# Patent

## Title
3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1H-pyrrolo[2,3-C]pyridine derivatives as NIK inhibitors for the treatment of cancer

## Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national stage of PCT Application No. PCT/EP2014/058361, filed Apr. 24, 2014, which claims priority for EPO Patent Application No. 13165167.1, filed Apr. 24, 2013 and EPO Patent Application No. 13186116.3, filed Sep. 26, 2013, all of which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer and inflammatory disorders. Nuclear factor-kappa B (NF-κB) is a transcription factor regulating the expression of various genes involved in the immune response, cell proliferation, apoptosis, and carcinogenesis. NF-κB dependent transcriptional activation is a tightly controlled signaling pathway, through sequential events including phosphorylation and protein degradation. NIK is a serine/threonine kinase which regulates NF-κB pathway activation. There are two NF-κB signaling pathways, the canonical and the non-canonical. NIK has a role in both but has been shown to be indispensable for the non-canonical signaling pathway where it phosphorylates IKKα, leading to the partial proteolysis of p100; liberating p52 which then heterodimerizes with RelB, translocates to the nucleus and mediates gene expression. The non-canonical pathway is activated by only a handful of ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin β receptor ligands and TNF-related weak inducer of apoptosis (TWEAK) and NIK has been shown to be required for activation of the pathway by these ligands. Because of its key role, NIK expression is tightly regulated. Under normal non-stimulated conditions NIK protein levels are very low, this is due to its interaction with a range of TNF receptor associated factors (TRAF), which are ubiquitin ligases and result in degradation of NIK. It is believed that when the non-canonical pathway is stimulated by ligands, the activated receptors now compete for TRAFs, dissociating the TRAF-NIK complexes and thereby increasing the levels of NIK. (Thu and Richmond, Cytokine Growth F. R. 2010, 21, 213-226)
Research has shown that blocking the NF-κB signaling pathway in cancer cells can cause cells to stop proliferating, to die and to become more sensitive to the action of other anti-cancer therapies. A role for NIK has been shown in the pathogenesis of both hematological malignancies and solid tumours.
The NF-κB pathway is dysregulated in multiple myeloma due to a range of diverse genetic abnormalities that lead to the engagement of the canonical and non-canonical pathways (Annuziata et al. Cancer Cell 2007, 12, 115-130; Keats et al. ibid 2007, 12, 131-144; Demchenko et al. Blood 2010, 115, 3541-3552). Myeloma patient samples frequently have increased levels of NIK activity. This can be due to chromosomal amplification, translocations (that result in NIK proteins that have lost TRAF binding domains), mutations (in the TRAF binding domain of NIK) or TRAF loss of function mutations. Researchers have shown that myeloma cell lines can be dependent on NIK for proliferation; in these cell lines if NIK activity is reduced by either shRNA or compound inhibition, this leads to a failure in NF-κB signaling and the induction of cell death (Annuziata 2007).
In a similar manner, mutations in TRAF and increased levels of NIK have also been seen in samples from Hodgkin lymphoma (HL) patients. Once again proliferation of cell lines derived from HL patients is susceptible to inhibition of NIK function by both shRNA and compounds (Ranuncolo et al. Blood First Edition Paper, 2012, DOI 10.1182/blood-2012-01-405951).
NIK levels are also enhanced in adult T cell leukemia (ATL) cells and targeting NIK with shRNA reduced ATL growth in vivo (Saitoh et al. Blood 2008, 111, 5118-5129). It has been demonstrated that the API2-MALT1 fusion oncoprotein created by the recurrent translocation t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation (due to loss of TRAF binding region). The presence of this truncated NIK leads to constitutive non-canonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Thus NIK inhibitors could represent a new treatment approach for refractory t(11;18)-positive MALT lymphoma (Rosebeck et al. Science 2011, 331, 468-472).
NIK aberrantly accumulates in diffuse large B-cell lymphoma (DLBCL) cells due to constitutive activation of B-cell activation factor (BAFF) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand. NIK accumulation in human DLBCL cell lines and patient tumor samples suggested that constitutive NIK kinase activation is likely to be a key signaling mechanism involved in abnormal lymphoma tumor cell proliferation. Growth assays showed that using shRNA to inhibit NIK kinase protein expression in GCB- and ABC-like DLBCL cells decreased lymphoma cell growth in vitro, implicating NIK-induced NF-κB pathway activation as having a significant role in DLBCL proliferation (Pham et al. Blood 2011, 117, 200-210).
As mentioned a role of NIK in tumour cell proliferation is not restricted to hematological cells, there are reports that NIK protein levels are stabilised in some pancreatic cancer cell lines and as seen in blood cells proliferation of these pancreatic cancer lines are susceptible to NIK siRNA treatment (Nishina et al. Biochem. Bioph. Res. Co. 2009, 388, 96-101). Constitutive activation of NF-κB, is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines, including elevated NIK protein levels in specific lines (Yamamoto et al. Cancer Sci. 2010. 101, 2391-2397). In melanoma tumours, tissue microarray analysis of NIK expression revealed that there was a statistically significant elevation in NIK expression when compared with benign tissue. Moreover, shRNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model (Thu et al. Oncogene 2011, 1-13). A wealth of evidence showed that NF-κB is often constitutively activated in non-small cell lung cancer tissue specimens and cell lines. Depletion of NIK by RNAi induced apoptosis and affected efficiency of anchorage-independent NSCLC cell growth.
In addition research has shown that NF-κB controls the expression of many genes involved in inflammation and that NF-κB signalling is found to be chronically active in many inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, sepsis and others. Thus pharmaceutical agents capable of inhibiting NIK and thereby reducing NF-κB signaling pathway can have a therapeutic benefit for the treatment of diseases and disorders for which over-activation of NF-κB signaling is observed.
Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and it has been shown that Nlrp12 deficient mice were highly susceptible to colitis and colitis-associated colon cancer. In this context work showed that NLRP12 functions as a negative regulator of the NF-κB pathway through its interaction and regulation of NIK and TRAF3, and as a checkpoint of critical pathways associated with inflammation and inflammation-associated tumorigenesis (Allen et al. Immunity 2012, 36, 742-754).
Tumor necrosis factor (TNF)-α, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. In a series of experiments in colonic epithelial cells and mouse embryonic fibroblasts, TNF-α mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-κB activation, leading to increased nuclear RelB and p52. TNF-α induced the ubiquitination of TRAFs, which interacts with NIK, leading to increased levels of phospho-NIK (Bhattacharyya et al. J Biol. Chem. 2011, 285, 39511-39522).
Inflammatory responses are a key component of chronic obstructive pulmonary disease (COPD) as such it has been shown that NIK plays a key role in exacerbating the disease following infection with the Gram-negative bacterium nontypeable Hemophilus influenza (Shuto et al. PNAS 2001, 98, 8774-8779). Likewise cigarette smoke (CS) contains numerous reactive oxygen/nitrogen species, reactive aldehydes, and quinones, which are considered to be some of the most important causes of the pathogenesis of chronic inflammatory lung diseases, such as COPD and lung cancer. Increased levels of NIK and p-IKKα have been observed in peripheral lungs of smokers and patients with COPD. In addition it has been shown that endogenous NIK is recruited to promoter sites of pro-inflammatory genes to induce post-translational modification of histones, thereby modifying gene expression profiles, in response to CS or TNFα (Chung et al 2011). A shRNA screen was used in an in vitro model of oxidative stress induced cell death (as a model of COPD) to interrogate a human druggable genome siRNA library in order to identify genes that modulate the cellular response to stress. NIK was one of the genes identified in this screen as a potential new therapeutic target to modulate epithelial apoptosis in chronic lung diseases (Wixted et al. Toxicol. In Vitro 2010, 24, 310-318).
Diabetic individuals can be troubled by a range of additional manifestations associated with inflammation. One such complication is cardiovascular disease and it has been shown that there are elevated levels of p-NIK, p-IKK-α/β and p-IκB-α in diabetic aortic tissues (Bitar et al. Life Sci. 2010, 86, 844-853). In a similar manner, NIK has been shown to regulate proinflammatory responses of renal proximal tubular epithelial cells via mechanisms involving TRAF3. This suggests a role for NF-κB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium (Zhao et al. Exp. Diabetes Res. 2011, 1-9). The same group has shown that NIK plays a critical role in noncanonical NF-κB pathway activation, induced skeletal muscle insulin resistance in vitro, suggesting that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes (Choudhary et al. Endocrinology 2011, 152, 3622-3627).
NF-κB is an important component of both autoimmunity and bone destruction in rheumatoid arthritis (RA). Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-κB ligand-stimulated osteoclastogenesis. Aya et al. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIK in murine models of inflammatory arthritis using Nik−/− mice. The serum transfer arthritis model was initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik−/− mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik−/− mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2−/− mice conferred susceptibility to AIA, while transfer of Nik−/− cells did not. Nik−/− mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2g7. The same group used transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), to demonstrate that constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli (Yang et al. PLoS One 2010, 5, 1-9, e15383). Thus this group concluded that NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.
It has also been hypothesized that manipulating levels of NIK in T cells may have therapeutic value. Decreasing NIK activity in T cells might significantly ameliorate autoimmune and alloresponses, like GVHD (Graft Versus Host Disease) and transplant rejection, without crippling the immune system as severely as do inhibitors of canonical NF-κB activation.
WO2010/042337 describes novel 6-azaindole aminopyrimidine derivatives having NIK inhibitory activity.


DESCRIPTION OF THE INVENTION
The present invention concerns novel compounds of Formula (I):




and tautomers and stereoisomeric forms thereof, wherein

R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;

R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het1, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;

Het1 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

or Het3 is 2-oxo-3-pyrrolidinyl optionally substituted with one C1-4alkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

Het4 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het5 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or

R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl; —OC1-4alkyl; and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH;

C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein

R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or

R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;

R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of

(i) fluoro,

(ii) —NR8aR8b,

(iii) —NR8cC(═O)R8d,

(iv) —NR8cC(═O)NR8aR8b,

(v) —NR8cC(═O)OR8e,

(vi) —NR8cS(═O)2NR8aR8b,

(vii) —NR8cS(═O)2R8d,

(viii) —OR8f,

(ix) —OC(═O)NR8aR8b,

(x) —C(═O)NR8aR8b,

(xi) —SR8e,

(xii) —S(O)2R8d, and

(xiii) —S(O)2NR8aR8b; wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;

R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;

R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of





Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het11 is selected from the group of





Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient.
Additionally, the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use as a medicament, and to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.
In a particular embodiment, the invention relates to a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, for use in the treatment or in the prevention of a haematological malignancy or solid tumour.
In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.
The invention also relates to the use of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, in combination with an additional pharmaceutical agent for use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.
Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof.
The invention also relates to a product comprising a compound of Formula (I), a pharmaceutically acceptable salt, or a solvate thereof, and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of cancer, inflammatory disorders, autoimmune disorders, and metabolic disorders such as diabetes and obesity.
Additionally, the invention relates to a method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, or a solvate thereof, as defined herein, or a pharmaceutical composition or combination as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
The chemical names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by IUPAC (International Union of Pure and Applied Chemistry) using the commercial MDL Isis AutoNom software (product version 2.5). In case of tautomeric forms, the name of the depicted form of the structure was generated. However it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.
The prefix ‘Cx-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a C1-6alkyl group contains from 1 to 6 carbon atoms, a C3-6cycloalkyl group contains from 3 to 6 carbon atoms, a C1-4alkoxy group contains from 1 to 4 carbon atoms, and so on.
The term ‘halo’ or ‘halogen’ as used herein represents fluoro, chloro, bromo and iodo.
The term ‘C1-4alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term ‘C1-6alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and n-pentyl, n-hexyl, 2-methylbutyl and the like.
The term ‘C2-6alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 2 to 6 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl and the like.
The term ‘C1-4alkoxy’ or ‘C1-4alkyloxy’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms bonded to an oxygen atom such as methoxy, ethoxy, isopropoxy and the like. Similar, the term ‘C1-6alkoxy’ or ‘C1-6alkyloxy’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms bonded to an oxygen atom.
The term ‘C3-6cycloalkyl’ as used herein as a group or part of a group represents cyclic saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. “Stable compound” is meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
The term C1-6alkyl substituted with one or more substituents as used herein as a group or part of a group refers to a C1-6alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with another group. The term therefore includes monosubstitutedC1-6alkyl and also polysubstitutedC1-6alkyl. There may be one, two, three or more hydrogen atoms replaced with a substituent, so the fully or partially substituted C1-6alkyl may have one, two, three or more substituents. Examples of such groups wherein the substituent is for example, fluoro include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl and the like.
In general, whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
The term optionally substituted, for example as used in optionally substituted C1-6alkyl, means that, unless otherwise is indicated or is clear from the context, the group is unsubstituted or substituted by one or more, for example 1, 2 or 3, substituents.
In a particular embodiment, the expression “C1-6alkyl optionally substituted with Het5” is limited to “C1-6alkyl optionally substituted with one Het5”. In a particular embodiment, the expression “C1-6alkyl optionally substituted with Het9” is limited to “C1-6alkyl optionally substituted with one Het5”.
C(O) or C(═O) represents a carbonyl moiety.
S(O)2 represents a sulfonyl moiety.
Substituents covered by the term “Hetx”, “heterocyclyl” or “heteroaryl” may be attached to the remainder of the molecule of Formula (I) through any available ring carbon or heteroatom as appropriate, if not otherwise specified.
The skilled person will realize that the group ‘C2-4alkyloxyC1-4alkyl’ which is present e.g. in the definition of R6b, is attached to the remainder of the molecule of Formula (I) via the C2-4alkyl: i.e. —C2-4alkyloxyC1-4alkyl. Similar, C2-4alkylNR6xR6y which is present e.g. in the definition of R6b, is attached to the remainder of the molecule of Formula (I) via the C2-4alkyl: i.e. —C2-4alkylNR6xR6y.
Whenever substituents are represented by chemical structure, “ - - - ” represents the bond of attachment to the remainder of the molecule of Formula (I).
When any variable occurs more than one time in any constituent, each definition is independent.
When any variable occurs more than one time in any formula (e.g. formula (I)), each definition is independent.
The term “subject” as used herein, refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The term “treatment”, as used herein, is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
The term “compounds of the invention” as used herein, is meant to include the compounds of Formula (I), and the salts and solvates thereof.
As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.
Hereinbefore and hereinafter, the term “compound(s) of Formula (I)” is meant to include the stereoisomers thereof and the tautomeric forms thereof.
The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.
Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.
Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.
Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.
The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers. Thus, when a compound of Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds according to Formula (I) may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above Formula (I) are intended to be included within the scope of the present invention.
It follows that a single compound may exist in both stereoisomeric and tautomeric form.
The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with one Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

Het4 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het5 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or

R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl; —OC1-4alkyl; and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein

R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or

R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;

R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of

(i) fluoro,

(ii) —NR8aR8b,

(iii) —NR8cC(═O)R8d,

(iv) —NR8cC(═O)NR8aR8b,

(v) —NR8cC(═O)OR8e,

(vi) —NR8cS(═O)2NR8aR8b,

(vii) —NR8cS(═O)2R8d,

(viii) —OR8f,

(ix) —OC(═O)NR8aR8b,

(x) —C(═O)NR8aR8b,

(xi) —SR8e,

(xii) —S(O)2R8d, and

(xiii) —S(O)2NR8aR8b; wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;

R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;

R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of





Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het11 is selected from the group of





Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;

R4 is hydrogen;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; and —OC2-6alkyl substituted with one —OC1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, —OC1-4alkyl, and —NHC1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (iii), (viii), (ix), (x), and (xii); wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;

R8d is C1-6alkyl;

R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of





Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;

R4 is hydrogen;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; and —OC2-6alkyl substituted with one —OC1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, —OC1-4alkyl, and —NHC1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (viii), (ix), (x), and (xii); wherein

R8a, R8b, and R8f are each independently selected from the group of hydrogen; C1-6alkyl; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;

R8d is C1-6alkyl;

R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of





Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;

R4 is hydrogen;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; and —OC2-6alkyl substituted with one —OC1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, —OC1-4alkyl, and —NHC1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (viii), (ix), (x), and (xii); wherein

R8a, R8b, and R8f are each independently selected from the group of hydrogen; C1-6alkyl; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;

R8d is C1-6alkyl;

R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of





Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —OC1-4alkyl and C3-6cycloalkyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het1; Het2; and phenyl;

R2c and R2d are each independently selected from C1-4alkyl;

Het1 is a heterocyclyl selected from the group of piperidinyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het2 is a heteroaryl selected from the group of thiazolyl, oxazolyl, isoxazolyl and pyridinyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydrofuranyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl; or Het3 is 2-oxo-3-pyrrolidinyl substituted with one C1-4alkyl on the nitrogen atom;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is hydrogen;

R5 is selected from the group of hydrogen; C1-6alkyl; and —C(═O)—NR5cR5d; wherein

R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one —OC1-4alkyl;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —O—C1-6alkyl; and —OC2-6alkyl substituted with one —OC1-4alkyl;

R7 is selected from the group of hydrogen, and C1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C1-4alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (ii), (iii), (viii), (x), (xii); wherein

R8a, R8b, R8c, and R8f are each independently selected from the group of hydrogen; C1-6alkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;

R8d is C1-6alkyl;

R8g and R8h are each independently selected from C1-4alkyl;

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, —C(═O)—C1-4alkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; or Het9 is





Het12 is 1-piperazinyl which may be optionally substituted with one C1-4alkyl substituent;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —OC1-4alkyl and C3-6cycloalkyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2 and phenyl; in particular R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —OC1-4alkyl and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

R2c and R2d are each independently selected from C1-4alkyl;

Het2 is a heteroaryl selected from the group of thiazolyl, oxazolyl, isoxazolyl and pyridinyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is hydrogen;

R5 is selected from the group of hydrogen; C1-6alkyl; and —C(═O)—NR5cR5d; wherein

R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one —OC1-4alkyl;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one NH2; and —OC2-6alkyl substituted with one —OC1-4alkyl;

R7 is selected from the group of hydrogen, and C1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C1-4alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (ii), (viii), (x), (xii); wherein

R8a, R8b, and R8f are each independently selected from the group of hydrogen; C1-6alkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;

R8d is C1-6alkyl;

R8g and R8h are each independently selected from C1-4alkyl;

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, —C(═O)—C1-4alkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; or Het9 is





Het12 is 1-piperazinyl which may be optionally substituted with one C1-4alkyl substituent;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R3 is selected from the group of hydrogen; C3-6cycloalkyl; and C1-4alkyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen; halogen; C1-6alkyl; and —OC1-6alkyl;
R7 is hydrogen;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl;
R3 is selected from the group of hydrogen; C3-6cycloalkyl; and C1-4alkyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of halogen; C1-6alkyl; and —OC1-6alkyl; in particular halogen;
R7 is hydrogen;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of methyl; and methyl substituted with one fluoro substituent;
R2 is selected from the group of methyl and cyclopropyl;
or R1 and R2 together with the carbon atom to which they are attached form a cyclopentyl;
R3 is selected from the group of hydrogen; cyclopropyl; and methyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen; fluoro; chloro; methyl; and methoxy;
R7 is hydrogen;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-4alkyl substituted with one or more —OR8f substituents;
R8f is CH3;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, cyclopropyl, C1-4alkyl substituted with 3 fluoro substituents, and C1-4alkyl substituted with one C3-6cycloalkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one methyl;

R9 is hydrogen;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of methyl; and methyl substituted with one fluoro substituent;
R2 is selected from the group of methyl and cyclopropyl;
R3 is selected from the group of hydrogen; cyclopropyl; and methyl;
R4 is hydrogen;
R5 is hydrogen; R6 is selected from the group of fluoro; chloro; methyl; and methoxy; in particular R6 is selected from fluoro and chloro; more in particular R6 is selected from fluoro;
R7 is hydrogen;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-4alkyl substituted with one or more —OR8f substituents;
R8f is CH3;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, cyclopropyl, C1-4alkyl substituted with 3 fluoro substituents, and C1-4alkyl substituted with one cyclopropyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one methyl;

R9 is hydrogen;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; C3-6cycloalkyl; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

Het4 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or

R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein

R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or

R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;

R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of

(i) fluoro,

(ii) —NR8aR8b,

(iii) —NR8cC(═O)R8d,

(iv) —NR8cC(═O)NR8aR8b,

(v) —NR8cC(═O)OR8e,

(vi) —NR8cS(═O)2NR8aR8b,

(vii) —NR8cS(═O)2R8d,

(viii) —OR8f,

(ix) —OC(═O)NR8aR8b,

(x) —C(═O)NR8aR8b,

(xi) —SR8e,

(xii) —S(O)2R8d, and

(xiii) —S(O)2NR8aR8b; wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;

R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het11 is selected from the group of





R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het1, Het2 and phenyl; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein

the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;

Het1 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

Het4 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or

R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein

R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or

R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;

R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of

(i) fluoro,

(ii) —NR8aR8b,

(iii) —NR8cC(═O)R8d,

(iv) —NR8cC(═O)NR8aR8b,

(v) —NR8cC(═O)OR8e,

(vi) —NR8cS(═O)2NR8aR8b,

(vii) —NR8cS(═O)2R8d,

(viii) —OR8f,

(ix) —OC(═O)NR8aR8b,

(x) —C(═O)NR8aR8b,

(xi) —SR8e,

(xii) —S(O)2R8d, and

(xiii) —S(O)2NR8aR8b; wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;

R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het11 is selected from the group of





and

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het2;
Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; in particular C3-6cycloalkyl; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, and Het4; and —C(═O)—NR5cR5d; wherein

R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;

Het4 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or

R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein

R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or

R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;

R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R7 is selected from the group of hydrogen, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of

(i) fluoro,

(ii) —NR8aR8b,

(iii) —NR8cC(═O)R8d,

(iv) —NR8cC(═O)NR8aR8b,

(v) —NR8cC(═O)OR8e,

(vi) —NR8cS(═O)2NR8aR8b,

(vii) —NR8cS(═O)2R8d,

(viii) —OR8f,

(ix) —OC(═O)NR8aR8b,

(x) —C(═O)NR8aR8b,

(xi) —SR8e,

(xii) —S(O)2R8d, and

(xiii) —S(O)2NR8aR8b; wherein

R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;

R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;

wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het11 is selected from the group of





and

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het2; wherein
Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, and isothiazolyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl group;
R3 is selected from the group of hydrogen;
R4 is selected from the group of hydrogen;
R5 is selected from the group of hydrogen;
R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH;
R7 is selected from the group of hydrogen; wherein
R8 is selected from the group of hydrogen; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(i) fluoro,
(ii) —NR8aR8b,
(iii) —NR8cC(═O)R8d,
(iv) —NR8cC(═O)NR8aR8b,
(v) —NR8cC(═O)OR8e,
(vi) —NR8cS(═O)2NR8aR8b,
(vii) —NR8cS(═O)2R8d,
(viii) —OR8f,
(ix) —OC(═O)NR8aR8b,
(x) —C(═O)NR8aR8b,
(xi) —SR8e,
(xii) —S(O)2R8d, and
(xiii) —S(O)2NR8aR8b; wherein
R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
R8d is selected from the group of C1-6alkyl;
R8e is selected from the group of C1-6alkyl;
wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;
and
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; and
R9 is hydrogen or C1-4alkyl;
and the pharmaceutically acceptable salts and the solvates thereof.
The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen and C1-4alkyl;
R2 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het1, Het2 and phenyl; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein

the phenyl group is optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;

