^s and R^l are independently selected from hydrogen and Ci-3-alkyl, -0(Ci-3-alkyl), carbonitrile, C3-8-cycloalkyl, Ci-4-alkyl, heterocycloalkyl, aryl, heteroaryl, and (Ci-4-alkyl)-R^u in which R^u is selected from hydroxyl, amino and halogen.

40. The compound of claim 38 or 39, wherein R³¹ and R³² are each independently hydrogen.

41. The compound of claim 1 characterized by formula (XIV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein

s is 0, 1, 2 or 3;

m, X¹, R², R⁴, R⁵ and R³⁰ are as defined in any one of the preceding claims.

42. The compound of claim 1 characterized by formula (XV),

or a pharmaceutically acceptable salt or prodrug thereof, wherein s, R⁴, R⁵, R¹⁶, R¹⁷, R³⁰ and R³⁶ are as defined in any one of the preceding claims.

43. The compound of claim 1 characterized by formula (XV a) or formula (XVb),

44. The compound of claim 1 characterized by formula (XVI),

or a pharmaceutically acceptable salt or prodrug thereof, wherein q, R⁴, R⁵, R¹⁶ to R¹⁸, R and R²⁵ are as defined in any one of the preceding claims.

45. The compound of claim 1 characterized by formula (XIV a) or formula (XlVb),

46. A compound selected from the group consisting of:

Compound 1 : (lR,2R)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)benzo[d]thiazol-2- yl)amino)cy clohexan- 1 -ol

Compound 2: (l S,2S)-2-({6-[(2-aminopyridin-4-yl)methoxy]-l ,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 3 : (1 R,2R)-2-[(6- { lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy } -1 ,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol

Compound 4: (lR,2R)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l ,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 5 : (l S,2S)-2-({6-[(2-amino-3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 6: (l S,2S)-2-[(6- {[2-(methylamino)pyridin-4-yl]methoxy} -l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol Compound 7: N-cyclohexyl-6-(pyridin-4-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 8: N-cyclohexyl-6-(pyridin-3-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 9: N-cyclohexyl-6-(l,3-thiazol-4-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 10: N-cyclohexyl-6-(pyridin-2-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 11 : N-cyclohexyl-6-(pyrazin-2-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 12: N-cyclohexyl-6-(pyrimidin-4-ylmethoxy)-l,3-benzothiazol-2-amine

Compound 13: N-cyclohexyl-6-(l,3-thiazol-2-ylmethoxy)-l,3-benzothiazol-2-amine Compound 14: N-cyclohexyl-6-(l,3-thiazol-5-ylmethoxy)-l,3-benzothiazol-2-amine Compound 15: 6-[(2-aminopyridin-4-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 16: 6-[(6-chloropyrazin-2-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 17: 6-[(5-chloropyridin-3-yl)methoxy]-N-cyclohexyl-l,3-benzothiazol-2-amine Compound 18: N-cyclohexyl-6-[(2-methylpyridin-4-yl)methoxy]-l,3-benzothiazol-2-amine Compound 19 : 4-( { [2-(cy clohexylamino)- 1 ,3 -benzothiazol-6-y 1] oxy } methy 1)-N- methylpyridine-2-carboxamide

Compound 20: N-cyclohexyl-6-[(3-methylpyridin-4-yl)methoxy]-l,3-benzothiazol-2-amine Compound 21 : 5-({[2-(cyclohexylamino)-l,3-benzothiazol-6-yl]oxy }methyl)-N- methylpyridine-2-carboxamide

Compound 25: (lS,2S)-2-({6-[(3-chloropyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 26: N-cyclohexyl-6-{lH-pyrrolo[2,3-b]pyridin-4-ylmethoxy}-l,3-benzothiazol-2- amine

Compound 29: (lR,2S)-l-({6-[(2-aminopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl}amino)-2,3-dihydro-lH-inden-2-ol Compound 30: (lS,2S)-2-({6-[(3-bromopyridin-4-yl)methoxy]-l,3-benzothiazol-2- yl } amino)cy clohexan- 1 -ol

Compound 37: (lR,2R)-2-{[6-({3-chloro-lH-pyrrolo[2,3-b]pyridin-4-yl}methoxy)-l,3- benzothiazol-2-yl]amino}cyclohexan-l-ol

Compound 42: N-cyclohexyl-6-{[2-(methylamino)pyridin-4-yl]methoxy}-l,3-benzothiazol- 2-amine

Compound 43: (lR,2R)-2-[(6-{[2-(methylamino)pyridin-4-yl]methoxy}-l,3-benzothiazol-2- yl)amino] cy clohexan- 1 -ol

Compound 44: (lR,2R)-2-[(6-{[2-amino-3-(trifluoromethoxy)pyridin-4-yl]methoxy}-l,3- benzothiazol-2-yl)amino] cy clohexan- 1 -ol

Compound 46: (lR,2R)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4- yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol Compound 47: (lS,2S)-2-((6-((2-amino-3-(trifluoromethyl)pyridin-4- yl)methoxy)benzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 48: (lR,2R)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 49: (1 S,2S)-2-((6-((2-amino-3-chloropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 54: (lS,2S)-2-((6-((2-amino-3-fluoropyridin-4-yl)methoxy)-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 56: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-yl)amino]pyrimidin- 4-y 1 } methoxy )- 1 ,3 -benzothiazol-2-y 1] amino } cy clohexan- 1 -ol