Het1 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; cyano; and —C(═O)—NR5cR5d; wherein

R5c is selected from the group of hydrogen and C1-4alkyl;

R5d is selected from the group of C1-4alkyl; and C2-4alkyl substituted with one —OC1-4alkyl;

or R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one —OH; —C1-4alkyloxyC1-4alkyl; —C1-4alkyl-C(═O)—NR6aR6b; —OC1-4alkyl; and —OC2-4alkyl substituted with one —OH or —OC1-4alkyl; wherein

R6a is selected from hydrogen and C1-4alkyl; and

R6b is selected from hydrogen, C1-4alkyl and C2-4alkyloxyC1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-4alkyl optionally substituted with Het9; and C2-4alkyl substituted with one or more substituents independently selected from the group of

(ii) —NR8aR8b,

(viii) —OR8f, and

(x) —C(═O)NR8aR8b; wherein

R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen and C1-4alkyl;
R2 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; C3-6cycloalkyl; Het2; and phenyl; wherein

the phenyl group is optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; cyano; and —C(═O)—NR5cR5d; wherein

R5c is selected from the group of hydrogen and C1-4alkyl;

R5d is selected from the group of C1-4alkyl; and C2-4alkyl substituted with one —OC1-4alkyl;

or R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one —OH; —C1-4alkyloxyC1-4alkyl; —C1-4alkyl-C(═O)—NR6aR6b; —OC1-4alkyl; and —OC2-4alkyl substituted with one —OH or —OC1-4alkyl; wherein

R6a is selected from hydrogen and C1-4alkyl; and

R6b is selected from hydrogen, C1-4alkyl and C2-4alkyloxyC1-4alkyl;

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-4alkyl optionally substituted with Het9; and C2-4alkyl substituted with one or more substituents independently selected from the group of

(ii) —NR8aR8b,

(viii) —OR8f, and

(x) —C(═O)NR8aR8b; wherein

R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention relates in particular to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen and C1-4alkyl;
R2 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het2; wherein
the phenyl group is optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;

Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; in particular C3-6cycloalkyl; wherein

Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;

R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;

R5 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; cyano; and —C(═O)—NR5cR5d; wherein

R5c is selected from the group of hydrogen and C1-4alkyl;

R5d is selected from the group of C1-4alkyl; and C2-4alkyl substituted with one —OC1-4alkyl;

or R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;

R6 is selected from the group of hydrogen; halogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one —OH; —C1-4alkyloxyC1-4alkyl; —C1-4alkyl-C(═O)—NR6aR6b; —OC1-4alkyl; and —OC2-4alkyl substituted with one —OH or —OC1-4alkyl; wherein

R6a is selected from hydrogen and C1-4alkyl; and

R6b is selected from hydrogen, C1-4alkyl and C2-4alkyloxyC1-4alkyl;

R7 is selected from the group of hydrogen, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

R8 is selected from the group of hydrogen; Het8; C1-4alkyl optionally substituted with Het9; and C2-4alkyl substituted with one or more substituents independently selected from the group of

(ii) —NR8aR8b,

(viii) —OR8f, and

(x) —C(═O)NR8aR8b; wherein

R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;

and

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen or C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R6 is selected from the group of hydrogen; halogen; cyano; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C1-4alkyl substituted with one —OH; —C1-4alkyloxyC1-4alkyl; —C1-4alkyl-C(═O)—NR6aR6b; —OC1-4alkyl; and —OC2-4alkyl substituted with one —OH or —OC1-4alkyl; wherein

R6a is selected from hydrogen and C1-4alkyl; and

R6b is selected from hydrogen, C1-4alkyl and C2-4alkyloxyC1-4alkyl; and

R7 is hydrogen; or

R6 is hydrogen; and

R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein

R7a and R7b are each independently selected from hydrogen and C1-4alkyl;

and the pharmaceutically acceptable salts and the solvates thereof.

In an additional embodiment, the present invention relates to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen and C1-4alkyl;
R2 is selected from the group of hydrogen, C1-4alkyl, and Het2; wherein
Het2 is a heteroaryl selected from the group of thiazolyl, pyrazolyl, and imidazolyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl group;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen and halogen;
R7 is hydrogen;
R8 is selected from the group of hydrogen; C1-4alkyl optionally substituted with Het9; and C2-4alkyl substituted with a substituent selected from the group of
(ii) —NR8aR8b, and
(viii) —OR8f; wherein
R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; and
R9 is hydrogen or C1-4alkyl;
and the pharmaceutically acceptable salts and the solvates thereof.
In an additional embodiment, the present invention relates to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is selected from the group of hydrogen and C1-4alkyl;
R2 is selected from the group of hydrogen, C1-4alkyl, and Het2; wherein
Het2 is thiazolyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl group;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen and halogen;
R7 is hydrogen;
R8 is selected from the group of hydrogen; C1-4alkyl optionally substituted with Het9; and C2-4alkyl substituted with a substituent selected from the group of
(ii) —NR8aR8b, and
(viii) —OR8f; wherein
R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, tetrahydrofuranyl, and oxetanyl; and
R9 is hydrogen or C1-4alkyl;
and the pharmaceutically acceptable salts and the solvates thereof.
In an additional embodiment, the present invention relates to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is C1-4alkyl;
R2 is C1-4alkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl group;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen and halogen; in particular hydrogen and chloro; more in particular chloro;
R7 is hydrogen;
R8 is selected from the group of hydrogen; C1-4alkyl; and C2-4alkyl substituted with one —OR8f substituent; wherein
R8f is selected from the group of hydrogen and C1-4alkyl;
R9 is hydrogen;
and the pharmaceutically acceptable salts and the solvates thereof.
Another embodiment of the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein one or more of the following restrictions apply:
a) R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
in particular R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl;
b) R3 is selected from the group of hydrogen; C3-6cycloalkyl; and C1-4alkyl;
c) R4 is hydrogen;
d) R5 is hydrogen;
e) R6 is selected from the group of hydrogen; halogen; C1-6alkyl; and —OC1-6alkyl; in particular R6 is selected from the group of halogen; C1-6alkyl; and —OC1-6alkyl; more in particular R6 is halogen; even more in particular R6 is fluoro;
f) R7 is hydrogen;
g) R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
h) R8f is C1-4alkyl;
i) Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

j) Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

k) R9 is hydrogen.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 is selected from the group of hydrogen, methyl and thiazolyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R9 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 is selected from the group of C1-4alkyl and thiazolyl; in particular methyl and thiazolyl; more in particular thiazolyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 is methyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; R2 is selected from the group of hydrogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl and Het2.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is C1-4alkyl; R2 is selected from the group of C1-4alkyl and Het2.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is C1-4alkyl; R2 is selected from the group of C1-4alkyl and Het2; or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is C1-4alkyl; R2 is C1-4alkyl; or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is selected from the group of C1-4alkyl and C1-4alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl and Het2;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 is C1-4alkyl; R2 is selected from the group of C1-4alkyl and Het2; or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 is hydrogen; R4 is hydrogen; R5 is hydrogen; R7 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het2 is thiazolyl optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents; and
Het9 is selected from the group of morpholinyl, tetrahydrofuranyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het2 is thiazolyl; and
Het9 is selected from the group of morpholinyl, tetrahydrofuranyl and oxetanyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is hydrogen, halogen or C1-4alkyl; in particular hydrogen or halogen; more in particular hydrogen or chloro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is hydrogen, halogen, C1-4alkyl or —OC1-6alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl; in particular methyl;
R2 is C1-4alkyl; in particular methyl;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen or halogen;
R7 is hydrogen;
R9 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl; in particular methyl;
R2 is C1-4alkyl; in particular methyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is hydrogen or halogen; in particular hydrogen or chloro;
R7 is hydrogen;
R9 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is chloro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl;
R2 is C1-4alkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R6 is chloro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl;
R2 is C1-4alkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R6 is chloro, fluoro, methyl, or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl;
R2 is selected from the group of C1-4alkyl and C3-6cycloalkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R6 is chloro, fluoro, methyl, or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl;
R2 is selected from the group of C1-4alkyl and C3-6cycloalkyl;
R6 is chloro, fluoro, methyl, or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl; in particular R1 is methyl;
R2 is C3-6cycloalkyl; in particular R2 is cyclopropyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R6 is chloro, fluoro, methyl or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is C1-4alkyl; in particular R1 is methyl;
R2 is C3-6cycloalkyl; in particular R2 is cyclopropyl;
R6 is chloro, fluoro, methyl, or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 and R2 are other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 and R2 are not taken together.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R1 and R2 are taken together.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when R1 and R2 are taken together with the carbon atom to which they are attached form a C3-6cycloalkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is selected from the group of hydrogen; halogen; C1-6alkyl; and —OC1-6alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is selected from the group of halogen; C1-6alkyl; and —OC1-6alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is selected from the group of halogen and C1-6alkyl; in particular R6 is halogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is chloro, fluoro, methyl, or methoxy; in particular R6 is chloro, fluoro, or methyl; more in particular R6 is chloro or fluoro; even more in particular R6 is fluoro.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R6 is chloro, fluoro, methyl, or methoxy; and wherein R9 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8f is C1-6alkyl; in particular C1-4alkyl; more in particular methyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R8 is other than —C(═O)—NR8gR8h; —C(═O)—Het12; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents; in particular R8 is other than —C(═O)—NR8gR8h; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (viii), (ix), and (xii); in particular R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), and (viii); more in particular R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; C1-6alkyl substituted with one cyano; and C2-6alkyl substituted with one or more —OR8f substituents.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R6 is other than hydrogen; in particular R6 is halogen.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R8 is other than —C(═O)—NR8gR8h; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; in particular Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R8 is other than —C(═O)—NR8gR8h; —C(═O)—Het12; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; in particular Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R6 is other than hydrogen;

R8 is other than —C(═O)—NR8gR8h; —C(═O)—Het12; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; in particular Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; and C1-4alkyl;

R7 is hydrogen;

R8 is other than —C(═O)—NR8gR8h; —C(═O)—Het12; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents;

Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;

Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; in particular Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;

R9 is hydrogen.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, and C3-6cycloalkyl; —C(═O)—NR2cR2d; and C3-6cycloalkyl;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R6 is selected from the group of halogen; C1-6alkyl; and —OC1-6alkyl;

R9 is hydrogen.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is other than —C(═O)—NR8gR8h; —CH2—C(═O)NR8aR8b; and
C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is other than —C(═O)—NR8gR8h; —C(═O)—Het12; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more —C(═O)NR8aR8b substituents.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl; R9 is hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl; R9 is hydrogen; R6 is other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl; R9 is hydrogen; R6 is other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(ii) —NR8aR8b,
(viii) —OR8f.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R2 is selected from the group of hydrogen and C1-6alkyl;
R8 is selected from the group of hydrogen; C1-6alkyl; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(ii) —NR8aR8b,
(viii) —OR8f.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(ii) —NR8aR8b,
(viii) —OR8f,
R8a, R8b and R8f are each independently selected from the group of hydrogen and C1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, tetrahydrofuranyl and oxetanyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and
C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (viii), (ix), (x), and (xii).
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from hydrogen, CH3, —CH(CH3)2,




More in particular, R8 is selected from





In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from hydrogen, —CH(CH3)2,




In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from —CH(CH3)2,




In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8 is selected from CH3, —CH(CH3)2,




In an additional embodiment, the present invention relates to compounds of Formula (I) as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R1 is C1-4alkyl;
R2 is C1-4alkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl group;
R3 is hydrogen;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen and halogen; in particular hydrogen and chloro; more in particular chloro;
R7 is hydrogen;
R8 is selected from the group of from hydrogen, —CH(CH3)2,




R9 is hydrogen;

and the pharmaceutically acceptable salts and the solvates thereof.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl;
C3-6cycloalkyl; Het2; and phenyl; wherein the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;

or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.

In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2; and phenyl; wherein the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents; or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein Het3 is 2-oxo-3-pyrrolidinyl optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), and (xiii).
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, and C1-4alkyl substituted with one —OC1-4alkyl; provided that when Het8 is oxetanyl, then R3 is other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl; provided that when Het8 is oxetanyl, then R3 is other than hydrogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when Het8 is a heterocyclyl containing a N-atom, then said heterocyclyl is attached to the remainder of the molecule via a carbon atom, and is substituted on the N-atom.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein when Het9 is a heterocyclyl containing a N-atom, then said heterocyclyl is attached to the remainder of the molecule via a carbon atom, and is substituted on the N-atom.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, and C1-4alkyl substituted with one —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het1 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is hydrogen or halogen.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl; and —OC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R7 is selected from the group of hydrogen, C1-4alkyl, —OC1-4alkyl, and —NHC1-4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I) and the pharmaceutically acceptable addition salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH and —OC1-4alkyl; and C3-6cycloalkyl;
R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl.
All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.
In an embodiment the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds,
tautomers and stereoisomeric forms thereof,
and the free bases, the pharmaceutically acceptable addition salts, and the solvates thereof.
Specific compounds according to the invention include:
















and the pharmaceutically acceptable salts and solvates forms of such compounds.

Specific compounds according to the invention include:
















































































































tautomers and stereoisomeric forms thereof,

and the pharmaceutically acceptable salts and the solvates thereof.

More specific compounds according to the invention include:







    
    
        tautomers thereof,
        and the pharmaceutically acceptable salts and the solvates thereof.
    
    


More specific compounds according to the invention include:




























tautomers and stereoisomeric forms thereof,

and the pharmaceutically acceptable salts and the solvates thereof.

For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts”. Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Conversely, said salt forms can be converted into the free base form by treatment with an appropriate base.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, beta-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid, and undecylenic acid.
Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylene-diamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Conversely, said salt forms can be converted into the free acid forms by treatment with an appropriate acid.
The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like.
In the framework of this application, an element, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Radiolabelled compounds of Formula (I) may comprise a radioactive isotope selected from the group of 2H, 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 2H, 3H, 11C and 18F. More preferably, the radioactive isotope is 2H. In particular, deuterated compounds are intended to be included within the scope of the present invention
Methods of Synthesis
Compounds of Formula (I) can be prepared by methods known to those who are skilled in the art. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
The symbol ‘Δ’ means that the reaction step typically may be performed under heating.
Herein, the term ‘Ac’ means acetyl, ‘Me’ means methyl, ‘DIPEA’ means diisopropylethylamine, ‘DCM’ means dichloromethane, ‘DMF’ means N,N-dimethylformamide, ‘DMF.DMA’ means N,N-dimethylformamide dimethyl acetal, ‘HATU’ means 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate, ‘NMP’ means N-methyl-2-pyrrolidone, ‘TsCl’ means tosyl chloride, ‘DMAP’ means 4-dimethylaminopyridine, ‘NIS’ means N-iodosuccinimide, ‘NCS’ means N-chlorosuccinimide, ‘AcOH’ means acetic acid, ‘Et3N’ means trietylamine, ‘Pd(PPh3)4’ means tetrakis(triphenylphosphine)palladium, ‘PhN(SO2CF3)2’ means N-phenyl-bis(trifluoromethanesulfonimide), ‘Boc’ means example tert-butyl carbonate, ‘[Ir(OMe)cod]2’ means (1,5-cyclooctadiene)(methoxy) iridium(I) dimer, ‘TFA’ means trifluoroacetic acid.







Scheme 1 illustrates methods of preparing compounds of Formula (I), wherein R3-R7 are hydrogen and R8 is hydrogen or C1-6alkyl, hereby represented by formulae 8 and 8a, respectively, and wherein R1, R2 and R9 are as defined in Formula (I) and Alk represents C1-6alkyl. Methylpyridine 1 can be treated with N,N-dimethylformamide dimethyl acetal to give vinylamine 2. Reduction and cyclisation of vinylamine 2 can be achieved using iron in acetic acid to yield azaindole 3. Treatment of azaindole 3 with aluminum chloride/acyl chloride gives ketone 4 which, in turn, can be reacted with tosyl chloride (TsCl) to yield N-substituted azaindole 5. Heating intermediate 5 with tert-butoxybis(dimethylamino)methane gives aminopropenone 6 which, when reacted with a suitable guanidine in the presence of a base such as sodium methoxide in a protic solvent, such as n-butanol, with heating, yields aminopyrimidines 7. The aryl bromide group in aminopyrimidine 7 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 8. Final compound 8 can be further N-alkylated under appropriate conditions, such as using a C1-6alkylhalide, such us a C1-6alkyl iodide in the presence of a suitable base in an appropriate solvent, to furnish final products such as 8a. Final compound 8 can also be N-alkylated with an optionally substituted C1-6alkylhalide or an optionally substituted C2-6alkylhalide, under the conditions used for carrying out the N-alkylation of compounds 8 to final compound 8a, to yield final compounds wherein R8 is an optionally substituted C1-6alkyl or C2-6alkyl.




Scheme 2 illustrates methods of preparing compounds of Formula (I), wherein R3-R5 and R7 are hydrogen, R6 is chloro, and R8 is hydrogen or C1-6alkyl, hereby represented by formula 10 or 10a, respectively, wherein R1, R2 and R9 are as defined in Formula (I) and Alk represents C1-6alkyl. Aminopyrimidines 7 can be treated with N-chlorosuccinimide under appropriate conditions, such as for example in acetonitrile under heating, to yield chloropyrimidines 9. The aryl bromide moiety in 9 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 10. Final compounds 10 can be further N-alkylated under appropriate conditions, such as using a C1-6alkylhalide, such as a C1-6alkyl iodide in the presence of a suitable base in an appropriate solvent, to furnish final products such as 10a. Aminopyrimidines 7 can also be treated with N-bromosuccinimide and N-iodosuccinimide, under the conditions used for carrying out the chlorination of aminopyrimidines 7 to chloropyrimidines 9, to yield the corresponding bromopyrimidine and iodopyrimidine intermediates. The bromopyrimidine and iodopyrimidine intermediates can be converted to final compounds of formula 10 and 10a, wherein chloro has been replaced with bromo or iodo, in the same way as described for compounds 10 and 10a from chloropyrimidines 9.




Scheme 3 illustrates methods of preparing compounds of Formula (I) wherein R3-R5 and R7 are hydrogen, and R6 is hydrogen, hereby represented by formula 12, or R6 is chloro, hereby represented by formula 14, wherein R1, R2, R8 and R9 are as defined in Formula (I). Treatment of azaindole 7 with a suitable alkylating agent under basic conditions, such as R8-LG, wherein LG is a leaving group, such as chloro, bromo or iodo, using for instance, cesium carbonate in DMF under heating, yields N-substituted azaindoles 11. The aryl bromide function in N-substituted azaindole 11 can then be reacted with alkynes under palladium-catalyzed Sonogashira conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 12. Alternatively, the aminopyrimidine moiety in N-substituted azaindole 11 can be treated with N-chlorosuccinimide to yield chloropyrimidines 13. As above, the aryl bromide moiety in 13 can be reacted with alkynes under palladium-catalyzed Sonogashira conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 14. N-Substituted azaindoles 11 can also be treated with N-bromosuccinimide and N-iodosuccinimide, under the conditions used for carrying out the chlorination of azaindoles 11 to chloropyrimidines 13, to yield the corresponding bromopyrimidine and iodopyrimidine intermediates. The bromopyrimidine and iodopyrimidine intermediates can be converted to final compounds of formula 14, wherein chloro has been replaced with bromo or iodo, in the same way as described for compounds 14 from chloropyrimidines 13.




Scheme 4 illustrates methods of preparing compounds of Formula (I), wherein R3-R5, R7 and R9 are hydrogen, and R6 is hydrogen, hereby referred to as compound of formula 12a or R6 is chloro, hereby referred to as compound of formula 14a, wherein R1, R2 and R8 are as defined in Formula (I). Azaindole ketone 4 can be reacted with an appropriate alkylating agent such as LG-R8′ under suitable conditions, wherein LG is a suitable leaving group, for example, mesylate, triflate or halo, such as chloro, bromo, or iodo, and wherein R8′ is R8 as defined in Formula (I), except hydrogen, to yield N-substituted azaindoles 15. Alternatively, azaindole ketone 4 can be reacted with a reagent such as Alk1-OH under Mitsunobu type conditions, wherein Alk1 represents an optionally substituted C1-6alkyl or an optionally substituted C2-6alkyl as in R8 in Formula (I), to yield N-substituted azaindoles 15. Heating intermediate 4 or 15 with tert-butoxybis(dimethylamino)methane gives the corresponding aminopropenone 16 which, when reacted with guanidine, yields the corresponding aminopyrimidine 11a. The aryl bromide moiety in 11a can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 12a. Alternatively, the aminopyrimidine moiety in 11a can be treated with N-chlorosuccinimide to yield the corresponding chloropyrimidine in 13a. As above, the aryl bromide moiety in 13a can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, to furnish final products such as 14a. Aminopyrimidines 11a can also be treated with N-bromosuccinimide and N-iodosuccinimide, under the conditions used for carrying out the chlorination of Aminopyrimidines 11a to chloropyrimidines 13a, to yield the corresponding bromopyrimidine and iodopyrimidine intermediates. The bromopyrimidine and iodopyrimidine intermediates can be converted to final compounds of formula 14a, wherein chloro has been replaced with bromo or iodo, in the same way as described for compounds 14a from chloropyrimidines 13a.




Scheme 5 illustrates methods of preparing compounds of Formula (I) wherein R3-R5 and R7 are hydrogen, R6 is chloro and R1, R2, R8 and R9 are as defined in Formula (I), hereby referred to as compound of formula 14b. Treatment of the aminopyrimidine moiety in 13a with sodium nitrite in acetic acid yields hydroxypyrimidine 17, which when treated with phosphorous oxychloride/phosphorus pentachloride, gives dichloropyrimidine 18. Dichloropyrimidine 18 can be reacted with appropriate amines under acid or base-catalysis, such as for instance N,N-diisopropylethylamine in N-methyl-2-pyrrolidone (NMP), or p-toluenesulfonic acid in dioxane under heating, to yield aminopyrimidines 13b. As above, the aryl bromide moiety in 13b can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, to furnish final products such as 14b.







Scheme 6 illustrates methods of preparing compounds of Formula (I) wherein R3-R5, and R9 are hydrogen, and R1, R2, R6 and R7 are as defined in Formula (I), and R8 are hydrogen or R8′, hereby referred to as compounds of formula 28 or 28a, respectively, wherein R8′ is R8 as defined in Formula (I), except hydrogen. Protection of azaindole 19 by treatment for instance, with di-tert-butyl dicarbonate, yields azaindole 20, wherein PG is a suitable protecting group, such as a carbamate type, for example tert-butyl carbonate (Boc). The iridium-catalyzed C—H borylation of 20 (e.g. wherein [Ir(OMe)cod]2 means (1,5-cyclooctadiene)(methoxy) iridium(I) dimer) yields boronate 21. Reaction of 21 with heteroaryl chlorides 22 under palladium-catalyzed conditions yields 23 which, after deprotection under suitable conditions, for instance by treatment with trifluoroacetic acid (TFA) when the protecting group is Boc, yields intermediates 24. Methyl ethers 24 can be converted to the corresponding hydroxyl intermediates 25 upon treatment with for example, aqueous hydrobromic acid in acetic acid under heating. The resulting hydroxyl functionality in 25 can then be reacted to form an appropriate leaving group, followed by Sonogashira coupling, with or without sequential protection/deprotection steps at the NH functionality of the azaindole. Advantageously, when 25 is treated with N-phenyl-bis(trifluoromethanesulfonimide), it can give bis-triflates 26, which in turn can be reacted with alkynes under palladium-catalyzed Sonogashira conditions, to give alkynes 27. Finally, intermediates 27 can be treated with lithium hydroxide to furnish final products 28. Final products 28 can be further N-alkylated by treatment with an appropriate alkylating agent such as LG-R8′ under suitable conditions, wherein LG is a suitable leaving group, for example, mesylate, triflate or halo, such as chloro, bromo, or iodo, to yield N-substituted azaindoles 28a. Alternatively, final products 28 can be reacted with a reagent such as Alk1-OH under Mitsunobu type conditions, wherein Alk1 represents an optionally substituted C1-6alkyl or an optionally substituted C2-6alkyl as in R8 in Formula (I), to yield N-substituted azaindoles 28a.




Scheme 7 illustrates methods of preparing compounds of Formula (I), wherein R1-R4, R5c, R5d, R6 and R9 are as defined in Formula (I), R7 is hydrogen and R8 is hydrogen, hereby represented by formula 35, or R8 is as defined in Formula (I), hereby represented by formula 37. Azaindole 29, wherein LG1 is a leaving group such as a suitable halide, can be reacted with an amine under standard coupling conditions, such as 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU) in N,N-dimethylformamide (DMF) to give amide 30. Treatment of 30 with aluminium chloride and an acid chloride gives ketone 31, which can in turn be protected with a suitable group, such as tosyl for instance to give N-substituted azaindole 32. Heating intermediate 32 with tert-butoxybis(dimethylamino)methane gives aminopropenone 33 which, when reacted with a suitable guanidine in the presence of a base such as sodium methoxide in a protic solvent, such as n-butanol, with heating, yields aminopyrimidine 34. The aryl-LG1 group in compound 34 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 35. Alternatively, intermediate 34 can be further functionalised by treatment with a suitable electrophile under appropriate conditions, such as a C1-6alkyl iodide in the presence of a suitable base in an appropriate solvent, to furnish 36. As above, the aryl-LG1 moiety in 36 can be reacted with alkynes under palladium-catalyzed Sonogashira conditions, using for example tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 37.




Scheme 8 illustrates methods of preparing compounds of Formula (I), wherein R3-R5 and R7 are hydrogen and R1, R2, R6, R8 and R9 are as defined in Formula (I), hereby represented by formula 41. Aminopyrimidines 7 can be N-functionalised with a suitable electrophile under appropriate conditions, such as using a C1-6alkyl halide in the presence of a suitable base in an appropriate solvent, to furnish 38. Compound 38 can be treated with N-iodosuccinimide under appropriate conditions, such as in acetonitrile under heating, to yield iodopyrimidine 39. Compound 39 can be further functionalised by reacting with a suitable coupling partner R6-LG2, wherein LG2 is a suitable leaving group, under appropriate conditions, such as using copper cyanide under palladium catalysis where R6 is nitrile, to give substituted pyrimidine 40. The aryl bromide moiety in 40 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 41.







Scheme 9 illustrates methods of preparing compounds of Formula (I), wherein R7 is hydrogen, R1-R5, R8 and R9 are as defined in Formula (I) and R6 is selected from the group of hydrogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; and —C(═O)—NR6aR6b as defined in Formula (I), hereby represented by compounds of formula 47. Treatment of azaindole 42, wherein LG3 is a leaving group such as a suitable halide, with aluminum chloride and an acid chloride gives ketone 43, which, in turn, can be further N-functionalised by reaction with a suitable electrophile under appropriate conditions, such as using a C1-6alkylhalide in the presence of a suitable base in an appropriate solvent, to furnish 44. Heating intermediate 44 with tert-butoxybis(dimethylamino)methane gives aminopropenone 45 which, when reacted with a suitable guanidine in the presence of a base such as sodium methoxide in a protic solvent, such as n-butanol, with heating, yields aminopyrimidine 46. The aryl-LG3 moiety in aminopyrimidine 46 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 47.




Scheme 10 illustrates methods of preparing compounds of Formula (I) wherein R1-R7 and R9 are as defined in Formula (I), and wherein R8′ is as defined before; hereby referred to as compounds of formula 55. Protection of azaindole 48, wherein LG4 is a leaving group such as a suitable halogen, by treatment for instance, with di-tert-butyl dicarbonate, yields azaindole 49, wherein PG is a suitable protecting group, such as a carbamate type, for example tert-butyl carbonate (Boc). The iridium-catalyzed C—H borylation of 49 (e.g. wherein [Ir(OMe)cod]2 means (1,5-cyclooctadiene)(methoxy) iridium(I) dimer) yields boronate 50. Reaction of 50 with heteroaryl chlorides 51 under palladium-catalyzed conditions yields 52 which, after deprotection under suitable conditions, for instance by treatment with TFA when the protecting group is Boc, yields intermediate 53. Intermediate 53 can be N-functionalised by treatment with a suitable electrophile, such as LG5-R8′ under suitable conditions, wherein LG5 is a suitable leaving group, for example, mesylate, triflate or halogen, to yield N-substituted azaindoles 54. Alternatively, intermediate 53 can be reacted with a reagent such as Alk1-OH under Mitsunobu type conditions, wherein Alk1 represents C1-6alkyl or C2-6alkyl optionally substituted as in R8 in Formula (I), to yield N-substituted azaindoles 54. The aryl-LG4 moiety in aminopyrimidine 54 can be reacted with alkynes under palladium-catalyzed Sonogashira coupling conditions, using for example Pd(PPh3)4, CuI and a base such as triethylamine in acetonitrile, with heating, to furnish final products such as 55.
It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatised by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.
The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
Compounds of the invention may be prepared from commercially available starting materials using the general methods illustrated herein.
Pharmacology
It has been found that the compounds of the present invention inhibit NF-κB-inducing kinase (NIK—also known as MAP3K14). The compounds according to the invention and the pharmaceutical compositions comprising such compounds may be useful for treating or preventing diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders. In particular, the compounds according to the present invention and the pharmaceutical compositions thereof may be useful in the treatment of a haematological malignancy or solid tumour. In a specific embodiment said haematological malignancy is selected from the group consisting of multiple myeloma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In another specific embodiment of the present invention, the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.
Examples of cancers which may be treated (or inhibited) include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (for example adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (e.g. gastrointestinal stromal tumours), cervix, endometrium, thyroid, prostate, or skin (for example squamous cell carcinoma or dermatofibrosarcoma protuberans); pituitary cancer, a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia/lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumour of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
Hence, the invention relates to compounds of Formula (I), the tautomers and the stereoisomeric forms thereof, and the pharmaceutically acceptable salts and the solvates thereof, for use as a medicament.
The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament.
The present invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, control or reduction of the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase. Also, the present invention relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with NF-κB-inducing kinase dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by inhibition of NF-κB-inducing kinase.
The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, for use in the treatment or prevention of any one of the diseases mentioned hereinbefore.
The invention also relates to a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, for use in treating or preventing any one of the diseases mentioned hereinbefore.
The invention also relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.
The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.
In view of the utility of the compounds of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore.
Said method comprises the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound of Formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, to warm-blooded animals, including humans.
Therefore, the invention also relates to a method for the treatment of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.
One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of a compound of the present invention to be administered as a therapeutic agent for treating the disorders referred to herein will be determined on a case by case by an attending physician.
The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect may vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to admission. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
The present invention also provides compositions for preventing or treating the disorders referred to herein. Said compositions comprising a therapeutically effective amount of a compound of formula (I), a tautomer or a stereoisomeric form thereof or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. The compounds are preferably orally administered. The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound according to the present invention and one or more additional therapeutic agents, as well as administration of the compound according to the present invention and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound according to the present invention and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
For the treatment of the above conditions, the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (supporting agents in the therapy) include but are not limited to:

    
    
        platinum coordination compounds for example cisplatin optionally combined with amifostine, carboplatin or oxaliplatin;
        taxane compounds for example paclitaxel, paclitaxel protein bound particles (AbraxaneTM) or docetaxel;
        topoisomerase I inhibitors such as camptothecin compounds for example irinotecan, SN-38, topotecan, topotecan hcl;
        topoisomerase II inhibitors such as anti-tumour epipodophyllotoxins or podophyllotoxin derivatives for example etoposide, etoposide phosphate or teniposide;
        anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine;
        anti-tumour nucleoside derivatives for example 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine;
        alkylating agents such as nitrogen mustard or nitrosourea for example cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide optionally in combination with mesna, pipobroman, procarbazine, streptozocin, temozolomide, uracil;
        anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin optionally in combination with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;
        molecules that target the IGF-1 receptor for example picropodophilin;
        tetracarcin derivatives for example tetrocarcin A;
        glucocorticoïden for example prednisone;
        antibodies for example trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;
        estrogen receptor antagonists or selective estrogen receptor modulators or inhibitors of estrogen synthesis for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;
        aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozole;
        differentiating agents such as retinoids, vitamin D or retinoic acid and retinoic acid metabolism blocking agents (RAMBA) for example accutane;
        DNA methyl transferase inhibitors for example azacytidine or decitabine;
        antifolates for example premetrexed disodium;
        antibiotics for example antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;
        antimetabolites for example clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;
        apoptosis inducing agents and antiangiogenic agents such as Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;
        tubuline-binding agents for example combrestatin, colchicines or nocodazole;
        kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi target kinase inhibitors), mTOR inhibitors) for example flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib maleate, temsirolimus;
        farnesyltransferase inhibitors for example tipifarnib;
        histone deacetylase (HDAC) inhibitors for example sodium butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, quisinostat, trichostatin A, vorinostat;
        Inhibitors of the ubiquitin-proteasome pathway for example PS-341, MLN 0.41 or bortezomib;
        Yondelis;
        Telomerase inhibitors for example telomestatin;
        Matrix metalloproteinase inhibitors for example batimastat, marimastat, prinostat or metastat;
        Recombinant interleukins for example aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b;
        MAPK inhibitors;
        Retinoids for example alitretinoin, bexarotene, tretinoin;
        Arsenic trioxide;
        Asparaginase;
        Steroids for example dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), dexamethasone;
        Gonadotropin releasing hormone agonists or antagonists for example abarelix, goserelin acetate, histrelin acetate, leuprolide acetate;
        Thalidomide, lenalidomide;
        Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburicase;
        BH3 mimetics for example ABT-737;
        MEK inhibitors for example PD98059, AZD6244, CI-1040;
        colony-stimulating factor analogs for example filgrastim, pegfilgrastim, sargramostim; erythropoietin or analogues thereof (e.g. darbepoetin alfa); interleukin 11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin;
        a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.
    
    


Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
The weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
The platinum coordination compound is advantageously administered in a dosage of 1 to 500 mg per square meter (mg/m2) of body surface area, for example 50 to 400 mg/m2, particularly for cisplatin in a dosage of about 75 mg/m2 and for carboplatin in about 300 mg/m2 per course of treatment.
The taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m2) of body surface area, for example 75 to 250 mg/m2, particularly for paclitaxel in a dosage of about 175 to 250 mg/m2 and for docetaxel in about 75 to 150 mg/m2 per course of treatment.
The camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m2) of body surface area, for example 1 to 300 mg/m2, particularly for irinotecan in a dosage of about 100 to 350 mg/m2 and for topotecan in about 1 to 2 mg/m2 per course of treatment.
The anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m2) of body surface area, for example 50 to 250 mg/m2, particularly for etoposide in a dosage of about 35 to 100 mg/m2 and for teniposide in about 50 to 250 mg/m2 per course of treatment.
The anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m2) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m2, for vincristine in a dosage of about 1 to 2 mg/m2, and for vinorelbine in dosage of about 10 to 30 mg/m2 per course of treatment.
The anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m2) of body surface area, for example 700 to 1500 mg/m2, particularly for 5-FU in a dosage of 200 to 500 mg/m2, for gemcitabine in a dosage of about 800 to 1200 mg/m2 and for capecitabine in about 1000 to 2500 mg/m2 per course of treatment.
The alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m2) of body surface area, for example 120 to 200 mg/m2, particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m2, for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m2, and for lomustine in a dosage of about 100 to 150 mg/m2 per course of treatment.
The anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m2) of body surface area, for example 15 to 60 mg/m2, particularly for doxorubicin in a dosage of about 40 to 75 mg/m2, for daunorubicin in a dosage of about 25 to 45 mg/m2, and for idarubicin in a dosage of about 10 to 15 mg/m2 per course of treatment.
The antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20-100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.
Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m2) of body surface area, or as known in the art, if different. Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m2) of body surface area, particularly 2 to 4 mg/m2 per course of treatment.
These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.
The following examples further illustrate the present invention.
EXAMPLES
Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
Herein, the term ‘Ac’ means acetyl, ‘Me’ means methyl, ‘DIPEA’ means diisopropylethylamine, ‘HPLC’ means High Performance Liquid Chromatography, ‘DCM’ means dichloromethane, ‘DMF’ means N,N-dimethylformamide, ‘DMSO’ means dimethylsulfoxide, ‘Et2O’ means diethyl ether, ‘EtOAc’ means ethyl acetate, ‘HATU’ means 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate, ‘HPLC’ means high performance liquid chromatography, ‘LCMS’ means liquid chromatography/mass spectrometry, ‘MeOH’ means methanol, ‘MTBE’ means methyl tert-butyl ether, ‘NMP’ means N-methyl-2-pyrrolidone, ‘Rt’ means retention time, ‘TLC’ means thin layer chromatography, ‘RT’ means room temperature, ‘SCX-2’ means an ISOLUTE® silica propylsulfonic acid strong cation exchanger (SCX) column and ‘SFC’ means supercritical fluid chromatography.
When in the Examples below, intermediates or compounds were prepared according to the reaction protocol of a fully described Example, this means that the intermediate or compound was prepared by an analogous reaction protocol (but not necessarily identical) as the Example referred to.
Preparation of Intermediates
Example A1
a) Preparation of Intermediate 1




A stirred mixture of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.00 g, 10.2 mmol) in anhydrous DCM (65 ml) at ambient temperature was treated portionwise with aluminium chloride (2.70 g, 20.3 mmol). After stirring for 15 minutes, the mixture was treated dropwise with acetyl chloride (1.44 ml, 20.3 mmol) and the resulting mixture was stirred at ambient temperature for 24 hours. The mixture was treated cautiously with MeOH until no further effervescence was observed. The mixture was then concentrated in vacuo and the residue partitioned between 2.0 M aqueous sodium hydroxide and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with Et2O to afford the desired product (2.12 g, 87%).
LCMS (Method B): Rt=2.29 min, m/z [M+H]+=239/241
b) Preparation of Intermediate 2




A stirred mixture of intermediate 1 (2.12 g, 8.87 mmol), 4-methylbenzenesulfonyl chloride (1.86 g, 9.76 mmol), N,N-diisopropylethylamine (3.08 ml, 17.7 mmol) and anhydrous DCM (20 ml) at ambient temperature was treated with 4-dimethylaminopyridine (0.01 g, 0.09 mmol). The resulting mixture was stirred for 3 hours and then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (0:1 to 1:99 by volume), to afford the desired product (3.14 g, 90%).
LCMS (Method C): Rt=3.91 min, m/z [M+H]+=393/395
Example A2
a) Preparation of Intermediate 3




A stirred mixture of intermediate 2 (0.98 g, 2.50 mmol) and tert-butoxy bis(dimethylamino)methane (1.03 ml, 5.0 mmol) was heated at 100° C. for 2.5 hour. The mixture was cooled to ambient temperature and stood for 18 hours. A second aliquot of tert-butoxy bis(dimethylamino)methane (0.52 ml, 2.50 mmol) was added and the mixture was heated at 100° C. for 2.5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to afford the desired product as a brown semi-solid (1.40 g).
LCMS (Method D): Rt=2.04 min, m/z [M+H]+=294/296
b) Preparation of Intermediate 4




A stirred mixture of guanidine hydrochloride (2.38 g, 25.0 mmol) and 1-butanol (9.0 ml) under a nitrogen atmosphere at ambient temperature was treated portionwise with sodium methoxide (1.35 g, 25.0 mmol). After stirring for 30 minutes, a slurry of intermediate 3 (1.40 g, 4.75 mmol) in 1-butanol (8.0 ml) was added and the resulting mixture heated at 100° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and extracted with a mixture of EtOAc and MeOH (9:1 by volume). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was triturated with Et2O to afford the desired product as a fawn solid (0.47 g, 64% over two steps).
LCMS (Method D): Rt=1.51 min, m/z [M+H]+=290/292
c) Preparation of Intermediate 5




A solution of intermediate 4 (0.47 g, 1.62 mmol) and N-chlorosuccinimide (0.22 g, 1.62 mmol) in acetonitrile (10 ml) was stirred at 85° C. for 5 hours. The mixture was cooled to 0° C. and the resulting precipitate collected by filtration to afford the desired product as a colourless solid (0.24 g, 46%).
LCMS (Method C): Rt=2.58 min, m/z [M+H]+=324/326
Example A3
a) Preparation of Intermediate 6




A stirred mixture of N-methylguanidine hydrochloride (1.99 g, 18.2 mmol) and 1-butanol (8.0 ml) under a nitrogen atmosphere at ambient temperature was treated with sodium methoxide (0.98 g, 18.2 mmol). After stirring for 30 minutes, the mixture was treated with a slurry of intermediate 3 (1.05 g, 3.57 mmol) in 1-butanol (3.0 ml) and the resulting mixture heated at 100° C. for 16 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and extracted sequentially with EtOAc and a mixture of EtOAc and MeOH (9:1 by volume). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and EtOAc (0:1 to 1:9 by volume), followed by trituration with Et2O to afford the desired product (0.12 g, 22%).
LCMS (Method C): Rt=1.88 min, m/z [M+H]+=304/306
Example A4
a) Preparation of Intermediate 7




A mixture of intermediate 4 (0.11 g, 0.38 mmol), methyl iodide (0.03 ml, 0.42 mmol), potassium carbonate (0.10 g, 0.76 mmol) and DMF (2.0 ml) was heated by microwave irradiation at 100° C. for 1 hour. The mixture was cooled to ambient temperature, filtered and the filtrate concentrated in vacuo to afford the desired product (0.12 g, 100%).
LCMS (Method D): Rt=1.67 min, m/z [M+H]+=304/306
Intermediates 8 to 15, 25 to 32, and 162 to 165 were prepared according to the reaction protocol of example A4 using the appropriate starting materials (Table 1).










TABLE 1





Intermediate
Structure
Starting Materials
LCMS Data


















8




a) Intermediate 4 b) 3-Bromomethyl- tetrahydrofuran
Rt = 2.13 min, m/z [M + H]+ = 374/376 (Method D)


 


9




a) Intermediate 4 b) 4-(2-Chloroethyl)- morpholine hydrochloride
Rt = 2.07 min, m/z [M + H]+ = 403/405 (Method D)


 


10




a) Intermediate 5 b) 2-Bromoethanol
Rt = 2.17 min, m/z [M + H]+ = 368/370 (Method D)


 


11




a) Intermediate 4 b) (3- Bromopropyl)carbamic acid tert-butyl ester
Rt = 1.32 min, m/z [M + H]+ = 447/449 (Method C)


 


12




a) Intermediate 4 b) 2-Bromoethanol
Rt = 1.67 min, m/z [M + H]+ = 334/336 (Method B)


 


13




a) Intermediate 4 b) 2-Bromoethyl methyl ether
Rt = 1.83 min, m/z [M + H]+ = 348/350 (Method B)


 


14




a) Intermediate 4 b) 2,2-Dimethyl-oxirane
Rt = 1.70 min, m/z [M + H]+ = 362/364 (Method D)


 


15




a) Intermediate 4 b) Toluene-4-sulfonic acid oxetan-3-yl methyl ester
Rt = 1.85 min, m/z [M + H]+ = 360/362 (Method A)


 


25




a) Intermediate 4 b) 3-Chloro(N-methyl)- propanamide
Rt = 1.73 min, m/z [M + H]+ = 375/377 (Method C)


 


26




a) Intermediate 123 b) 2,2-Dimethyl-oxirane
Rt = 1.85 min, m/z [M + H]+ = 332/334 (Method C)


 


27




a) Intermediate 4 b) 3-Chloro(N,N- dimethyl)propanamide
Rt = 1.85 min, m/z [M + H]+ = 389/391 (Method C)


 


28




a) Intermediate 119 b) Methyl iodide
Rt = 0.34 min, m/z [M + H]+ = 387/389 (Method C)


 


29




a) Intermediate 119 b) 2-Iodopropane
Rt = 1.57 min, m/z [M + H]+ = 415/417 (Method C)


 


30




a) Intermediate 119 b) Ethyl iodide
Rt = 1.62 min, m/z [M + H]+ = 401/403 (Method B)


 


31




a) Intermediate 120 b) Ethyl iodide
Rt = 1.60 min, m/z [M + H]+ = 419/421 (Method C)


 


32




a) Intermediate 120 b) 1-Bromo-2-methoxy- ethane
Rt = 1.83 min, m/z [M + H]+ = 449/451 (Method C)


 


162




a) Intermediate 161 b) Ethyl iodide
Rt = 1.86 min, m/z [M + H]+ = 435/437 (Method C)


 


163




a) Intermediate 121 b) Ethyl iodide
Rt = 1.74 min, m/z [M + H]+ = 391/393 (Method C)


 


164




a) Intermediate 171 b) Ethyl iodide
Rt = 1.89 min, m/z [M + H]+ = 419/421 (Method C)


 


165




a) Intermediate 128 b) Ethyl iodide
Rt = 1.80 min, m/z [M + H]+ = 405/407 (Method C)









Example A5
a) Preparation of Intermediate 16




A stirred solution of intermediate 11 (0.17 g, 0.50 mmol) in DCM (3.0 ml) under a nitrogen atmosphere at ambient temperature was treated with trifluoroacetic acid (0.39 ml, 5.0 mmol), and the resulting mixture stirred for 2 hours. The mixture was concentrated in vacuo and the residue purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume), to afford the desired product as a pale yellow solid (0.13 g, 96%).
LCMS (Method C): Rt=1.32 min, m/z [M+H]+=347/349
Example A6
a) Preparation of Intermediate 17




A stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.0 g, 10.2 mmol) in anhydrous DMF (80 ml) under a nitrogen atmosphere at ambient temperature was treated portionwise with sodium hydride (0.49 g, 12.2 mmol, 60% in mineral oil). After stirring for 20 minutes, 2-iodopropane (1.1 ml, 11.2 mmol) was added dropwise and the resulting mixture stirred for 18 hours. The mixture was concentrated in vacuo and the residue partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (1:9 to 1:1 by volume), to afford the desired product as a brown oil (1.87 g, 77%).
LCMS (Method C): Rt=3.19 min, m/z [M+H]+=239/241
b) Preparation of Intermediate 18




A stirred mixture of intermediate 17 (1.87 g, 7.81 mmol), aluminium chloride (2.08 g, 15.6 mmol) and anhydrous DCM (40 ml) at ambient temperature was treated dropwise with acetyl chloride (1.1 ml, 15.6 mmol), and the resulting mixture stirred for 4 hours. The mixture was treated sequentially with MeOH (2.0 ml), aqueous ammonium hydroxide (10 ml) and water. The separated aqueous phase was extracted with DCM and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (1:9 to 1:0 by volume), to afford the desired product as a pale yellow solid (1.67 g, 76%).
LCMS (Method B): Rt=2.88 min, m/z [M+H]+=281/283
c) Preparation of Intermediate 19




A mixture of intermediate 18 (1.66 g, 5.92 mmol) and tert-butoxy bis(dimethylamino)methane (2.44 ml, 11.8 mmol) was stirred at 100° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated in vacuo to afford the desired product as a pale yellow solid (1.99 g, 100%).
LCMS (Method C): Rt=2.80 min, m/z [M+H]+=336/338
d) Preparation of Intermediate 20




A stirred mixture of guanidine hydrochloride (5.65 g, 59.2 mmol) and 1-butanol (40 ml) under a nitrogen atmosphere at 0° C. was treated portionwise with sodium methoxide (3.20 g, 59.2 mmol). After stirring for 30 minutes, intermediate 19 (1.99 g, 5.92 mmol) was added and the resulting mixture heated at 100° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with Et2O to afford the desired product as a colourless solid (1.77 g, 90%).
LCMS (Method C): Rt=2.04 min, m/z [M+H]+=332/334
e) Preparation of Intermediate 21




A mixture of intermediate 20 (0.50 g, 1.45 mmol), N-chlorosuccinimide (0.19 g, 1.45 mmol) and acetonitrile (10 ml) under a nitrogen atmosphere was stirred at 85° C. for 3.5 hours. The mixture was cooled to 0° C. and the resulting precipitate collected by filtration. The filtrate was concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with a mixture of EtOAc and DCM (1:4 by volume). The fractions containing the desired product were combined with the solid recovered by filtration and the mixture was concentrated in vacuo. Purification of the residue by trituration with Et2O, followed by column chromatography on silica gel, eluting with a mixture of EtOAc and DCM (1:9 to 1:4 by volume), afforded the desired product as an off-white solid containing traces of succinimide. The solid was dissolved in EtOAc, washed with saturated aqueous sodium carbonate solution and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired product as an off-white solid (0.42 g, 79%).
LCMS (Method B): Rt=3.17 min, m/z [M+H]+=366/368
Intermediates 22 to 24 were prepared according to the reaction protocol of intermediate 21 using the appropriate starting material (Table 2).