Compound 58: (lS,2S)-2-{[4-methoxy-6-({2-[(l,2-oxazol-4-yl)amino]pyrimidin-4- yl }methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

Compound 59: (lS,2S)-2-{[4-methoxy-6-({2-[(lH-pyrazol-4-yl)amino]pyrimidin-4- yl }methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

Compound 60: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-l,2,3-triazol-4- yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2-yl]amino}cyclohexan-l-ol

Compound 61 : 6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine

Compound 62: 6-((2-aminopyrimidin-4-yl)methoxy)-N-(3,3-difluorocyclohexyl)-4- methoxybenzo[d]thiazol-2-amine Compound 63 : 6-((2-aminopyrimidin-4-yl)methoxy)-N-(4,4-difluorocy clohexyl)-4- methoxybenzo [d]thiazol-2-amine

Compound 66: (lS,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-4-methoxybenzo[d]thiazol- 2-yl)amino)cy clohexan- 1 -ol

Compound 68: l-{4-[({2-[(3,3-difluorocyclohexyl)amino]-4-methoxy-l,3-benzothiazol-6- yl } oxy)methyl]pyridin-2-yl} -3-methylurea

Compound 69: (1 S,2S)-2-((6-((2-aminopyrimidin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-yl)amino)cyclohexan-l-ol

Compound 72: N-(4-{[(2-{[(lR,2R)-2-hydroxycyclohexyl]amino}-4-methoxy-l,3- benzothiazol-6-yl)oxy] methyl }pyridin-2-yl)acetamide

Compound 74: (lS,2S)-2-(6-((2-amino-3-fluoropyridin-4-yl)methoxy)-7-chloro-4- methoxybenzo[d]thiazol-2-ylamino)cyclohexanol

Compound 77: (lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-l,2,3-triazol-4- yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2-yl]amino}cyclohexan-l-ol

Compound 78: (lS,2S)-2-{[7-chloro-4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3- yl)amino]pyrimidin-4-yl}methoxy)-l,3-benzothiazol-2-yl]amino}cyclohexan-l-ol Compound 79: Methyl 4-((2-((lS,2S)-2-hydroxycyclohexylamino)-4-methoxybenzo[d] thiazol-6-yloxy)methyl)pyridin-2-ylcarbamate

Compound 80: l-(4-((2-((lS,2S)-2 -hydroxy cy clohexylamino)-4-methoxybenzo[d]thiazol-6- yloxy)methyl)pyridin-2-yl)-3-methylurea

Compound 82: (lS,2S)-2-{[4-methoxy-6-({2-[(l-methyl-lH-pyrazol-3-yl)amino]pyridin-4- yl }methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

Compound 83: (lS,2S)-2-{[4-methoxy-6-({2-[(2-methylpyrimidin-4-yl)amino]pyridin-4- yl }methoxy)- 1 ,3-benzothiazol-2-yl] amino} cy clohexan- 1 -ol

and

and the pharmaceutically acceptable salts and prodrugs thereof.

47. The compound of any one of the preceding claims having an inhibitory activity (measured as IC50 value) against CSF-IR of less than 200 nM.

48. The compound of any one of the preceding claims which is selective for CSF-IR over PDGFR by a value of at least 5 times, and/or which is selective for CSF-IR over PDGFRa by a value of at least 10 times, and/or which is selective for CSF-IR over c-KIT by a value of at least 20 times, and/or which is selective for CSF-IR over FLT3 by a value of at least 200 times.

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, and at least one pharmaceutically acceptable excipient.

50. The pharmaceutical composition of claim 49 comprising a further active agent selected from the group consisting of anti-proliferative agents, anti-inflammatory agents, anti- angiogenic agents, chemotherapeutic agents and immunotherapeutic agents.

51. A compound according to any one of claims 1 to 48, or a pharmaceutical composition according to claim 49 or claim 50, for use in therapy.

52. A method for treating a CSF-1R mediated disease in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 48.

53. The method of claim 52, wherein the CSF-1R mediated disease is selected from cancer, a bone disorder, an inflammatory disorder, and a neurological disorder.

54. The method of claim 52 or claim 53, wherein the CSF-1R mediated disease is characterised by overexpression of CSF-1R, by aberrant CSF-1R signalling, by overexpression of CSF-1 and/or IL-34, and/or by mutations in the CSF-1R gene.

55. The method of claim 53 or claim 54, wherein the CSF-1R 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).

56. The method of any one of claims 53 to 55, for treating a subject diagnosed as having a cancer or being at risk of developing a cancer.

57. The method of claim 53 or claim 54, wherein the CSF-1R 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 such as HIV encephalitis, Alzheimer's disease and ALS.

58. The method of claim 53 or claim 54, wherein the CSF-IR mediated disease is a bone disorder selected from osteoporosis, osteoarthritis, periodontitis, periprosthetic osteolysis, and Paget' s disease.

59. The method of any one of claims 52 to 58, comprising administering said compound in combination with another therapeutic intervention for said CSF-IR mediated disease.

60. A compound according to any one of claims 1 to 48, for use in a method as defined in any one of claims 52 to 59.

61. Use of a compound according to any one of claims 1 to 48 in the manufacture of a medicament for use in a method as defined in any one of claims 52 to 59.