TABLE 2







Starting



Intermediate
Structure
Material
Analytical Data







22




Intermediate 14
1H NMR (300 MHz, DMSO-d6) δ ppm: 8.85 (d, J = 0.9 Hz, 1H), 8.68-8.67 (m, 2H), 8.26 (s, 1H), 6.93 (s, 2H), 4.83 (s, 1H), 4.31 (s, 2H), 1.12 (s, 6H).


 


23




Intermediate 13
LCMS (Method B): Rt = 2.83 min, m/z [M + H]+ = 382/384


 


24




Intermediate 90
LCMS (Method C): Rt = 3.10 min, m/z [M + H]+ = 410/412/414









Example A7
a) Preparation of Intermediate 33




A stirred mixture of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (0.50 g, 2.07 mmol), HATU (0.94 g, 2.48 mmol), DIPEA (0.79 ml, 4.55 mmol) and DMF (40.0 ml) under a nitrogen atmosphere at ambient temperature was treated with 2-methoxyethylamine (0.32 ml, 3.73 mmol). After stirring for 18 hours, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by trituration with DCM afforded the desired product as a white solid (0.28 g, 46%).
LCMS (Method D): Rt=2.20 min, m/z [M+H]+=298/300
Example A8
a) Preparation of Intermediate 34




A stirred solution of 6-bromo-2-methyl-3-nitro-pyridine (0.25 g, 1.15 mmol) in anhydrous tetrahydrofuran (11.5 ml) under an argon atmosphere at −40° C. was treated with 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran (3.46 ml, 3.46 mmol), and the resulting mixture was stirred for 1 hour. The mixture was diluted with saturated aqueous ammonium chloride solution (11.5 ml) and partitioned between water and EtOAc. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:1 by volume), to afford the desired product as a yellow gum (0.07 g, 25%).
LCMS (Method B): Rt=1.84 min, m/z [M+H]+=211/213
Example A9
a) Preparation of Intermediate 35




A stirred suspension of 5-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (0.40 g, 2.41 mmol) in DCM (10 ml) at 0° C. was treated sequentially with 4-dimethylaminopyridine (0.02 g, 0.14 mmol), triethylamine (0.67 ml, 4.8 mmol) and di-tert-butyldicarbonate (0.63 g, 2.89 mmol). The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The mixture was partitioned between DCM and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:1 by volume), to afford the desired product as a white solid (0.58 g, 90%).
LCMS (Method B): Rt=3.98 min, m/z [M+H]+=267/269
Intermediates 36 to 38 were prepared according to the reaction protocol of example A9 using the appropriate starting materials (Table 3).










TABLE 3





Intermediate
Structure
Starting Materials
LCMS Data







36




Imidazolidine-2,4-dione



 


37




Intermediate 34
Rt = 4.16 min, m/z [M + H]+ = 311/313 (Method C)


 


38




5,7-Dibromo-1H- pyrrolo[2,3-c]pyridine
Rt = 4.20 min, m/z [M + H]+ =  375/377/379 (Method B)









Example A10
a) Preparation of Intermediate 39




A stirred suspension of intermediate 38 (1.38 g, 3.67 mmol) and tetrakis(triphenylphosphine) palladium (0.21 g, 0.184 mmol) in anhydrous tetrahydrofuran (14 ml) under a nitrogen atmosphere at ambient temperature was treated with 0.5 M solution of cyclopropyl zinc bromide in tetrahydrofuran (11.0 ml, 5.51 mmol), and the resulting mixture was stirred for 4 hours. The mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of DCM and pentane (0:1 to 2:3 by volume), to afford the desired product as a white solid (0.91 g, 74%).
LCMS (Method C): Rt=4.61 min, m/z [M+H]+=337/339
Example A11
a) Preparation of Intermediate 40




A stirred mixture of 5-chloro-7-methyl-1H-pyrrolo[2,3-c]pyridine (0.95 g, 5.71 mmol) in anhydrous 1,2-dichloroethane (33.3 ml) at ambient temperature was treated portionwise with aluminium chloride (1.52 g, 11.4 mmol). After stirring for 15 minutes, the mixture was treated dropwise with acetyl chloride (0.81 ml, 11.4 mmol) and the resulting mixture was stirred at ambient temperature for 5 hours. The mixture was treated cautiously with MeOH until no further effervescence was observed. The mixture was then concentrated in vacuo and the residue partitioned between 2.0 M aqueous sodium hydroxide solution and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the desired product (1.06 g, 78%).
LCMS (Method B): Rt=2.25 min, m/z [M+H]+=209/211
Intermediates 41 to 43 and 188 were prepared according to the reaction protocol of intermediate 40 using the appropriate starting materials (Table 4).










TABLE 4





Intermediate
Structure
Starting Materials
LCMS Data


















41




a) Intermediate 33 b) Acetyl chloride
Rt = 2.70 min, m/z [M + H]+ = 340/342 (Method C)


 


42




a) 5-Bromo-1H- pyrrolo[2,3- c]pyridine b) Propionyl chloride
Rt = 2.63 min, m/z [M + H]+ = 353/355 (Method C)


 


43




a) Intermediate 17 b) 5-Chloro- pentanoyl chloride



 


188




a) Intermediate 17 b) 3-Methoxy- propionyl chloride
Rt = 3.02 min, m/z [M + H]+ = 325/327 (Method C)









b) Preparation of Intermediate 44




A stirred mixture of intermediate 40 (1.06 g, 5.08 mmol), 4-methylbenzenesulfonyl chloride (1.06 g, 5.59 mmol), DIPEA (1.77 ml, 10.2 mmol) and anhydrous DCM (51.6 ml) at ambient temperature was treated with 4-dimethylaminopyridine (0.06 g, 0.51 mmol). The resulting mixture was stirred for 2 hours and then partitioned between water and DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 3:1 by volume), to afford the desired product as an off-white solid (1.36 g, 74%).
LCMS (Method B): Rt=3.90 min, m/z [M+H]+=363/365
Intermediates 45 and 46 were prepared according to the reaction protocol of intermediate 44 using the appropriate starting materials (Table 5).










TABLE 5





Intermediate
Structure
Starting Materials
LCMS Data







45




Intermediate 42
Rt = 4.20 min, m/z [M + H]+ = 407/409 (Method B)


 


46




Intermediate 41
Rt = 3.61 min, m/z [M + H]+ = 494/496 (Method C)









c) Preparation of Intermediate 47




A stirred mixture of intermediate 40 (1.36 g, 3.75 mmol) and tert-butoxy bis(dimethylamino)methane (3.09 ml, 14.9 mmol) was heated at 100° C. for 3.5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to afford the desired product as a brown semi-solid (0.99 g, 100%).
LCMS (Method B): Rt=2.10 min, m/z [M+H]+=264/266
Intermediates 48 to 50 and 180 were prepared according to the reaction protocol of intermediate 47 using the appropriate starting materials (Table 6).










TABLE 6





Intermediate
Structure
Starting Materials
LCMS Data


















48




Intermediate 41
Rt = 2.61 min, m/z [M + H]+ = 395/397 (Method C)


 


49




Intermediate 42



 


50




Intermediate 55



 


180




Intermediate 188









d) Preparation of Intermediate 51




A stirred mixture of guanidine hydrochloride (3.58 g, 37.5 mmol) and 1-butanol (38 ml) under a nitrogen atmosphere at ambient temperature was treated portionwise with sodium methoxide (2.02 g, 37.5 mmol). After stirring for 30 minutes, a slurry of intermediate 47 (0.99 g, 37.5 mmol) in 1-butanol (18.0 ml) was added and the resulting mixture heated at 100° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was triturated with Et2O to afford the desired product as a brown solid (0.61 g, 63%).
LCMS (Method B): Rt=1.67 min, m/z [M+H]+=260/262
Intermediates 52 to 54 and 181 were prepared according to the reaction protocol of intermediate 51 using the appropriate starting materials (Table 7).










TABLE 7





Intermediate
Structure
Starting Materials
LCMS Data


















52




a) Intermediate 48 b) Guanidine hydrochloride
Rt = 2.31 min, m/z [M + H]+ = 391/393 (Method C)


 


53




a) Intermediate 49 b) Guanidine hydrochloride
Rt = 1.73 min, m/z [M + H]+ = 304/306 (Method C)


 


54




a) Intermediate 50 b) Guanidine hydrochloride



 


181




a) Intermediate 180 b) Guanidine hydrochloride
Rt = 2.28 min, m/z [M + H]+ = 376/378 (Method B)









Example A12
a) Preparation of Intermediate 55




A mixture of intermediate 43 (0.3 g, 0.84 mmol), sodium azide (0.1 g, 1.5 mmol), sodium iodide (catalic amount) and DMF (15 ml) was stirred at 55° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to afford the desired product (0.3 g, 97%).
Example A13
a) Preparation of Intermediate 56




A degassed mixture of 5-bromo-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (0.10 g, 0.34 mmol), 4,4,-di-tert-butyl-2,2-dipyridyl (9.0 mg, 0.03 mmol) and cyclohexane (2.5 ml) under an argon atmosphere at ambient temperature was treated sequentially with di-μ-methoxobis(1,5-cyclooctadiene)diiridium (0.01 g, 0.02 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.24 ml, 1.69 mmol). The resulting mixture was stirred at 60° C. for 2 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:1 by volume), to afford the desired product as a white solid.
LCMS (Method B): Rt=4.83 min, m/z [M+H]+=423/425
Intermediates 57 to 61 and 182 were prepared according to the reaction protocol of intermediate 56 using the appropriate starting materials (Table 8).










TABLE 8





Intermediate
Structure
Starting Materials
LCMS Data


















57




Intermediate 35
Rt = 4.98 min, m/z [M + H]+ = 393/395 (Method C)


 


58




5-Methoxy-pyrrolo[2,3- c]pyridine-1-carboxylic acid tert-butyl ester
Rt = 4.64 min, m/z [M + H-t-Bu]+ = 319 (Method C)


 


59




Intermediate 37
Rt = 5.05 min, m/z [M + H]+ = 381/383 (Method C)


 


60




Intermediate 39
Rt = 5.32 min, m/z [M-(tBu) + H]+ =  407/409 (Method C)


 


61




5-Bromo-7-chloro- pyrrolo[2,3-c]pyridine-1- carboxylic acid tert-butyl ester
Rt = 5.01 min, m/z [M + H]+ = 457/459 (Method B)


 


182




Intermediate 17
Rt = 4.18 min, m/z [M + H]+ = 365/367 (Method C)









b) Preparation of Intermediate 62




A mixture of intermediate 56 (0.36 g, 0.84 mmol), 4-chloro-5-fluoropyrimidin-2-amine (0.10 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.07 mmol), sodium carbonate (1.01 ml, 2.02 mmol), toluene (12.5 ml) and MeOH (1.5 ml) was stirred under an argon atmosphere at 85° C. for 4 hours. The mixture was cooled to ambient temperature and purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:0 by volume), to afford the desired product as a yellow solid (0.09 g, 36%).
LCMS (Method C): Rt=2.26 min, m/z [M+H]+=308/310
Intermediates 63 to 71, 183 and 184 were prepared according to the reaction protocol of intermediate 62 using the appropriate starting materials (Table 9).










TABLE 9





Intermediate
Structure
Starting Materials
LCMS Data


















63




a) Intermediate 57 b) 4-Chloro-pyrimidin- 2-ylamine
Rt = 3.07 min, m/z [M + H]+ = 360/362 (Method C)


 


64




a) Intermediate 56 b) (4-Chloro-pyrimidin- 2-yl)-ethyl-amine
Rt = 2.03 min, m/z [M + H]+ = 318/320 (Method C)


 


65




a) Intermediate 58 b) 4-Chloro-5-methyl- pyrimidin-2-ylamine
Rt = 2.78 min, m/z [M + H]+ = 356 (Method B)


 


66




a) Intermediate 56 b) 4-Chloro-5- trifluoromethyl- pyrimidin-2-ylamine
Rt = 2.80 min, m/z [M + H]+ = 358/360 (Method C)


 


67




a) Intermediate 56 b) 4-Chloro-6-methyl- pyrimidin-2-ylamine
Rt = 1.72 min, m/z [M + H]+ = 304/306 (Method C)


 


68




a) Intermediate 59 b) 4-Chloro-5-fluoro- pyrimidin-2-ylamine
Rt = 4.02 min, m/z [M + H]+ = 422/424 (Method C)


 


69




a) Intermediate 56 b) 2,4-Dichloro-5- fluoro -pyrimidine
Rt = 4.52 min, m/z [M + H]+ = 427-430 (Method C)


 


70




a) Intermediate 60 b) 4-Chloro-5-fluoro- pyrimidin-2-ylamine
Rt = 4.52 min, m/z [M + H]+ = 448/450 (Method C)


 


71




a) Intermediate 61 b) 4-Chloro-5-fluoro- pyrimidin-2-ylamine
Rt = 4.14 min, m/z [M + H]+ = 442 (Method C)


 


183




a) Intermediate 182 b) 4-Chloro-5-fluoro- pyrimidin-2-ylamine
Rt = 2.90 min, m/z [M + H]+ = 350/352 (Method C)


 


184




a) Intermediate 182 b) 4-Chloro-5-methoxy- pyrimidin-2-ylamine
Rt = 2.21 min, m/z [M + H]+ = 362/364 (Method C)









Example A14
a) Preparation of Intermediate 72




A mixture of intermediate 65 (0.17 g, 0.49 mmol), 48% aqueous hydrobromic acid solution (1.24 ml, 7.38 mmol) and glacial acetic acid (3.5 ml) was stirred at 110° C. for 2 hours and then stood at ambient temperature for 18 hours. The mixture was stirred at 110° C. for further 7 hours, cooled to ambient temperature and the solids were collected by filtration. Purification by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume), afforded the desired product as a yellow solid (0.09 g, 71%).
LCMS (Method D): Rt=0.29 min, m/z [M+H]+=242
b) Preparation of Intermediate 73




A solution of intermediate 72 (0.08 g, 0.35 mmol), triethylamine (0.24 ml, 1.76 mmol) and N-phenylbis(trifluoromethanesulphonimide) (0.31 g, 0.880 mmol) in DMF (5 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the desired product (0.18 g, 100%).
LCMS (Method C): Rt=4.00 min, m/z [M+H]+=506
Example A15
a) Preparation of Intermediate 74




A mixture of intermediate 36 (0.23 g, 1.16 mmol), 1,2-dibromoethane (0.11 ml, 1.28 mmol), potassium carbonate (0.53 g, 3.86 mmol) and DMF (4.6 ml) was stirred at 50° C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 3:1 by volume), to afford the desired product as a white solid (229 mg, 64%).
Example A16
Preparation of Intermediate 75




A mixture of intermediate 36 (0.25 g, 1.25 mmol), 1,3-dibromopropane (0.14 ml, 1.37 mmol), potassium carbonate (0.57 g, 4.12 mmol) and DMF (5 ml) was stirred at ambient temperature for 18 hours. The mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 3:1 by volume), to afford the desired product as a colorless oil (0.22 g, 56%).
Example A17
a) Preparation of Intermediate 76




A stirred solution of intermediate 62 (0.81 g, 2.63 mmol) in anhydrous DMF (25 ml), under a nitrogen atmosphere at ambient temperature, was treated portionwise with sodium hydride (0.32 g, 7.89 mmol, 60% in mineral oil). After stirring for 30 minutes, 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 4.6 mmol) was added portionwise and the resulting mixture stirred at 100° C. for 24 hours. The mixture was cooled to ambient temperature, quenched with water and partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (0:1 to 1:9 by volume), to afford the desired product as a yellow solid (0.53 g, 41%).
LCMS (Method C): Rt=3.44 min, m/z [M+H]+=491/493
Intermediates 77 to 79 and 166 to 168 were prepared according to the reaction protocol of example A17 using the appropriate starting materials (Table 10).










TABLE 10





Intermediate
Structure
Starting Materials
LCMS Data


















77




a) Intermediate 4 b) 4- Methanesulfonyloxy- piperidine-1- carboxylic acid tert- butyl ester
Rt = 2.52 min, m/z [M + H]+ = 473/475 (Method C)


 


78




a) Intermediate 62 b) Dimethyl- carbamylchloride
Rt = 2.61 min, m/z [M + H]+ = 379/381 (Method B)


 


79




a) Intermediate 62 b) 3- Methanesulfonyloxy- pyrrolidine-1- carboxylic acid tert- butyl ester
Rt = 3.28 min, m/z [M + H]+ = 477 (Method C)


 


166




a) Intermediate 62 b) 1- Methoxypropan-2- yl-methanesulfonate
Rt = 2.81 min, m/z [M + H]+ = 380/382 (Method B)


 


167




a) Intermediate 62 b) Methanesulfonic acid tetrahydro- furan-3-yl ester
Rt = 2.56 min, m/z [M + H]+ = 378/380 (Method C)


 


168




a) Intermediate 62 b) 4-Methyl- piperazine-1- carbonyl chloride
Rt = 2.29 min, m/z [M + H]+ = 436/438 (Method C)









Example A18
a) Preparation of Intermediate 96




A mixture of intermediate 62 (0.50 g, 1.62 mmol), 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (0.64 g, 2.27 mmol), caesium carbonate (1.19 g, 3.65 mmol) and DMF (14 ml) was heated by microwave irradiation at 110° C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:9 by volume), to afford the desired product as an off-white solid (0.50 g, 66%).
LCMS (Method A): Rt=3.30 min, m/z [M+H]+=463/465
Example A19
a) Preparation of Intermediate 100




A mixture of intermediate 62 (0.50 g, 1.62 mmol), 3-iodo oxetane (1.45 g, 7.86 mmol), caesium carbonate (2.11 g, 6.48 mmol) and DMF (0.95 ml) was heated at 100° C. for 48 hours. The mixture was cooled to ambient temperature and partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the desired product as pale yellow solid (0.32 g, 55%).
LCMS (Method C): Rt=2.49 min, m/z [M+H]+=364/366
Intermediates 80 to 116, 160, 169, 170, 176, 185, 193, 194 and 195 were prepared according to the reaction protocol of example A19 using the appropriate starting materials (Table 11).










TABLE 11





Intermediate
Structure
Starting Materials
LCMS Data


















80




a) Intermediate 4 b) 2-Chloro-N- isopropylacetamide
Rt = 0.30/1.87 min, m/z [M + H]+ = 375/377 (Method A)


 


81




a) Intermediate 62 b) 2-Bromoethyl methyl ether
Rt = 2.65 min, m/z [M + H]+ = 366/368 (Method C)


 


82




a) Intermediate 62 b) 2,2-Dimethyl- oxirane
Rt = 2.41 min, m/z [M + H]+ = 380/382 (Method A)


 


83




a) Intermediate 4 b) 4-Bromomethyl- piperidine-1- carboxylic acid tert-butyl ester
Rt = 2.32 min, m/z [M + H]+ = 487/489 (Method D)


 


84




a) Intermediate 4 b) 4-Bromo-2- methylbutanol
Rt = 1.60 min, m/z [M + H]+ = 376/378 (Method D)


 


85




a) Intermediate 4 b) 3-Iodo- azetidine-1- carboxylic acid tert-butyl ester
Rt = 2.39 min, m/z [M + H]+ = 445/447 (Method B)


 


86




a) Intermediate 4 b) 1-Bromo-3- methoxypropane
Rt = 1.73 min, m/z [M + H]+ = 362/364 (Method C)


 


87




a) Intermediate 4 b) 4-Bromomethyl- tetrahydro-pyran
Rt = 1.78 min, m/z [M + H]+ = 388/390 (Method C)


 


88




a) Intermediate 4 b) Chloro- acetonitrile
Rt = 1.85 min, m/z [M + H]+ = 329/331 (Method C)


 


89




a) Intermediate 4 b) 3-Chloro- propionitrile
Rt = 1.81 min, m/z [M + H]+ = 343/345 (Method C)


 


90




a) Intermediate 6 b) 2,2-Dimethyl- oxirane
Rt = 2.01 min, m/z [M + H]+ = 376/378 (Method C)


 


91




a) Intermediate 4 b) Intermediate 74
Rt = 2.22 min, m/z [M + H]+ = 516/518 (Method C)


 


92




a) Intermediate 4 b) 3-Iodo-oxetane
Rt = 1.83 min, m/z [M + H]+ = 346/348 (Method B)


 


93




a) Intermediate 4 b) Methyl 2- bromoisobutyrate
Rt = 1.89 min, m/z [M + H]+ = 390/392 (Method C)


 


94




a) Intermediate 4 b) Intermediate 75
Rt = 2.28 min, m/z [M + H]+ = 530/532 (Method C)


 


95




a) Intermediate 52 b) Methyl iodide
Rt = 1.83 min, m/z [M + H]+ = 405/407 (Method C)


 


97




a) Intermediate 66 b) 4-(Bromomethyl) tetrahydropyran
Rt = 3.21 min, m/z [M + H]+ = 456/458 (Method C)


 


98




a) Intermediate 66 b) 2,2-Dimethyl- oxirane
Rt = 2.93 min, m/z [M + H]+ = 430/432 (Method C)


 


99




a) Intermediate 62 b) 4-Bromomethyl- tetrahydro-pyran
Rt = 2.76 min, m/z [M + H]+ = 406/408 (Method C)


 


101




a) Intermediate 62 b) 1-Bromo-3- methoxy-propane
Rt = 2.72 min, m/z [M + H]+ = 380/382 (Method B)


 


102




a) Intermediate 67 b) 1-Bromo-3- methoxy-propane
Rt = 1.89 min, m/z [M + H]+ = 376/.78 (Method C)


 


103




a) Intermediate 53 b) 4-Bromomethyl- tetrahydro-pyran
Rt = 2.01 min, m/z [M + H]+ = 402/404 (Method C)


 


104




a) Intermediate 53 b) 1-Bromo-3- methoxy-propane
Rt = 2.00 min, m/z [M + H]+ = 376/378 (Method C)


 


105




a) Intermediate 51 b) 1-Bromo-3- methoxy-propane
Rt = 1.96 min, m/z [M + H]+ = 332/334 (Method B)


 


106




a) Intermediate 117 b) 1-Bromo-3- methoxy-propane
Rt = 2.83 min, m/z [M + H]+ = 394/396 (Method C)


 


107




a) Intermediate 118 b) 1-Bromo-3- methoxy-propane
Rt = 3.70 min, m/z [M + H]+ = 399/401 (Method B)


 


108




a) Intermediate 66 b) 3-Iodo-oxetane
Rt = 2.69 min, m/z [M + H]+ = 414/416 (Method D)


 


109




a) Intermediate 62 b) 1-Iodo-2- methoxy-2-methyl- propane
Rt = 3.00 min, m/z [M + H]+ = 394/396 (Method C)


 


110




a) Intermediate 62 b) 4-(3-Chloro- propyl)-morpholine
Rt = 1.78 min, m/z [M + H]+ = 435/437 (Method B)


 


111




a) Intermediate 66 b) 3-Iodo-azetidine- 1-carboxylic acid tert-butyl ester
Rt = 3.21 min, m/z [M + H]+ = 513/515 (Method D)


 


112




a) Intermediate 125 b) 3-Iodo-azetidine- 1-carboxylic acid tert-butyl ester
Rt = 3.34 min, m/z [M + H]+ = 503/505 (Method D)


 


113




a) Intermediate 125 b) 3-Iodo-oxetane
Rt = 2.82 min, m/z [M + H]+ = 404/406 (Method C)


 


114




a) Intermediate 125 b) 1-Bromo-3- methoxypropane
Rt = 3.11 min, m/z [M + H]+ = 420/422 (Method C)


 


115




a) Intermediate 127 b) 1-Bromo-3- methoxypropane
Rt = 3.43 min, m/z [M + H]+ = 414/416 (Method C)


 


116




a) Intermediate 62 b) Methanesulfonic acid 1-methyl-1H- pyrazol-4-ylmethyl ester
Rt = 2.44 min, m/z [M + H]+ = 402/404 (Method C)


 


160




a) Intermediate 62 b) 2-Chloromethyl- morpholine-4- carboxylic acid tert-butyl ester
Rt = 3.35 min, m/z [M + H]+ = 507/509 (Method C)


 


169




a) Intermediate 62 b) Methanesulfonic acid 3-methyl- oxetan-3-ylmethyl ester
Rt = 2.57 min, m/z [M + H]+ = 392/394 (Method B)


 


170




a) Intermediate 117 b) 3-Iodo-oxetane
Rt = 2.51 min, m/z [M + H]+ = 378/380 (Method C)


 


176




a) Intermediate 62 b) 2-Bromomethyl- tetrahydro-furan
Rt = 2.82 min, m/z [M + H]+ = 392/394 (Method C)


 


185




a) Intermediate 4 b) (3-Bromo- propyl)-carbamic acid tert-butyl ester
Rt = 2.19 min, m/z [M + H]+ = 447/449 (Method B)


 


193




a) Intermediate 121 b) 1-Bromo-2- methoxy-ethane
Rt = 1.80 min, m/z [M + H]+ = 421/423 (Method A)


 


194




a) Intermediate 121 b) 1-Bromo-3- methoxy-propane
Rt = 1.80 min, m/z [M + H]+ = 435/437 (Method B)


 


195




a) Intermediate 121 b) 1-Bromo-2- ethoxy-ethane
Rt = 1.84 min, m/z [M + H]+ = 435/437 (Method C)









Example A20
a) Preparation of Intermediate 121




A stirred solution of intermediate 96 (0.50 g, 1.073 mmol) in DCM (20 ml) under a nitrogen atmosphere at ambient temperature was treated with trifluoroacetic acid (5.0 ml, 65.0 mmol) and the resulting mixture stirred for 1 hours. The mixture was concentrated in vacuo and the residue was triturated with MeOH to afford the desired product as an off-white solid (0.41 g, 100%).
LCMS (Method B): Rt=1.98 min, m/z [M+H]+=363/365
Intermediates 117 to 128, 161, 171 and 186 were prepared according to the reaction protocol of example A20 using the appropriate starting materials (Table 12).










TABLE 12





Intermediate
Structure
Starting Materials
LCMS Data







117




Intermediate 68
Rt = 2.22 min, m/z [M + H]+ = 322/324 (Method C)


 


118




Intermediate 69
Rt = 3.25 min, m/z [M + H]+ = 327/329 (Method B)


 


119




Intermediate 77



 


120




Intermediate 76
Rt = 1.47 min, m/z [M + H]+ = 391/393 (Method C)


 


122




Intermediate 111
Rt = 1.98 min, m/z [M + H]+ = 413/415 (Method D)


 


123




Intermediate 63
Rt = 1.73 min, m/z [M + H]+ = 260 (Method B)


 


124




Intermediate 85
Rt = 0.83 min, m/z [M + H]+ = 345/347 (Method C)


 


125




Intermediate 70
Rt = 2.93 min, m/z [M + H]+ = 348/350 (Method C)


 


126




Intermediate 112
Rt = 2.10 min, m/z [M + H]+ = 403/405 (Method D)


 


127




Intermediate 71
Rt = 2.67 min, m/z [M + H]+ = 42/444/346 (Method D)


 


128




Intermediate 79
Rt = 1.76 min, m/z [M + H]+ = 377/379 (Method C)


 


161




Intermediate 160
Rt = 1.80 min, m/z [M + H]+ = 407/409 (Method C)


 


171




Intermediate 175
Rt = 0.33 min, m/z [M + H]+ = 391/393 (Method C)


 


186




Intermediate 185









Example A21
Preparation of Intermediate 129




A stirred solution of intermediate 124 (0.38 g, 0.83 mmol) in a mixture of MeOH (13 ml) and 1,2-dichloroethane (7.6 ml) under a nitrogen atmosphere at ambient temperature was treated sequentially with sodium acetate (0.07 g, 0.832 mmol), formaldehyde solution (37 wt % in water) (0.12 ml, 1.664 mmol) and sodium triacetoxyborohydride (0.35 g, 1.664 mmol), and the resulting mixture was stirred for 3 hours. The mixture was purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume), to afford the desired product as a yellow solid (231 mg, 77%).
LCMS (Method C): Rt=0.86 min, m/z [M+H]+=359/361
Intermediates 130 to 134, 172, 173, 176, 187, 189, 196 and 197 were prepared according to the reaction protocol of example A21 using the appropriate starting materials (Table 13).










TABLE 13





Intermediate
Structure
Starting Materials
LCMS Data







130




a) Intermediate 121 b) Formaldehyde solution (37 wt % in water)
Rt = 1.82 min, m/z [M + H]+ = 377/379 (Method C)


 


131




a) Intermediate 124 b) Acetone
Rt = 1.20 min, m/z [M + H]+ = 387/389 (Method C)


 


132




a) Intermediate 122 b) Formaldehyde solution (37 wt % in water)
Rt = 2.04 min, m/z [M + H]+ = 427/429 (Method D)


 


133




a) Intermediate 126 b) Formaldehyde solution (37 wt % in water)
Rt = 1.98 min, m/z [M + H]+ = 417/419 (Method D)


 


134




a) Intermediate 128 b) Formaldehyde solution (37 wt % in water)
Rt = 1.76 min, m/z [M + H]+ = 391/393 (Method C)


 


172




a) Intermediate 121 b) Propionaldehyde
Rt = 1.80 min, m/z [M + H]+ = 405/407 (Method C)


 


173




a) Intermediate 121 b) Cyclopropane carbaldehyde
Rt = 1.85 min, m/z [M + H]+ = 417/419 (Method C)


 


189




a) Intermediate 121 b) Cyclopentanone
Rt = 1.88 min, m/z [M + H]+ = 431/433 (Method B)


 


187




a) Intermediate 121 b) Cyclopentane- carbaldehyde
Rt = 2.06 min, m/z [M + H]+ = 445/447 (Method C)


 


196




a) Intermediate 121 b) Acetone
Rt = 1.80 min, m/z [M + H]+ = 405/407 (Method C)


 


197




a) Intermediate 121 b) 1-Methoxy-propan- 2-one
Rt = 1.72 min, m/z [M + H]+ = 435/437 (Method C)









Example A22
a) Preparation of Intermediate 135




A mixture of intermediate 13 (0.15 g, 0.43 mmol), N-iodosuccinimide (0.29 g, 1.29 mmol) and DMF (3 ml) was stirred at 100° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH in DCM (0:1 to 1:19 by volume), to afford the desired product (0.30 g, 51%).
LCMS (Method C): Rt=2.96 min, m/z [M+H]+=474/476
Intermediates 136, 137 and 202 were prepared according to the reaction protocol of intermediate 135 using the appropriate starting materials (Table 14).










TABLE 14





Intermediate
Structure
Starting Materials
LCMS Data







136




Intermediate 14
Rt = 2.72 min, m/z [M + H]+ = 488/490 (Method C)


 


137




Intermediate 87



 


202




Intermediate 20
Rt = 3.26 min, m/z [M + H]+ = 458/460 (Method C)









b) Preparation of Intermediate 138




A mixture of intermediate 135 (0.10 g, 0.22 mmol), copper cyanide (0.02 g, 0.22 mmol) and DMF (1.0 ml) was stirred under a nitrogen atmosphere at 100° C. for 9 hours. The mixture was cooled to ambient temperature and partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:0 by volume), to afford the desired product (0.06 g, 68%).
LCMS (Method A): Rt=2.78 min, m/z [M+H]+=373/375
Intermediates 139 and 140 were prepared according to the reaction protocol of intermediate 138 using the appropriate starting materials (Table 15).










TABLE 15





Intermediate
Structure
Starting Materials
LCMS Data







139




Intermediate 136
Rt = 2.59 min, m/z [M + H]+ = 387/389 (Method C)


 


140




Intermediate 137
Rt = 2.92 min, m/z [M + H]+ = 413/415 (Method C)









Example A23
a) Preparation of Intermediate 141




A stirred solution of intermediate 93 (0.10 g, 0.26 mmol) in anhydrous tetrahydrofuran (6 ml) under nitrogen atmosphere at 0° C. was treated with a 1 M solution of lithium aluminium hydride in tetrahydrofuran (0.38 ml, 0.38 mmol). After 0.5 hour, the mixture was diluted sequentially with water (1.0 ml) and 3.75 M aqueous solution of sodium hydroxide (0.5 ml), and the resulting mixture was stirred for 10 minutes. The mixture was filtered through celite, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of DCM and MeOH (1:0 to 9:1 by volume), to afford the desired product (0.06 g, 65%).
LCMS (Method C): Rt=1.88 min, m/z [M+H]+=362/364
Example A24
a) Preparation of Intermediate 142




A mixture of intermediate 4 (0.10 g, 0.35 mmol), methanesulfonyl-ethene (0.26 ml, 2.92 mmol), triethylamine (0.12 ml, 0.828 mmol) and MeOH (2.0 ml) was heated by microwave irradiation at 120° C. for 0.5 hour. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of DCM and 2 M ammonia solution in MeOH (1:0 to 19:1 by volume), to afford the desired product as a beige solid (0.11 g, 81%).
LCMS (Method B): Rt=1.59/1.72 min, m/z [M+H]+=396/398
Example A25
a) Preparation of Intermediate 143




A mixture of intermediate 107 (0.21 g, 0.52 mmol), methylamine hydrochloride (0.14 g, 2.10 mmol), DIPEA (0.55 ml, 3.15 mmol), 1-butanol (2.5 ml) and tetrahydrofuran (1.5 ml) was heated by microwave irradiation at 150° C. for 8 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and cyclohexane (0:1 to 1:0 by volume), to afford the desired product as a white solid (0.18 g, 86%).
LCMS (Method C): Rt=3.14 min, m/z [M+H]+=394/396
Example A26
a) Preparation of Intermediate 144




A stirred solution of intermediate 121 (0.34 g, 0.94 mmol) in a mixture of MeOH (9 ml) and acetic acid (4.5 ml) under nitrogen atmosphere at ambient temperature was treated with (1-ethoxycyclopropoxy)trimethylsilane (0.94 ml, 4.68 mmol). After stirring for 10 minutes, the mixture was treated with sodium cyanoborohydride (0.35 g, 5.62 mmol) and the resulting mixture was stirred at 55° C. for 1.5 hours. The mixture was cooled to ambient temperature and purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:19 by volume), afforded the desired product as a white solid (0.09 g, 25%).
LCMS (Method B): Rt=1.82 min, m/z [M+H]+=403/405
Intermediate 199 was prepared according to the reaction protocol of example A26 using the appropriate starting materials (Table 16).










TABLE 16





Intermediate
Structure
Starting Materials
LCMS Data







199




a) Intermediate 119 b) (1-ethoxycyclo propoxy) trimethylsilane
Rt = 1.39 min, m/z [M + H]+ = 413/415 (Method C)









Example A27
a) Preparation of Intermediate 145




A stirred suspension of intermediate 101 (0.20 g, 0.526 mmol) and zinc difluoromethanesulfinate (0.31 g, 1.05 mmol) in a mixture of DCM (8.0 ml) and water (3.2 ml) at ambient temperature was treated sequentially with trifluoroacetic acid (0.04 ml, 0.52 mmol) and tert-butylhydroperoxide 70% solution in water (1.84 mmol). After stirring for 24 hours, the mixture was treated sequentially with zinc difluoromethanesulfinate (0.31 g, 1.05 mmol) and tert-butylhydroperoxide 70% solution in water (0.94 mmol), and the resulting mixture was stirred for 48 hours. The mixture was partitioned between DCM and saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (0:100 to 1:19 by volume), to afford the desired product (0.06 g, 24%).
LCMS (Method B): Rt=3.22 min, m/z [M+H]+=430/432
Example A28
a) Preparation of Intermediate 146




A stirred solution of intermediate 54 (0.2 g, 0.48 mmol) in a mixture of tetrahydrofuran (3.6 ml) and water (0.4 ml) at ambient temperature was treated sequentially with triethylamine (0.15 g, 1.44 mmol), di-tert-butyldicarbonate (0.2 g, 0.96 mmol) and triphenyl phosphine (0.25 g, 0.96 mmol), and the resulting mixture was stirred at 30° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative TLC to afford the desired product (0.05 g, 21%).
Example A29
a) Preparation of Intermediate 147




A stirred solution of 1-(3-methyl-oxetan-3-yl)-ethanone (0.5 g, 4.4 mmol) in anhydrous tetrahydrofuran (7.0 ml) under a nitrogen atmosphere at −78° C. was treated with 0.5 M solution of ethynylmagnesium bromide in tetrahydrofuran (9.7 ml, 4.85 mmol). The resulting mixture was warmed to ambient temperature and stirred for 3.5 hours. The mixture was cooled to 0° C., diluted with a saturated aqueous solution of ammonium chloride and extracted with Et2O. The combined extracts were washed with water and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired product (0.67 g, 100%).
Intermediates 148, 149, 159 and 174 were prepared according to the reaction protocol of example A29 using the appropriate starting materials (Table 17).









TABLE 17





Intermediate
Structure
Starting Materials







148




1-Cyclopropyl-propan-2-one


 


149




Cyclopropyl methyl ketone- d8


 


159




3-Acetyl azetidine-1- carboxylic acid tert-butyl ester


 


174




1-Cyclopropyl-2-fluoro- ethanone









Example A30
a) Preparation of Intermediate 150




A degassed suspension of intermediate 85 (0.07 g, 0.16 mmol), 2-methyl-but-3-yn-2-ol (0.02 ml, 0.20 mmol), tetrakis(triphenylphosphine) palladium (0.04 g, 0.04 mmol), copper iodide (3.7 mg, 0.020 mmol) and triethylamine (0.191 ml, 1.37 mmol) in acetonitrile (2.6 ml) was heated by microwave irradiation at 100° C. for 1.25 hours. The mixture was cooled to ambient temperature, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH in DCM (0:1 to 1:10 by volume), to afford the desired product (0.04 g, 55%).
LCMS (Method B): Rt=2.18 min, m/z [M+H]+=449
Intermediates 151 to 158 were prepared according to the reaction protocol of example A30 using the appropriate starting materials (Table 18).










TABLE 18





Intermediate
Structure
Starting Materials
LCMS Data







151




a) Intermediate 13 b) 4-(1-Hydroxy-1- methyl-prop-2- ynyl)-piperidine-1- carboxylic acid tert- butyl ester
Rt = 2.92 min, m/z [M + H]+ = 521 (Method E)


 


152




a) Intermediate 73 b) 2-Methyl-but-3- yn-2-ol
Rt = 2.94 min, m/z [M + H]+ = 440 (Method B)


 


153




a) Intermediate 91 b) 2-Methyl-but-3- yn-2-ol
Rt = 1.99 min, m/z [M + H]+ = 520 (Method C)


 


154




a) Intermediate 94 b) 2-Methyl-but-3- yn-2-ol
Rt = 2.02 min, m/z [M + H]+ = 534 (Method C)


 


155




a) Intermediate 83 b) 2-Methyl-but-3- yn-2-ol
Rt = 1.95 min, m/z [M + H]+ = 491 (Method A)


 


156




a) Intermediate 146 b) 2-Methyl-but-3- yn-2-ol



 


157




a) Intermediate 13 b) Intermediate 159
Rt = 2.10 min, m/z [M + H]+ = 493 (Method B)


 


158




a) Intermediate 13 b) 3-Ethynyl-3- hydroxy-azetidine-1- carboxylic acid tert- butyl ester
Rt = 1.90 min, m/z [M + H]+ = 465 (Method C)









Example A31
a) Preparation of Intermediate 175




A stirred mixture of intermediate 62 (0.70 g, 1.66 mmol), powdered potassium hydroxide (0.11 g, 1.96 mmol), toluene (15.0 ml) and DMF (1.0 ml) under a nitrogen atmosphere at 80° C. was treated portionwise with 3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.98 mmol) over 1 hour. After 6 hours, a second aliquot of 3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 0.98 mmol) was added and the resulting mixture stirred at 80° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and DCM. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the desired product as a yellow oil (0.79 g, 97%).
LCMS (Method C): Rt=3.51 min, m/z [M+H]+=491/493
Example A32
a) Preparation of Intermediate 177




A stirred mixture of intermediate 186 (0.17 g, 0.49 mmol), triethylamine (0.10 ml, 0.73 mmol) and DMF (5.0 ml) at ambient temperature was treated with pentanoyl chloride (0.06 ml, 0.54 mmol). After 0.5 hour, the mixture was concentrated in vacuo and the residue purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:9 by volume) afforded the desired product as a yellow foam (0.12 g, 57%). LCMS (Method C): Rt=2.08 min, m/z [M+H]+=431/433
Intermediate 191 was prepared according to the reaction protocol of example A32 using the appropriate starting materials (Table 19).










TABLE 19





Intermediate
Structure
Starting Materials
LCMS Data







191




a) Intermediate 186 b) Acetyl chloride
Rt = 1.81 min, m/z [M + H]+ = 359/391 (Method B)









Example A33
a) Preparation of Intermediate 178




A stirred mixture of intermediate 128 (0.23 g, 0.61 mmol), DIPEA (0.16 ml, 0.92 mmol) and DMF (6.0 ml) at ambient temperature was treated with 1,1,1-trifluoro-3-iodo-propane (0.09 ml, 0.79 mmol), and the resulting mixture was heated at 50° C. for 72 hours and then at 70° C. for 10 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:19 by volume), afforded the desired product as a cream solid (0.12 g, 43%).
LCMS (Method C): Rt=2.18 min, m/z [M+H]+=473/475
Intermediate 179, 198, 200 and 201 were prepared according to the reaction protocol of example A33 using the appropriate starting materials (Table 20).










TABLE 20





Intermediate
Structure
Starting Materials
LCMS Data







179




a) Intermediate 128 b) 1-Bromo-2- fluoro-ethane
Rt = 1.81 min, m/z [M + H]+ = 423/425 (Method C)


 


198




a) Intermediate 120 b) 1-Bromo-2- fluoro-ethane
Rt = 1.84 min, m/z [M + H]+ = 437/439 (Method B)


 


200




a) Intermediate 120 b) Iodomethyl- cyclopropane
Rt = 1.91 min, m/z [M + H]+ = 445/447 (Method B)


 


201




a) Intermediate 120 b) 1,1,1-Trifluoro-3- iodo-propane
Rt = 2.01 min, m/z [M + H]+ = 487/489 (Method C)









Example A34
a) Preparation of Intermediate 190




A stirred mixture of intermediate 121 (0.25 g, 0.52 mmol), DIPEA (0.27 ml, 1.57 mmol) and tetrahydrofuran (7.0 ml) under a nitrogen atmosphere at 0° C. was treated with trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.08 ml, 0.55 mmol). After stirring at ambient temperature for 2 hours, a second aliquot of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.18 ml, 1.24 mmol) was added and the resulting mixture was stirred at 50° C. for 2.5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (0:1 to 1:19 by volume), to afford the desired product as a white solid (0.12 g, 74%).
LCMS (Method B): Rt=3.12 min, m/z [M+H]+=445/447
Example A35
a) Preparation of Intermediate 192




A stirred mixture of intermediate 121 (0.20 g, 0.42 mmol), triethylamine (0.17 ml, 1.22 mmol) and tetrahydrofuran (4.0 ml) under a nitrogen atmosphere at 0° C. was treated with acetyl chloride (0.04 ml, 0.61 mmol), and the resulting mixture was stirred at ambient temperature for 1.5 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with a mixture of 2 M ammonia solution in MeOH and DCM (0:1 to 1:9 by volume), to afford the desired product as a white solid (0.10 g, 59%).
LCMS (Method B): Rt=2.29 min, m/z [M+H]+=405/407
Example A36
a) Preparation of Intermediate 203




A stirred suspension of intermediate 202 (0.47 g, 1.03 mmol) in THF (12 ml) under a nitrogen atmosphere at ambient temperature was treated sequentially with 4-dimethylaminopyridine (0.03 g, 0.21 mmol), triethylamine (0.43 ml, 3.09 mmol) and di-tert-butyldicarbonate (0.49 g, 2.27 mmol). The resulting mixture was stirred at 50° C. for 2 hour. A second aliquot of di-tert-butyldicarbonate (0.49 g, 2.27 mmol) was added and the mixture was heated at 50° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between water and EtOAc. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 7:3 by volume), to afford the desired product as a brown solid (0.55 g, 81%).
LCMS (Method B): Rt=4.64 min, m/z [M+H]+=658/660b)
Preparation of Intermediate 204




A stirred mixture of intermediate 203 (0.50 g, 0.76 mmol), copper iodide (0.06 g, 0.30 mmol), 1,10-phenanthroline (0.11 g, 0.608 mmol), caesium carbonate (0.49 g, 1.52 mmol) and 2-methoxyethanol (10.0 ml, 127 mmol) was heated by microwave irradiation at 100° C. for 0.5 hour. The mixture was cooled to ambient temperature, filtered and the filtrate concentrated in vacuo. The residue was diluted with DCM (10 ml) and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then concentrated in vacuo and the residue purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of EtOAc and pentane (0:1 to 1:0) followed by 2.0 M ammonia solution in MeOH and DCM (0:1 to 1:19 by volume), afforded the desired product as a white solid (0.09 g, 30%).
LCMS (Method B): Rt=2.28 min, m/z [M+H]+=406/408
Example A37
a) Preparation of Intermediate 205




A stirred solution of (methyldiphenylsilyl)acetylene (1.10 ml, 4.99 mmol) in anhydrous tetrahydrofuran (20 ml) under an argon atmosphere at −78° C. was treated with 1.6 M solution of n-butyllithium in hexanes (3.2 ml, 5.12 mmol) maintaining the temperature below −70° C. After stirring for 1 hour, the mixture was treated with 1-fluoro-2-propanone (0.36 ml, 5.00 mmol) and the resulting mixture stirred at 0° C. for 1.5 hours. The mixture was quenched by the addition of water and partitioned between water and diethyl ether. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and pentane (0:1 to 1:19 by volume), to afford the desired product as a colourless oil (0.91 g, 61%).
Intermediate 206 was prepared according to the reaction protocol of example A37 using the appropriate starting materials (Table 21).









TABLE 21





Intermediate
Structure
Starting Materials







206




1-Cyclopropyl-ethanone









Example A38
a) Preparation of Intermediate 207
Intermediate 206 (1.40 g, 4.57 mmol) was purified by chiral preparative HPLC with the following conditions: column, Diacel Chiralpak IC, 250×20 mm, 5 μm; mobile phase, DCM in Heptane (40%), flow 18 ml/min; detector, UV 254 nm. The first eluting enantiomer was isolated as a colourless oil (0.45 g, 32%) and second eluting enantiomer (intermediate 207) as a colourless oil (0.49 g, 35%).
Preparation of Compounds
The values of acid content (e.g. formic acid or acetic acid) in the compounds as provided herein, are those obtained experimentally and may vary when using different analytical methods. The content of formic acid or acetic acid reported herein was determined by 1H NMR integration and is reported together with the 1H NMR results. Compounds with an acid content of below 0.5 equivalents may be considered as free bases.
Example B1
Example B1.a
Preparation of Compound 1




A mixture of intermediate 4 (0.07 g, 0.21 mmol), 2-methylbut-3-yn-2-ol (0.02 g, 0.23 mmol), tetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol), copper(I) iodide (4.0 mg, 0.02 mmol), triethylamine (0.24 ml, 1.43 mmol) and acetonitrile (1.5 ml) was heated by microwave irradiation at 100° C. for 15 minutes. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (1:19 to 1:4 by volume), followed by trituration with Et2O to afford the desired product as a pale yellow solid (0.022 g, 31%).
LCMS (Method E): Rt=1.69 min, m/z [M+H]+=294
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.27 (s, 1H), 8.73 (d, J=1.1 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J=2.9 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.04 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 1.52 (s, 6H).
A second batch was isolated with 1.0 equivalents of formic acid present.
Example B1.b
Preparation of Compound 97




A mixture of intermediate 100 (0.35 g, 0.96 mmol), 2-cyclopropyl-but-3-yn-2-ol (0.33 g, 2.96 mmol), tetrakis(triphenylphosphine) palladium (0.22 g, 0.19 mmol), copper(I) iodide (0.02 g, 0.09 mmol), triethylamine (0.95 ml, 6.82 mmol) and acetonitrile (15 ml) was heated by microwave irradiation at 100° C. for 2 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (1:19 by volume), afforded the desired product as a pale yellow solid (0.24 g, 62%).
LCMS (Method E): Rt=2.62 min, m/z [M+H]+=394
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=0.9 Hz, 1H), 8.60 (d, J=0.9 Hz, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.30 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 6.01-5.93 (m, 1H), 5.35 (s, 1H), 5.11 (t, J=7.5 Hz, 2H), 5.00 (t, J=6.6 Hz, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.60-0.39 (m, 4H).
Example B1.c
a) Preparation of Compound 104




A mixture of intermediate 144 (0.09 g, 0.23 mmol), 2-cyclopropyl-but-3-yn-2-ol (0.07 g, 0.69 mmol), tetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol), copper(I) iodide (4.0 mg, 0.02 mmol), triethylamine (0.23 ml, 1.62 mmol) and acetonitrile (3.0 ml) was heated by microwave irradiation at 100° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of 2.0 M ammonia solution in MeOH and DCM (1:0 to 1:19 by volume). Further purification by reverse phase preparative HPLC, eluting with a mixture of acetonitrile and water containing 0.1% ammonium hydroxide (1:19 to 7:3 by volume over 20 min), afforded the desired product as a white solid (0.044 g, 43%).
LCMS (Method E): Rt=2.25 min, m/z [M+H]+=433
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.37-5.29 (m, 2H), 3.90-3.85 (m, 2H), 3.63-3.58 (m, 2H), 2.13-2.07 (m, 1H), 1.54 (s, 3H), 1.21-1.14 (m, 1H), 0.61-0.48 (m, 2H), 0.48-0.36 (m, 4H), 0.34-0.30 (m, 2H).
Compounds 2 to 96, 98 to 103, 105 to 110, 123, 126 to 156, 158 to 160, and 162 to 168 were prepared according to the reaction protocols of example B1 (B1.a, B1.b, B1.c) (Table 22).









TABLE 22





Compound
Structure
Starting Materials

















2




a) Intermediate 13 b) 2-Methylbut-3-yn- 2-ol


 


3




a) Intermediate 14 b) 2-Methylbut-3-yn- 2-ol


 


4




a) Intermediate 6 b) 2-Methylbut-3-yn- 2-ol


 


5




a) Intermediate 7 b) 2-Methylbut-3-yn- 2-ol


 


6




a) Intermediate 8 b) 2-Methylbut-3-yn- 2-ol


 


7




a) Intermediate 9 b) 2-Methylbut-3-yn- 2-ol


 


8




a) Intermediate 10 b) 2-Methylbut-3-yn- 2-ol


 


9




a) Intermediate 4 b) 1-Ethynyl- cyclopropanol


 


10




a) Intermediate 20 b) But-3-yn-2-ol


 


11




a) Intermediate 16 b) 2-Methylbut-3-yn- 2-ol


 


12




a) Intermediate 12 b) 2-Methylbut-3-yn- 2-ol


 


13




a) Intermediate 20 b) Prop-2-yn-1-ol


 


14




a) Intermediate 5 b) 2-Methylbut-3-yn- 2-ol


 


15




a) Intermediate 20 b) 2-Methylbut-3-yn- 2-ol


 


16




a) Intermediate 21 b) 2-Methylbut-3-yn- 2-ol


 


17




a) Intermediate 21 b) 2-Thiazol-2-yl-but- 3-yn-2-ol


 


18




a) Intermediate 20 b) 1- Ethynylcyclopentanol


 


19




a) Intermediate 21 b) 1- Ethynylcyclopentanol


 


20




a) Intermediate 23 b) 2-Thiazol-2-yl-but- 3-yn-2-ol


 


21




a) Intermediate 22 b) 1-Ethynyl- cyclopropanol


 


22




a) Intermediate 14 b) 1-Ethynyl- cyclopropanol


 


23




a) Intermediate 22 b) 2-Thiazol-2-yl-but- 3-yn-2-ol


 


24




a) Intermediate 22 b) 2-Methylbut-3-yn- 2-ol


 


25




a) Intermediate 23 b) 2-Methylbut-3-yn- 2-ol


 


26




a) Intermediate 13 b) 2-Thiazol-2-yl-but- 3-yn-2-ol


 


27




a) Intermediate 14 b) 2-Thiazol-2-yl-but- 3-yn-2-ol


 


28




a) Intermediate 15 b) 2-Methylbut-3-yn- 2-ol


 


29




a) Intermediate 14 b) 3-Ethynyl-tetrahydro- furan-3-ol


 


30




a) Intermediate 80 b) 2-Methylbut-3-yn- 2-ol


 


31




a) Intermediate 13 b) 2-Oxazol-2-yl-but- 3-yn-2-ol


 


32




a) Intermediate 13 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


33




a) Intermediate 22 b) 1-Ethynyl- cyclopentanol


 


34




a) Intermediate 129 b) 2-Methylbut-3-yn- 2-ol


 


35




a) Intermediate 13 b) 3-Ethyl-pent-1-yn- 3-ol


 


36




a) Intermediate 14 b) 2-Phenyl-but-3-yn- 2-ol


 


37




a) Intermediate 14 b) 2-Cyclobutyl-but- 3-yn-2-ol


 


38




a) Intermediate 14 b) 1-Ethynyl- cyclohexanol


 


39




a) Intermediate 14 b) 5-Methoxy-3-methyl- pent-1-yn-3-ol


 


40




a) Intermediate 14 b) 3,4-Dimethyl-pent- 1-yn-3-ol


 


41




a) Intermediate 138 b) 2-Methylbut-3-yn- 2-ol


 


42




a) Intermediate 14 b) 1-Ethynyl- cyclobutanol


 


43




a) Intermediate 14 b) 3-Methyl-pent-1- yn-3-ol


 


44




a) Intermediate 86 b) 2-Methylbut-3-yn- 2-ol


 


45




a) Intermediate 62 b) 2-Methylbut-3-yn- 2-ol


 


46




a) Intermediate 26 b) 2-Methylbut-3-yn- 2-ol


 


47




a) Intermediate 14 b) Intermediate 147


 


48




a) Intermediate 64 b) 2-Methylbut-3-yn- 2-ol


 


49




a) Intermediate 25 b) 2-Methylbut-3-yn- 2-ol 


 


50




a) Intermediate 27 b) 2-Methylbut-3-yn- 2-ol


 


51




a) Intermediate 84 b) 2-Methylbut-3-yn- 2-ol


 


52




a) Intermediate 52 b) 2-Methylbut-3-yn- 2-ol


 


53




a) Intermediate 14 b) Intermediate 148


 


54




a) Intermediate 81 b) 2-Methylbut-3-yn- 2-ol


 


55




a) Intermediate 87 b) 2-Methylbut-3-yn- 2-ol


 


56




a) Intermediate 88 b) 2-Methylbut-3-yn- 2-ol


 


57




a) Intermediate 89 b) 2-Methylbut-3-yn- 2-ol


 


58




a) Intermediate 24 b) 2-Methylbut-3-yn- 2-ol


 


59




a) Intermediate 14 b) 2-Pyridin-2-yl-but-3- yn-2-ol


 


60




a) Intermediate 139 b) 2-Methylbut-3-yn- 2-ol


 


61




a) Intermediate 66 b) 2-Methylbut-3-yn- 2-ol


 


62




a) Intermediate 14 b) Prop-2-yn-1-ol


 


63




a) Intermediate 14 b) 2,2-Dimethyl-but-3- ynoic acid dimethylamide


 


64




a) Intermediate 82 b) 2-Methylbut-3-yn- 2-ol


 


65




a) Intermediate 92 b) 2-Methylbut-3-yn- 2-ol


 


66




a) Intermediate 141 b) 2-Methylbut-3-yn-2- ol


 


67




a) Intermediate 142 b) 2-Methylbut-3-yn- 2-ol


 


68




a) Intermediate 90 b) 2-Methylbut-3-yn- 2-ol


 


69




a) Intermediate 95 b) 2-Methylbut-3-yn- 2-ol


 


70




a) Intermediate 130 b) 2-Methylbut-3-yn- 2-ol


 


71




a) Intermediate 97 b) 2-Methylbut-3-yn- 2-ol


 


72




a) Intermediate 98 b) 2-Methylbut-3-yn- 2-ol


 


73




a) Intermediate 99 b) 2-Methylbut-3-yn- 2-ol


 


74




a) Intermediate 100 b) 2-Methylbut-3-yn- 2-ol


 


75




a) Intermediate 140 b) 2-Methylbut-3-yn- 2-ol


 


76




a) Intermediate 101 b) 2-Methylbut-3-yn- 2-ol


 


77




a) Intermediate 28 b) 2-Methylbut-3-yn- 2-ol


 


78




a) Intermediate 29 b) 2-Methylbut-3-yn- 2-ol


 


79




a) Intermediate 30 b) 2-Methylbut-3-yn- 2-ol


 


80




a) Intermediate 131 b) 2-Methylbut-3-yn- 2-ol


 


81




a) Intermediate 102 b) 2-Methylbut-3-yn- 2-ol


 


82




a) Intermediate 103 b) 2-Methylbut-3-yn- 2-ol


 


83




a) Intermediate 104 b) 2-Methylbut-3-yn- 2-ol


 


84




a) Intermediate 105 b) 2-Methylbut-3-yn- 2-ol


 


85




a) Intermediate 31 b) 2-Methylbut-3-yn- 2-ol


 


86




a) Intermediate 106 b) 2-Methylbut-3-yn- 2-ol


 


87




a) Intermediate 101 b) 1-Ethynyl- cyclopentanol


 


88




a) Intermediate 101 b) 2-Cyclopropyl-but-3- yn-2-ol


 


89




a) Intermediate 143 b) 1-Ethynyl- cyclopentanol


 


90




a) Intermediate 143 b) 2-Methylbut-3-yn- 2-ol


 


91




a) Intermediate 101 b) 2-(5-Methyl-isoxazol- 3-yl)-but-3-yn-2-ol


 


92




a) Intermediate 115 b) 2-Methylbut-3-yn- 2-ol


 


93




a) Intermediate 114 b) 1-Ethynyl- cyclopentanol


 


94




a) Intermediate 113 b) 1-Ethynyl- cyclopentanol


 


95




a) Intermediate 101 b) 2-Cyclobutyl-but- 3-yn-2-ol


 


96




a) Intermediate 145 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


98




a) Intermediate 113 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


99




a) Intermediate 132 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


100




a) Intermediate 108 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


101




a) Intermediate 109 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


102




a) Intermediate 133 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


103




a) Intermediate 78 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


105




a) Intermediate 110 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


106




a) Intermediate 31 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


107




a) Intermediate 134 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


108




a) Intermediate 32 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


109




a) Intermediate 116 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


110




a) Intermediate 100 b) Intermediate 149


 


123




a) Intermediate 13 b) 4-Ethynyl-1-methyl- piperidin-4-ol


 


126




a) Intermediate 32 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


127




a) Intermediate 162 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


128




a) Intermediate 166 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


129




a) Intermediate 169 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


130




a) Intermediate 176 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


131




a) Intermediate 167 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


132




a) Intermediate 62 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


133




a) Intermediate 170 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


134




a) Intermediate 168 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


135




a) Intermediate 130 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


136




a) Intermediate 163 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


137




a) Intermediate 100 b) Intermediate 174


 


138




a) Intermediate 164 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


139




a) Intermediate 172 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


140




a) Intermediate 173 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


141




a) Intermediate 165 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


142




a) Intermediate 189 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


143




a) Intermediate 181 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


144




a) Intermediate 181 b) 2-Methylbut-3-yn- 2-ol


 


145




a) Intermediate 190 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


146




a) Intermediate 187 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


147




a) Intermediate 177 b) 2-Methylbut-3-yn- 2-ol


 


148




a) Intermediate 191 b) 2-Methylbut-3-yn- 2-ol


 


149




a) Intermediate 184 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


150




a) Intermediate 183 b) 3-Ethynyl-3-hydroxy- 1-methyl-pyrrolidin-2- one


 


151




a) Intermediate 179 b) 2-Methylbut-3-yn- 2-ol


 


152




a) Intermediate 178 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


153




a) Intermediate 179 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


154




a) Intermediate 192 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


155




a) Intermediate 193 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


156




a) Intermediate 194 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


158




a) Intermediate 195 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


159




a) Intermediate 196 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


160




a) Intermediate 144 b) 1,1,1-Trideutero-2- trideutermethyl-3- butyn-2-ol


 


162




a) Intermediate 197 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


163




a) Intermediate 198 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


164




a) Intermediate 199 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


165




a) Intermediate 200 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


166




a) Intermediate 144 b) 2-Methylbut-3-yn- 2-ol


 


167




a) Intermediate 201 b) 2-Cyclopropyl-but- 3-yn-2-ol


 


168




a) Intermediate 204 b) 2-Cyclopropyl-but- 3-yn-2-ol









Example B2
a) Preparation of Compound 111




A degassed mixture of intermediate 14 (0.06 g, 0.166 mmol), 1,1,1-trifluoro-2-methyl-4-trimethylsilanyl-but-3-yn-2-ol (0.35 g, 1.67 mmol), tetrakis(triphenylphosphine) palladium (0.04 g, 0.033 mmol), copper iodide (3.2 mg, 0.017 mmol), triethylamine (0.17 ml, 1.20 mmol) and acetonitrile (1.5 ml) was treated with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.67 ml, 1.67 mmol). The resulting mixture was heated by microwave irradiation at 100° C. for 1 hour. The mixture cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and DCM (0:1 to 1:9 by volume). Further purification by ISOLUTE® SCX-2 SPE column, eluting with a mixture of MeOH and 2.0 M ammonia solution in MeOH (1:0 to 0:1 by volume), afforded the desired product (0.03 g, 50%).
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.13 (s, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 4.83 (s, 1H), 4.28 (s, 2H), 1.68 (s, 3H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.49 min, m/z [M+H]+=420
Compounds 157 and 161 were prepared according to the reaction protocols of example B2 (Table 23). Compound 157 is an enantiomerically pure compound of unknown configuration (S or R enantiomer).









TABLE 23





Compound
Structure
Starting Materials







157




a) Intermediate 144 b) Intermediate 207


 


161




a) Intermediate 144 b) Intermediate 205









Example B3
a) Preparation of Compound 112




A mixture of intermediate 152 (0.17 mmol), 2.0 M aqueous lithium hydroxide solution (3 ml) and dioxane (3 ml) was stirred at ambient temperature for 2 hours. The mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:19 to 1:1 by volume over 20 min), to afford the desired product as a white solid (0.02 g, 35%).
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.22 (s, 1H), 8.74 (d, J=1.0 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 8.16 (d, J=2.6 Hz, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 6.35 (s, 2H), 5.44 (s, 1H), 2.28 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.78 min, m/z [M+H]+=308
Example B4
a) Preparation of Compound 113




A mixture of intermediate 150 (0.04 g, 0.09 mmol), trifluoroacetic acid (0.4 ml) and DCM (1.6 ml) under an argon atmosphere at ambient temperature was stirred for 2 hours. The mixture was concentrated in vacuo and the residue purified by ISOLUTE® SCX-2 SPE column, eluting with a mixture of DCM, MeOH and 2.0 M ammonia solution in MeOH (1:1:0 to 1:0:1 by volume), followed by trituration in Et2O to afford the desired product as an off-white solid (0.03 g, 92%).
1H NMR (400 MHz, CD3OD) δ ppm: 8.79 (d, J=0.9 Hz, 1H), 8.67 (s, 1H), 8.65 (d, J=0.9 Hz, 1H), 8.18 (d, J=5.4 Hz, 1H), 7.12 (d, J=5.5 Hz, 1H), 5.64-5.58 (m, 1H), 4.19-4.05 (m, 4H), 1.62 (s, 6H).
LCMS (Method E): Rt=1.55 min, m/z [M+H]+=349
Compounds 114 to 118, 124 and 125 were prepared according to the reaction protocol of example B4 (Table 24).









TABLE 24





Compound
Structure
Starting Materials







114




Intermediate 155


 


115




Intermediate 151


 


116




Intermediate 153


 


117




Intermediate 154


 


118




Intermediate 156


 


124




Intermediate 157


 


125




Intermediate 158









Example C1
a) Preparation of Compounds 119 and 120




Compound 88 (0.04 g, 0.09 mmol) was purified by chiral preparative SFC with the following conditions: column, Phenomenex Lux® 5u Cellulose-4, 250×21.2 mm, 5 μm; mobile phase, CO2 (60%), MeOH (40%); detector, UV 240 nm. This afforded Compound 119 (first eluting enantiomer; R or S) as a pale yellow solid (0.01 g, 33%) and Compound 120 (second eluting enantiomer; S or R) as a pale yellow solid (0.01 g, 32%).
Example C2
a) Preparation of Compound 121 and 122




Compound 97 (0.20 g, 0.51 mmol) was purified by chiral preparative SFC with the following conditions: column, Phenomenex Lux® 5u Cellulose-4, 250×21.2 mm, 5 μm; mobile phase, CO2 (45%), isopropyl alcohol (55%); detector, UV 240 nm. This afforded Compound 121 (first eluting enantiomer; R or S) as a pale yellow solid (0.08 g, 41%) and Compound 122 (second eluting enantiomer; S or R) as a pale yellow solid (0.08 g, 42%).
Analytical Part
LCMS
Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using the following methods:
Method A: Experiments were performed on a Waters ZMD quadrupole mass spectrometer linked to a Waters 1525 LC system with a diode array detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Luna 3 micron 30×4.6 mm C18 column and a 2 ml/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. The final solvent system was held constant for a further 1 minute.
Method B: Experiments were performed on a Waters VG Platform II quadrupole spectrometer linked to a Hewlett Packard 1050 LC system with a diode array detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Luna 3 micron 30×4.6 mm C18 column and a 2 ml/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.3 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. The final solvent system was held constant for a further 1 minute.
Method C: Experiments were performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with diode array detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 85 evaporative light scattering detector. LC was carried out using a Phenomenex Luna 3 micron 30×4.6 mm C18 column and a 2 ml/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. The final solvent system was held constant for a further 1 minute.
Method D: Experiments were performed on a Waters ZQ quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with quaternary pump and PDA detector. The spectrometer had an electrospray source operating in positive and negative ion mode. Additional detection was achieved using a Sedex 65 evaporative light scattering detector. LC was carried out using a Phenomenex Luna 3 micron 30×4.6 mm C18 column and a 2 ml/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.3 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 min. The final solvent system was held constant for a further 1 minute.
Method E: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Acquity BEH 1.7 micron C18 column, an Acquity BEH Shield 1.7 micron RP18 column or an Acquity HST 1.8 micron column. Each column has dimensions of 100×2.1 mm and was maintained at 40° C. with a flow rate of 0.4 ml/minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.2 min. The final solvent system was held constant for a further 0.8 min.
NMR Data
The values of acid content (e.g. formic acid or acetic acid) in the compounds as provided herein, are those obtained experimentally and may vary when using different analytical methods. The content of formic acid or acetic acid reported herein was determined by 1H NMR integration. Compounds with an acid content of below 0.5 equivalents may be considered as free bases.
The NMR experiments herein were carried out using a Varian Unity Inova spectrometer with standard pulse sequences, operating at 400 MHz at ambient temperature. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard.
Compound 2
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (d, J=1.1 Hz, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.48 (s, 1H), 4.52 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.96 min, m/z [M+H]+=352
Compound 3
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=1.1 Hz, 1H), 8.45 (d, J=1.1 Hz, 1H), 8.32 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 4.82 (s, 1H), 4.26 (s, 2H), 1.52 (s, 6H), 1.13 (s, 6H).
LCMS (Method E): Rt=1.89 min, m/z [M+H]+=366
Compound 4
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.30-12.10 (br s, 1H), 8.73 (d, J=1.1 Hz, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.47 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.04-7.03 (m, 2H), 5.47 (s, 1H), 2.91 (s, 3H), 1.50 (s, 6H).
LCMS (Method E): Rt=1.89 min, m/z [M+H]+=308
Compound 5
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.84 (d, J=1.1 Hz, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.41 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 6.95 (d, J=5.3 Hz, 1H), 6.55 (s, 2H), 5.47 (s, 1H), 3.96 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.78 min, m/z [M+H]+=308
Compound 6 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=1.1 Hz, 1H), 8.52 (s, 1H), 8.50 (d, J=1.1 Hz, 1H), 8.33 (s, 0.5H), 8.17 (d, J=5.3 Hz, 1H), 6.99 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 4.36-4.32 (m, 2H), 3.86-3.81 (m, 1H), 3.69-3.64 (m, 2H), 3.49-3.47 (m, 1H), 2.86-2.83 (m, 1H), 1.93-1.88 (m, 1H), 1.65-1.61 (m, 1H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.01 min, m/z [M+H]+=378
Compound 7
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.1 Hz, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.46 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.55 (s, 2H), 5.47 (s, 1H), 4.45 (t, J=6.1 Hz, 2H), 3.50 (t, J=4.4 Hz, 4H), 2.74 (t, J=6.1 Hz, 2H), 2.45-2.40 (m, 4H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.67 min, m/z [M+H]+=407
Compound 8
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.93 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.52 (d, J=1.0 Hz, 1H), 8.27 (s, 1H), 6.90 (s, 2H), 5.46 (s, 1H), 5.00 (t, J=5.0 Hz, 1H), 4.46 (t, J=5.0 Hz, 2H), 3.81-3.75 (m, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.29 min, m/z [M+H]+=372/374
Compound 9
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.28 (br s, 1H), 8.73 (d, J=1.1 Hz, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.45 (s, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.04 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 6.29 (s, 1H), 1.01 (s, 4H).
LCMS (Method E): Rt=1.64 min, m/z [M+H]+=292
Compound 10
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.61 (s, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.48 (d, J=5.4 Hz, 1H), 4.99-4.98 (m, 1H), 4.64-4.63 (m, 1H), 1.55 (d, J=6.6 Hz, 6H), 1.44 (d, J=6.6 Hz, 3H).
LCMS (Method E): Rt=1.06 min, m/z [M+H]+=322
Compound 11
1H NMR (400 MHz, DMSO-d6, trifluoroacetic acid) δ ppm: 9.51 (s, 1H), 9.39 (s, 1H), 8.97 (s, 1H), 8.37 (d, J=6.6 Hz, 1H), 7.41 (d, J=6.6 Hz, 1H), 4.55 (t, J=7.1 Hz, 2H), 2.82 (t, J=7.1 Hz, 2H), 2.18-2.11 (m, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.55 min, m/z [M+H]+=351
Compound 12
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.89 (d, J=1.0 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.42 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 5.01 (t, J=5.2 Hz, 1H), 4.39 (t, J=5.2 Hz, 2H), 3.79 (q, J=5.2 Hz, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.71 min, m/z [M+H]+=338
A second batch was isolated with 1.5 equivalents of formic acid present.
Compound 13
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.97 (d, J=1.1 Hz, 1H), 8.61 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.36 (t, J=5.9 Hz, 1H), 4.99-4.98 (m, 1H), 4.35 (d, J=5.9 Hz, 2H), 1.55 (d, J=6.6 Hz, 6H).
LCMS (Method E): Rt=1.83 min, m/z [M+H]+=308
Compound 14 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.39 (s, 1H), 8.79 (s, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.17 (s, 0.5H), 6.90 (s, 2H), 5.46 (s, 1H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.33 min, m/z [M+H]+=328/330
Compound 15 (Formic Acid 1.8 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=0.9 Hz, 1H), 8.59 (s, 1H), 8.52 (d, J=0.9 Hz, 1H), 8.17 (d, J=5.5 Hz, 1H), 8.14 (s, 1.8H), 7.08 (d, J=5.4 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 5.02-4.93 (m, 1H), 1.54 (d, J=6.6 Hz, 6H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.07 min, m/z [M+H]+=336
Compound 16
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (d, J=1.1 Hz, 1H), 8.62 (s, 1H), 8.46 (d, J=1.1 Hz, 1H), 8.28 (s, 1H), 6.90 (s, 2H), 5.47 (s, 1H), 5.06-4.98 (m, 1H), 1.56 (d, J=6.6 Hz, 6H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.88 min, m/z [M+H]+=370/372
A second batch was isolated with 1.0 equivalents of formic acid present.
Compound 17 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.1 Hz, 1H), 8.62 (s, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.29 (s, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.05 (s, 1H), 6.90 (s, 2H), 5.04-5.03 (m, 1H), 1.93 (s, 3H), 1.56 (d, J=6.7 Hz, 6H).
LCMS (Method E): Rt=3.19 min, m/z [M+H]+=439/441
Compound 18 (Formic Acid 1.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=1.1 Hz, 1H), 8.59 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 8.15 (s, 1.5H), 7.08 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.46-5.20 (br s, 1H), 4.98-4.97 (m, 1H), 1.96-1.93 (m, 4H), 1.78-1.72 (m, 4H), 1.55 (d, J=6.6 Hz, 6H).
LCMS (Method E): Rt=2.33 min, m/z [M+H]+=362
Compound 19
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J=1.0 Hz, 1H), 8.62 (s, 1H), 8.47 (d, J=1.0 Hz, 1H), 8.28 (s, 1H), 6.90 (s, 2H), 5.32 (s, 1H), 5.02-5.01 (m, 1H), 1.96-1.93 (m, 4H), 1.75-1.72 (m, 4H), 1.57 (d, J=6.7 Hz, 6H).
LCMS (Method E): Rt=3.17 min, m/z [M+H]+=396/398
Compound 20 (Formic Acid 0.2 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=1.1 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.28 (s, 1H), 8.25 (s, 0.2H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.04 (s, 1H), 6.90 (s, 2H), 4.60 (t, J=5.0 Hz, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.93 (s, 3H).
LCMS (Method E): Rt=2.92 min, m/z [M+H]+=455/457
Compound 21
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=1.1 Hz, 1H), 8.62 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.26 (s, 1H), 6.90 (s, 2H), 6.28 (s, 1H), 4.82 (s, 1H), 4.31 (s, 2H), 1.13 (s, 6H), 1.01 (s, 4H).
LCMS (Method E): Rt=2.53 min, m/z [M+H]+=398/400
Compound 22
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=1.1 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.33 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 6.29 (s, 1H), 4.81 (s, 1H), 4.25 (s, 2H), 1.13 (s, 6H), 1.01 (s, 4H).
LCMS (Method E): Rt=1.85 min, m/z [M+H]+=364
Compound 23
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J=1.1 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.27 (s, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.03 (s, 1H), 6.89 (s, 2H), 4.83 (s, 1H), 4.32 (s, 2H), 1.93 (s, 3H), 1.12 (s, 6H).
LCMS (Method E): Rt=2.76 min, m/z [M+H]+=469/471
Compound 24
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=1.1 Hz, 1H), 8.61 (s, 1H), 8.50 (d, J=1.1 Hz, 1H), 8.27 (s, 1H), 6.90 (s, 2H), 5.46 (s, 1H), 4.83 (s, 1H), 4.32 (s, 2H), 1.51 (s, 6H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.54 min, m/z [M+H]+=400/402
Compound 25 (Formic Acid 0.2 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.93 (d, J=1.1 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J=1.1 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 0.2H), 6.90 (s, 2H), 5.46 (s, 1H), 4.59 (t, J=5.0 Hz, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.69 min, m/z [M+H]+=386/388
Compound 26 (Formic Acid 0.2 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92 (d, J=1.1 Hz, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 0.2H), 8.17 (d, J=5.3 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.06 (s, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 4.53 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.93 (s, 3H).
LCMS (Method E): Rt=2.20 min, m/z [M+H]+=421
Compound 27 (Formic Acid 0.4 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.34 (s, 1H), 8.29 (s, 0.4H), 8.17 (d, J=5.3 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.11-7.00 (br s, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 4.90-4.74 (br s, 1H), 4.26 (s, 2H), 1.93 (s, 3H), 1.12 (s, 6H).
LCMS (Method E): Rt=2.13 min, m/z [M+H]+=435
Compound 28
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.1 Hz, 1H), 8.53 (s, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.01 (d, J=5.3 Hz, 1H), 6.64 (s, 2H), 5.48 (s, 1H), 4.65-4.66 (m, 4H), 4.44 (t, J=6.1 Hz, 2H), 3.55-3.57 (m, 1H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.91 min, m/z [M+H]+=364
Compound 29
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.15 (d, J=4.8 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.48 (s, 2H), 6.05 (s, 1H), 5.00 (s, 1H), 4.24 (s, 2H), 3.93-3.85 (m, 4H), 2.32-2.18 (m, 2H), 1.10 (s, 6H).
LCMS (Method E): Rt=1.84 min, m/z [M+H]+=394
Compound 30
1H NMR (400 MHz, CD3OD) δ ppm: 8.63 (d, J=1.0 Hz, 1H), 8.60 (d, J=1.0 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.00-6.98 (m, 1H), 5.35 (s, 2H), 3.19 (s, 3H), 2.96 (s, 3H), 1.59 (s, 6H).
LCMS (Method E): Rt=1.82 min, m/z [M+H]+=379
Compound 31 (Formic Acid 0.5 Equivalents).
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.93 (d, J=1.0 Hz, 1H), 8.54 (d, J=1.0 Hz, 1H), 8.44 (s, 1H), 8.18 (d, J=5.3 Hz, 1.5H), 8.15 (d, J=0.6 Hz, 1H), 7.23 (s, 1H), 6.99 (d, J=5.3 Hz, 1H), 6.72 (s, 1H), 6.57 (s, 2H), 4.54 (t, J=5.0 Hz, 2H), 3.74 (t, J=5.0, 2H), 3.23 (s, 3H), 1.93 (s, 3H).
LCMS (Method E): Rt=2.11 min, m/z [M+H]+=405
Compound 32 (Formic Acid 0.5 Equivalents).
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (d, J=1.1 Hz, 1H), 8.45 (d, J=1.1 Hz, 1H), 8.41 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 8.15 (s, 0.5H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.33 (s, 1H), 4.52 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.1 Hz, 2H), 3.23 (s, 3H), 1.54 (s, 3H), 1.21-1.13 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.26 min, m/z [M+H]+=378
Compound 33
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=0.9 Hz, 1H), 8.61 (s, 1H), 8.50 (d, J=0.8 Hz, 1H), 8.27 (s, 1H), 6.89 (s, 2H), 5.29 (s, 1H), 4.84 (s, 1H), 4.32 (s, 2H), 1.98-1.91 (m, 4H), 1.79-1.68 (m, 4H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.84 min, m/z [M+H]+=426/428
Compound 34 (Formic Acid 1.7 Equivalents)
1H NMR (400 MHz, CD3OD) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.72 (s, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.19 (d, J=5.2 Hz, 1H), 8.16 (s, 1.7H), 7.14 (d, J=5.2 Hz, 1H), 6.59 (s, 2H), 5.33-5.26 (m, 1H), 3.81 (t, J=7.0 Hz, 2H), 3.48 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.56 min, m/z [M+H]+=363
A second batch was isolated as a free base.
Compound 35
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (d, J=1.0 Hz, 1H), 8.45 (d, J=1.0 Hz, 1H), 8.41 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.54 (s, 2H), 5.16-5.12 (s, 1H), 4.52 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.72-1.64 (m, 4H), 1.03 (t, J=7.4 Hz, 6H).
LCMS (Method E): Rt=2.38 min, m/z [M+H]+=380
Compound 36
1H NMR (400 MHz, DMSO-d6) δ ppm: d 8.97 (d, J=0.9 Hz, 1H), 8.51 (d, J=0.9 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.71-7.68 (m, 2H), 7.42-7.37 (m, 2H), 7.32-7.26 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 6.21 (s, 1H), 4.82 (s, 1H), 4.26 (s, 2H), 1.77 (s, 3H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.56 min, m/z [M+H]+=428
Compound 37
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=0.9 Hz, 1H), 8.44 (d, J=0.9 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.54 (s, 2H), 5.28 (s, 1H), 4.82 (s, 1H), 4.26 (s, 2H), 2.57-2.53 (m, 1H), 2.15-2.02 (m, 2H), 1.97-1.68 (m, 4H), 1.36 (s, 3H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.40 min, m/z [M+H]+=406
Compound 38 (Formic Acid 1.5 Equivalents)
1H NMR (400 MHz, CD3OD) δ ppm: 8.87 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1.5H), 7.08 (d, J=5.6 Hz, 1H), 4.32 (s, 2H), 2.07-2.02 (m, 2H), 1.78-1.67 (m, 6H), 1.67-1.58 (m, 1H), 1.41-1.28 (m, 1H), 1.25 (s, 6H).
LCMS (Method E): Rt=2.36 min, m/z [M+H]+=406
Compound 39 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, CD3OD) δ ppm: 8.87 (s, 1H), 8.66 (s, 1H), 8.35 (s, 1H), 8.15 (d, J=4.9 Hz, 1.5H), 7.08 (d, J=5.6 Hz, 1H), 4.33 (s, 2H), 3.84-3.72 (m, 2H), 3.38 (s, 3H), 2.11-2.05 (m, 2H), 1.61 (s, 3H), 1.25 (s, 6H).
LCMS (Method E): Rt=2.05 min, m/z [M+H]+=410
Compound 40
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=0.9 Hz, 1H), 8.42 (d, J=0.9 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.55 (s, 2H), 5.25 (s, 1H), 4.82 (s, 1H), 4.26 (s, 2H), 1.86-1.78 (m, 1H), 1.43 (s, 3H), 1.13 (s, 6H), 1.03 (dd, J=6.8, 15.7 Hz, 6H).
LCMS (Method E): Rt=2.32 min, m/z [M+H]+=394
Compound 41
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.97 (s, 1H), 8.63 (d, J=3.2 Hz, 2H), 8.51 (s, 1H), 7.89 (s, 2H), 5.48 (s, 1H), 4.61 (t, J=4.9 Hz, 2H), 3.73 (t, J=4.9 Hz, 2H), 3.25 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.63 min, m/z [M+H]+=377
Compound 42 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.51 (d, J=0.9 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J=5.5 Hz, 1H), 8.13 (s, 0.5H), 6.98 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.88 (s, 1H), 4.82 (s, 1H), 4.26 (s, 2H), 2.48-2.40 (m, 2H), 2.29-2.20 (m, 2H), 1.87-1.79 (m, 2H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.04 min, m/z [M+H]+=378
Compound 43 (Formic Acid 0.6 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.89 (d, J=0.9 Hz, 1H), 8.39 (d, J=0.9 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J=5.3 Hz, 1H), 8.10 (s, 0.6H), 6.92 (d, J=5.3 Hz, 1H), 6.50 (s, 2H), 5.29 (s, 1H), 4.77 (s, 1H), 4.21 (s, 2H), 1.69-1.61 (m, 2H), 1.42 (s, 3H), 1.08 (s, 6H), 0.99 (t, J=7.4 Hz, 3H).
LCMS (Method E): Rt=2.10 min, m/z [M+H]+=380
Compound 44 (Formic Acid 0.6 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.87 (d, J=1.0 Hz, 1H), 8.51-8.46 (m, 2H), 8.17 (d, J=5.2 Hz, 1H), 8.14 (s, 0.6H), 6.99 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.46 (s, 1H), 4.40 (t, J=7.1 Hz, 2H), 3.27 (t, J=6.2 Hz, 2H), 3.21 (s, 3H), 2.12-2.04 (m, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.10 min, m/z [M+H]+=366
Compound 45 (Formic Acid 0.9 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.40 (s, 1H), 8.78 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.30 (d, J=2.6 Hz, 1H), 8.24 (d, J=4.0 Hz, 1H), 8.16 (s, 0.9H), 6.62 (s, 2H), 5.47 (s, 1H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.19 min, m/z [M+H]+=312
Compound 46 (Formic Acid 0.8 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.87 (s, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.22 (s, 0.8H), 7.98 (s, 1H), 6.79 (d, J=5.2 Hz, 1H), 6.54 (s, 2H), 5.44 (s, 1H), 4.77 (s, 1H), 4.26 (s, 2H), 2.75 (s, 3H), 1.49 (s, 6H), 1.17 (s, 6H).
LCMS (Method E): Rt=1.94 min, m/z [M+H]+=380
Compound 47
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=1.0 Hz, 1H), 8.45 (d, J=1.0 Hz, 1H), 8.33 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 6.53 (s, 2H), 5.80 (s, 1H), 4.81 (dd, J=5.5, 15.4 Hz, 3H), 4.26 (s, 2H), 4.15 (dd, J=5.5, 7.4 Hz, 2H), 1.49 (s, 3H), 1.40 (s, 3H), 1.12 (s, 6H).
LCMS (Method E): Rt=2.04 min, m/z [M+H]+=422
Compound 48 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.29 (s, 1H), 8.73 (d, J=1.0 Hz, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.19 (d, J=5.1 Hz, 2H), 7.12-7.06 (m, 1H), 7.03 (d, J=5.3 Hz, 1H), 5.47 (s, 1H), 3.35-3.17 (m, 2H), 1.50 (s, 6H), 1.22 (t, J=6.7 Hz, 3H).
LCMS (Method E): Rt=2.10 min, m/z [M+H]+=322
Compound 49 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.89 (d, J=1.0 Hz, 1H), 8.46 (d, J=1.0 Hz, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.88-7.82 (m, 1H), 6.95 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.47 (s, 1H), 4.57 (t, J=6.6 Hz, 2H), 2.68 (t, J=6.6 Hz, 2H), 2.50 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.82 min, m/z [M+H]+=379
Compound 50 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.47-8.45 (m, 2H), 8.18-8.16 (m, 2H), 6.95 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 4.55 (t, J=6.7 Hz, 2H), 2.96 (t, J=6.7 Hz, 2H), 2.89 (s, 3H), 2.79 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.96 min, m/z [M+H]+=393
Compound 51
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.86 (d, J=1.0 Hz, 1H), 8.50 (d, J=1.2 Hz, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 6.99 (d, J=5.4 Hz, 1H), 6.55 (s, 2H), 5.47 (s, 1H), 4.55 (s, 1H), 4.41 (dd, J=5.7, 10.5 Hz, 2H), 1.98-1.92 (m, 2H), 1.52 (s, 6H), 1.18 (s, 6H).
LCMS (Method E): Rt=2.04 min, m/z [M+H]+=380
Compound 52
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.82 (s, 1H), 11.23 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.02 (d, J=5.2 Hz, 1H), 6.86 (s, 2H), 5.48 (s, 1H), 3.63-3.53 (m, 4H), 3.28 (s, 3H), 1.49 (s, 6H).
LCMS (Method E): Rt=2.28 min, m/z [M+H]+=395
Compound 53
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=1.0 Hz, 1H), 8.44 (d, J=1.0 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 6.97 (d, J=5.4 Hz, 1H), 6.54 (s, 2H), 5.37 (s, 1H), 4.81 (s, 1H), 4.25 (s, 2H), 1.75 (dd, J=6.3, 13.6 Hz, 1H), 1.57-1.50 (m, 4H), 1.13 (s, 6H), 0.99-0.90 (m, 1H), 0.51-0.45 (m, 2H), 0.20-0.15 (m, 2H).
LCMS (Method E): Rt=2.33 min, m/z [M+H]+=406
Compound 54
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=1.1 Hz, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 8.25 (d, J=3.9 Hz, 1H), 6.64 (s, 2H), 5.47 (s, 1H), 4.59 (t, J=5.0 Hz, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.23 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.46 min, m/z [M+H]+=370
Compound 55
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.46 (s, 1H), 8.18-8.16 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 4.26 (d, J=7.3 Hz, 2H), 3.86-3.79 (m, 2H), 3.27-3.18 (m, 2H), 2.17-2.08 (m, 1H), 1.52 (s, 6H), 1.43-1.29 (m, 4H).
LCMS (Method E): Rt=2.07 min, m/z [M+H]+=392
Compound 56 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.0 Hz, 1H), 8.53-8.50 (m, 2H), 8.28 (s, 1H), 8.22 (d, J=5.3 Hz, 1H), 6.99 (d, J=5.3 Hz, 1H), 6.66 (s, 2H), 5.73 (s, 2H), 5.55-5.49 (m, 1H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.99 min, m/z [M+H]+=333
Compound 57 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (s, 1H), 8.50 (d, J=5.1 Hz, 2H), 8.20 (d, J=5.4 Hz, 1H), 8.15 (s, 1H), 6.95 (d, J=5.3 Hz, 1H), 6.60 (s, 2H), 5.49 (s, 1H), 4.69 (t, J=6.5 Hz, 2H), 3.19 (t, J=6.5 Hz, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.87 min, m/z [M+H]+=347
Compound 58
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 7.36 (s, 1H), 5.46 (s, 1H), 4.83 (s, 1H), 4.32 (s, 2H), 2.97-2.92 (m, 3H), 1.49 (s, 6H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.90 min, m/z [M+H]+=414/416
Compound 59 (Acetic Acid 0.87 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=0.9 Hz, 1H), 8.59-8.56 (m, 1H), 8.45 (d, J=1.0 Hz, 1H), 8.32 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.93-7.80 (m, 2H), 7.35-7.31 (m, 1H), 6.97 (d, J=5.4 Hz, 1H), 6.55 (s, 2H), 6.34 (s, 1H), 4.81 (s, 1H), 4.25 (s, 2H), 1.91 (s, 2.6H), 1.86 (s, 3H), 1.12 (s, 6H).
LCMS (Method E): Rt=1.95 min, m/z [M+H]+=429
Compound 60
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=0.9 Hz, 1H), 8.62 (d, J=4.3 Hz, 2H), 8.50 (d, J=1.0 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 5.47-5.45 (m, 1H), 4.87 (s, 1H), 4.33 (s, 2H), 1.52 (s, 6H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.42 min, m/z [M+H]+=391
Compound 61 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.30 (d, J=2.3 Hz, 1H), 8.77 (d, J=1.1 Hz, 1H), 8.56 (s, 1H), 8.21-8.19 (m, 1.5H), 8.02 (s, 1H), 7.49 (s, 2H), 5.48 (s, 1H), 1.50 (s, 6H).
LCMS (Method E): Rt=2.54 min, m/z [M+H]+=362
Compound 62 (Formic Acid 0.6 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=0.9 Hz, 1H), 8.49 (d, J=0.9 Hz, 1H), 8.29 (s, 1H), 8.15 (s, 0.6H), 8.12 (d, J=5.2 Hz, 1H), 6.92 (d, J=5.3 Hz, 1H), 6.51 (s, 2H), 5.29 (s, 1H), 4.76 (s, 1H), 4.30 (s, 2H), 4.21 (s, 2H), 1.08 (s, 6H).
LCMS (Method E): Rt=1.62 min, m/z [M+H]+=338
Compound 63
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.97 (d, J=0.9 Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J=5.4 Hz, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.57 (s, 2H), 6.18 (s, 1H), 4.83 (s, 1H), 4.26 (s, 2H), 3.40 (s, 3H), 2.91 (s, 3H), 1.68 (s, 3H), 1.12 (s, 6H).
LCMS (Method E): Rt=1.95 min, m/z [M+H]+=423
Compound 64
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (s, 1H), 8.60 (d, J=0.9 Hz, 1H), 8.27 (s, 1H), 8.25 (d, J=3.9 Hz, 1H), 6.64 (s, 2H), 5.48 (s, 1H), 4.83 (s, 1H), 4.32 (s, 2H), 1.52 (s, 6H), 1.12 (s, 6H).
LCMS (Method E): Rt=2.34 min, m/z [M+H]+=384
A second batch was isolated with 1.0 equivalents of formic acid present.
Compound 65 (Formic Acid 0.5 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.93 (d, J=1.1 Hz, 1H), 8.90 (s, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.20 (d, J=5.2 Hz, 1H), 8.17 (s, 0.5H), 7.15 (d, J=5.3 Hz, 1H), 6.61 (s, 2H), 5.99-5.92 (m, 1H), 5.49 (s, 1H), 5.11-4.98 (m, 4H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.87 min, m/z [M+H]+=350
Compound 66 (Formic Acid 0.6 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.07 (d, J=0.9 Hz, 1H), 8.56 (d, J=0.9 Hz, 1H), 8.38 (s, 1H), 8.20 (s, 0.6H), 8.18-8.15 (m, 1H), 7.11 (d, J=5.3 Hz, 1H), 6.54 (s, 2H), 5.48 (s, 1H), 5.18 (s, 1H), 3.84 (s, 2H), 1.70 (s, 6H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.93 min, m/z [M+H]+=366
Compound 67
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.51 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 8.19 (d, J=5.2 Hz, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.60 (s, 2H), 5.49 (s, 1H), 4.80 (t, J=6.9 Hz, 2H), 3.83 (t, J=6.9 Hz, 2H), 3.00 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.81 min, m/z [M+H]+=400
Compound 68
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=0.9 Hz, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J=5.3 Hz, 1H), 5.49 (s, 1H), 4.80 (s, 1H), 4.25 (s, 2H), 2.92 (s, 3H), 1.50 (s, 6H), 1.13 (s, 6H).
LCMS (Method E): Rt=2.06 min, m/z [M+H]+=380
Compound 69
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.27-9.21 (m, 1H), 8.93 (d, J=1.0 Hz, 1H), 8.38 (d, J=1.0 Hz, 1H), 8.20 (d, J=5.2 Hz, 1H), 6.75 (d, J=5.2 Hz, 1H), 6.65 (s, 2H), 5.48 (s, 1H), 3.87 (s, 3H), 3.52-3.49 (m, 4H), 3.28 (s, 3H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.96 min, m/z [M+H]+=409
Compound 70
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.49 (s, 1H), 5.39-5.31 (m, 1H), 3.80-3.75 (m, 2H), 3.51-3.46 (m, 2H), 2.37 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.82 min, m/z [M+H]+=381
Compound 71
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (d, J=1.0 Hz, 1H), 8.57 (s, 1H), 8.15 (d, J=1.0 Hz, 1H), 7.99 (s, 1H), 7.50 (s, 2H), 5.46 (s, 1H), 4.34 (d, J=7.3 Hz, 2H), 3.85-3.79 (m, 2H), 3.26-3.17 (m, 2H), 2.12-2.03 (m, 1H), 1.50 (s, 6H), 1.43-1.20 (m, 4H).
LCMS (Method E): Rt=2.98 min, m/z [M+H]+=460
Compound 72
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H), 8.56 (s, 1H), 8.20 (d, J=0.8 Hz, 1H), 8.01 (s, 1H), 7.49 (s, 2H), 5.48 (s, 1H), 4.82 (s, 1H), 4.31 (s, 2H), 1.50 (s, 6H), 1.11 (s, 6H).
LCMS (Method E): Rt=2.75 min, m/z [M+H]+=434
Compound 73
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H), 8.20 (d, J=3.7 Hz, 1H), 6.59 (s, 2H), 5.45 (s, 1H), 4.28 (d, J=7.3 Hz, 2H), 3.80-3.74 (m, 2H), 3.21-3.12 (m, 2H), 2.11-2.03 (m, 1H), 1.47 (s, 6H), 1.33-1.24 (m, 4H).
LCMS (Method E): Rt=2.57 min, m/z [M+H]+=410
A second batch was isolated with 1.3 equivalents of formic acid present.
Compound 74
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=0.9 Hz, 1H), 8.63 (d, J=0.9 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.69 (s, 2H), 6.02-5.93 (m, 1H), 5.50 (s, 1H), 5.11 (t, J=7.4 Hz, 2H), 5.00 (t, J=6.6 Hz, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.32 min, m/z [M+H]+=368
Compound 75 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: d 9.03 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.48-8.46 (m, 2H), 6.83 (s, 2H), 5.50 (s, 1H), 4.36 (d, J=7.3 Hz, 2H), 3.82 (dd, J=2.5, 11.3 Hz, 2H), 3.27-3.18 (m, 2H), 2.15-2.06 (m, 1H), 1.52 (s, 6H), 1.42-1.23 (m, 4H).
LCMS (Method E): Rt=2.68 min, m/z [M+H]+=417
Compound 76
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.0 Hz, 1H), 8.61 (d, J=1.0 Hz, 1H), 8.31 (d, J=2.6 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 6.64 (s, 2H), 5.48 (s, 1H), 4.46 (t, J=6.8 Hz, 2H), 3.28-3.23 (m, 2H), 3.21 (s, 3H), 2.10-2.02 (m, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=2.57 min, m/z [M+H]+=384
Compound 77 (Formic Acid 1.7 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=0.9 Hz, 1H), 8.61 (s, 1H), 8.54 (d, J=1.0 Hz, 1H), 8.17-8.15 (m, 2.7H), 7.09 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.48 (s, 1H), 4.64-4.54 (m, 1H), 2.94 (d, J=11.1 Hz, 2H), 2.27 (s, 3H), 2.24-1.99 (m, 6H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.56 min, m/z [M+H]+=391
Compound 78 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.97 (d, J=1.0 Hz, 1H), 8.65 (s, 1H), 8.55 (d, J=1.0 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.10 (d, J=5.4 Hz, 1H), 6.55 (s, 2H), 5.48 (s, 1H), 4.63-4.54 (m, 1H), 2.95 (d, J=11.5 Hz, 2H), 2.86-2.76 (m, 1H), 2.46-2.38 (m, 2H), 2.08-2.00 (m, 4H), 1.52 (s, 6H), 1.03 (d, J=6.6 Hz, 6H).
LCMS (Method E): Rt=1.67 min, m/z [M+H]+=419
Compound 79 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=0.9 Hz, 1H), 8.63 (s, 1H), 8.55 (d, J=1.0 Hz, 1H), 8.17-8.14 (m, 2H), 7.09 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.48 (s, 1H), 4.69-4.59 (m, 1H), 3.14-3.05 (m, 2H), 2.51-2.49 (m, 2H), 2.32-2.24 (m, 2H), 2.14-2.01 (m, 4H), 1.52 (s, 6H), 1.07 (t, J=7.2 Hz, 3H).
LCMS (Method E): Rt=1.59 min, m/z [M+H]+=405
Compound 80 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.93 (d, J=0.9 Hz, 1H), 8.70 (s, 1H), 8.52 (d, J=0.9 Hz, 1H), 8.19 (d, J=5.3 Hz, 1H), 8.15 (s, 1H), 7.13 (d, J=5.4 Hz, 1H), 6.59 (s, 2H), 5.49 (s, 1H), 5.28-5.23 (m, 1H), 3.84-3.78 (m, 2H), 3.45-3.38 (m, 2H), 2.51-2.50 (m, 1H), 1.51 (s, 6H), 0.94 (d, J=6.2 Hz, 6H).
LCMS (Method E): Rt=1.61 min, m/z [M+H]+=391
Compound 81
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.86 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.0 Hz, 1H), 8.42 (s, 1H), 6.91 (s, 1H), 6.46 (s, 2H), 5.48 (s, 1H), 4.39 (t, J=6.9 Hz, 2H), 3.29-3.23 (m, 2H), 3.21 (s, 3H), 2.25 (s, 3H), 2.12-2.03 (m, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.11 min, m/z [M+H]+=380
Compound 82 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.47 (d, J=1.0 Hz, 1H), 8.20-8.19 (m, 2H), 8.09 (s, 1H), 6.36 (s, 2H), 5.46 (s, 1H), 4.30 (d, J=7.4 Hz, 2H), 3.86-3.79 (m, 2H), 3.27-3.17 (m, 2H), 2.28 (s, 3H), 2.17-2.09 (m, 1H), 1.51 (s, 6H), 1.40-1.30 (m, 4H).
LCMS (Method E): Rt=2.16 min, m/z [M+H]+=406
Compound 83 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: d 8.87 (s, 1H), 8.49 (d, J=1.0 Hz, 1H), 8.18-8.17 (m, 2H), 8.09 (s, 1H), 6.36 (s, 2H), 5.46 (s, 1H), 4.44 (t, J=6.9 Hz, 2H), 3.30-3.24 (m, 2H), 3.21 (s, 3H), 2.29 (s, 3H), 2.12-2.03 (m, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.16 min, m/z [M+H]+=380
Compound 84
1H NMR (400 MHz, DMSO-d6) δ ppm: d 8.43 (s, 1H), 8.37 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.55 (s, 2H), 5.46 (s, 1H), 4.51 (t, J=7.3 Hz, 2H), 3.39-3.33 (m, 2H), 3.24 (s, 3H), 2.84 (s, 3H), 2.08-2.00 (m, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.98 min, m/z [M+H]+=380
Compound 85 (Formic Acid 1.2 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (d, J=0.9 Hz, 1H), 8.60 (d, J=1.0 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.26 (d, J=3.9 Hz, 1H), 8.16 (s, 1.2H), 6.64 (s, 2H), 5.50 (s, 1H), 4.73-4.65 (m, 1H), 3.09 (d, J=11.6 Hz, 2H), 2.49-2.45 (m, 2H), 2.32-2.22 (m, 2H), 2.14-2.04 (m, 4H), 1.52 (s, 6H), 1.07 (t, J=7.2 Hz, 3H).
LCMS (Method E): Rt=1.91 min, m/z [M+H]+=423
Compound 86
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.54 (s, 1H), 8.25-8.21 (m, 2H), 6.62 (s, 2H), 5.48 (s, 1H), 4.60-4.54 (m, 2H), 3.41-3.26 (m, 2H), 3.24 (s, 3H), 2.86 (s, 3H), 2.07-1.99 (m, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.55 min, m/z [M+H]+=398
Compound 87
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.1 Hz, 1H), 8.61 (d, J=1.0 Hz, 1H), 8.31 (d, J=2.7 Hz, 1H), 8.25 (d, J=3.9 Hz, 1H), 6.65 (s, 2H), 5.34 (s, 1H), 4.46 (t, J=6.9 Hz, 2H), 3.26 (t, J=6.0 Hz, 2H), 3.21 (s, 3H), 2.10-2.01 (m, 2H), 1.99-1.92 (m, 4H), 1.79-1.68 (m, 4H).
LCMS (Method E): Rt=2.86 min, m/z [M+H]+=410
Compound 88
1H NMR (400 MHz, CDCl3) δ ppm: 8.79 (d, J=1.0 Hz, 1H), 8.66 (d, J=1.0 Hz, 1H), 8.15 (d, J=3.6 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 5.03 (s, 2H), 4.41 (t, J=6.6 Hz, 2H), 3.33 (s, 3H), 3.27 (t, J=5.7 Hz, 2H), 2.17-2.09 (m, 2H), 1.73 (s, 3H), 1.33-1.24 (m, 1H), 0.80-0.50 (m, 4H).
LCMS (Method E): Rt=2.87 min, m/z [M+H]+=410
Compound 89
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.64 (d, J=0.8 Hz, 1H), 8.34-8.31 (m, 2H), 7.15 (s, 1H), 5.36 (s, 1H), 4.47 (t, J=6.8 Hz, 2H), 3.25 (t, J=5.9 Hz, 2H), 3.21 (s, 3H), 2.90 (d, J=4.4 Hz, 3H), 2.11-2.02 (m, 2H), 1.92 (dd, J=2.6, 4.3 Hz, 4H), 1.79-1.68 (m, 4H).
LCMS (Method E): Rt=3.26 min, m/z [M+H]+=424
Compound 90
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.64 (s, 1H), 8.34-8.31 (m, 2H), 7.15 (s, 1H), 5.49 (s, 1H), 4.47 (t, J=6.9 Hz, 2H), 3.26 (t, J=6.0 Hz, 2H), 3.20 (s, 3H), 2.90 (d, J=4.4 Hz, 3H), 2.10-2.02 (m, 2H), 1.50 (s, 6H).
LCMS (Method E): Rt=2.97 min, m/z [M+H]+=398
Compound 91
1H NMR (400 MHz, CDCl3) δ ppm: d 8.79 (d, J=0.9 Hz, 1H), 8.72 (d, J=0.9 Hz, 1H), 8.14 (d, J=3.6 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 6.24 (s, 1H), 5.10 (s, 2H), 4.41 (t, J=6.6 Hz, 2H), 3.32 (s, 3H), 3.26 (t, J=5.6 Hz, 2H), 2.43 (s, 3H), 2.17-2.08 (m, 2H), 2.02 (s, 3H).
LCMS (Method E): Rt=2.95 min, m/z [M+H]+=451
Compound 92
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.70 (s, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.72 (s, 2H), 5.54 (s, 1H), 4.69 (t, J=7.1 Hz, 2H), 3.35-3.32 (m, 2H), 3.22 (s, 3H), 2.11-2.03 (m, 2H), 1.52 (s, 6H).
LCMS (Method E): Rt=3.83 min, m/z [M+H]+=418/420
Compound 93
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.50 (s, 1H), 8.25-8.22 (m, 2H), 6.62 (s, 2H), 5.31 (s, 1H), 4.71 (t, J=7.1 Hz, 2H), 3.35-3.33 (m, 2H), 3.23 (s, 3H), 2.66-2.58 (m, 1H), 2.16-2.06 (m, 2H), 1.97-1.90 (m, 4H), 1.78-1.67 (m, 4H), 1.20-1.13 (m, 2H), 1.06-0.99 (m, 2H).
LCMS (Method E): Rt=3.32 min, m/z [M+H]+=450
Compound 94
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (d, J=2.1 Hz, 1H), 8.48 (s, 1H), 8.30 (d, J=3.8 Hz, 1H), 6.67 (s, 2H), 6.38-6.30 (m, 1H), 5.32 (s, 1H), 5.14 (t, J=7.3 Hz, 2H), 4.97 (t, J=6.5 Hz, 2H), 2.45-2.39 (m, 1H), 1.97-1.91 (m, 4H), 1.78-1.67 (m, 4H), 1.15-1.02 (m, 4H).
LCMS (Method E): Rt=2.97 min, m/z [M+H]+=434
Compound 95
1H NMR (400 MHz, CDCl3) δ ppm: 8.82 (d, J=1.0 Hz, 1H), 8.73 (d, J=1.0 Hz, 1H), 8.16 (d, J=3.6 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 5.04 (s, 2H), 4.44 (t, J=6.6 Hz, 2H), 3.34 (s, 3H), 3.29 (t, J=5.6 Hz, 2H), 2.70-2.62 (m, 2H), 2.44-2.35 (m, 2H), 2.19-2.13 (m, 2H), 2.01-1.88 (m, 2H), 1.27 (s, 1H).
LCMS (Method E): Rt=2.72 min, m/z [M+H]+=396
Compound 96
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.06 (d, J=1.0 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.70 (dd, J=1.0, 2.5 Hz, 1H), 7.55 (t, J=51.6 Hz, 1H), 6.77 (s, 2H), 5.38 (s, 1H), 4.59 (t, J=7.6 Hz, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.24 (s, 3H), 2.12-2.03 (m, 2H), 1.51 (s, 3H), 1.19-1.12 (m, 1H), 0.57-0.35 (m, 4H).
LCMS (Method E): Rt=3.68 min, m/z [M+H]+=460
Compound 98
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (d, J=2.0 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J=3.8 Hz, 1H), 6.66 (s, 2H), 6.38-6.30 (m, 1H), 5.32 (s, 1H), 5.14 (t, J=7.2 Hz, 2H), 4.98 (t, J=6.5 Hz, 2H), 2.45-2.37 (m, 1H), 1.53 (s, 3H), 1.20-1.03 (m, 5H), 0.59-0.48 (m, 2H), 0.47-0.35 (m, 2H).
LCMS (Method E): Rt=3.04 min, m/z [M+H]+=434
Compound 99
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J=1.0 Hz, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 8.11 (d, J=1.0 Hz, 1H), 7.54 (s, 2H), 5.40-5.31 (m, 2H), 3.80 (t, J=7.7 Hz, 2H), 3.45-3.37 (m, 2H), 2.37 (s, 3H), 1.52 (s, 3H), 1.19-1.11 (m, 1H), 0.57-0.37 (m, 4H).
LCMS (Method E): Rt=2.46 min, m/z [M+H]+=457
Compound 100
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.02 (d, J=1.0 Hz, 1H), 8.61 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.55 (s, 2H), 6.03-5.95 (m, 1H), 5.34 (s, 1H), 5.13 (t, J=7.5 Hz, 2H), 4.94-4.89 (m, 2H), 1.52 (s, 3H), 1.20-1.12 (m, 1H), 0.57-0.37 (m, 4H).
LCMS (Method E): Rt=3.07 min, m/z [M+H]+=444
Compound 101
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 8.18 (d, J=2.7 Hz, 1H), 6.63 (s, 2H), 5.33 (s, 1H), 4.43 (s, 2H), 3.16 (s, 3H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 1.11 (s, 6H), 0.60-0.39 (m, 4H).
LCMS (Method E): Rt=3.12 min, m/z [M+H]+=424
Compound 102
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.47 (d, J=2.3 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.75-5.68 (m, 1H), 5.32 (s, 1H), 3.76 (t, J=7.6 Hz, 2H), 3.54-3.49 (m, 2H), 2.47-2.43 (m, 1H), 2.35 (s, 3H), 1.53 (s, 3H), 1.19-1.09 (m, 3H), 1.06-1.00 (m, 2H), 0.58-0.37 (m, 4H).
LCMS (Method E): Rt=2.29 min, m/z [M+H]+=447
Compound 103
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.0 Hz, 1H), 8.61 (d, J=1.0 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H), 8.35 (d, J=3.5 Hz, 1H), 6.78 (s, 2H), 5.38 (s, 1H), 3.07 (s, 6H), 1.55 (s, 3H), 1.23-1.14 (m, 1H), 0.60-0.39 (m, 4H).
LCMS (Method E): Rt=3.04 min, m/z [M+H]+=409
Compound 105 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.58 (d, J=1.0 Hz, 1H), 8.35 (d, J=2.6 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 8.14 (s, 1H), 6.62 (s, 2H), 5.33 (s, 1H), 4.45 (t, J=6.5 Hz, 2H), 3.52 (t, J=4.5 Hz, 4H), 2.30-2.23 (m, 4H), 2.21 (t, J=6.5 Hz, 2H), 2.04-1.94 (m, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.62-0.49 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.14 min, m/z [M+H]+=465
Compound 106 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.26 (d, J=3.7 Hz, 1H), 8.16 (s, 1H), 6.62 (s, 2H), 5.39-5.38 (m, 1H), 4.72-4.62 (m, 1H), 3.05 (d, J=11.4 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 2.23-2.03 (m, 6H), 1.54 (s, 3H), 1.22-1.14 (m, 1H), 1.05 (t, J=7.1 Hz, 3H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.16 min, m/z [M+H]+=449
Compound 107
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.10 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.42-5.35 (m, 1H), 5.33 (s, 1H), 3.13-3.01 (m, 2H), 2.68-2.52 (m, 2H), 2.36 (s, 3H), 2.27 (q, J=8.5 Hz, 1H), 2.04-1.94 (m, 1H), 1.54 (s, 3H), 1.21-1.13 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.12 min, m/z [M+H]+=421
Compound 108 (Formic Acid 0.7 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.26 (d, J=3.7 Hz, 1H), 8.17 (s, 0.7H), 6.63 (s, 2H), 5.34 (s, 1H), 4.70-4.60 (m, 1H), 3.48 (t, J=5.8 Hz, 2H), 3.26 (s, 3H), 3.06 (d, J=12.0 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H), 2.34-2.24 (m, 2H), 2.11-2.00 (m, 4H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.22 min, m/z [M+H]+=479
Compound 109
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.1 Hz, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.25 (d, J=3.7 Hz, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 6.62 (s, 2H), 5.48 (s, 2H), 5.33 (s, 1H), 3.77 (s, 3H), 1.54 (s, 3H), 1.21-1.13 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.67 min, m/z [M+H]+=432
Compound 110
1H NMR (400 MHz, CDCl3) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.69 (d, J=1.0 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.20 (d, J=3.5 Hz, 1H), 5.73-5.65 (m, 1H), 5.27 (t, J=7.5 Hz, 2H), 5.11-5.03 (m, 4H).
LCMS (Method E): Rt=2.61 min, m/z [M+H]+=402
Compound 114
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.92 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.0 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 6.99 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.47 (s, 1H), 4.21 (d, J=7.1 Hz, 2H), 2.88 (d, J=12.0 Hz, 2H), 2.40-2.31 (m, 2H), 1.96-1.88 (m, 1H), 1.52 (s, 6H), 1.39 (d, J=10.5 Hz, 2H), 1.19-1.06 (m, 2H).
LCMS (Method E): Rt=1.60 min, m/z [M+H]+=391
Compound 115
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.0 Hz, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.62 (s, 2H), 5.75 (s, 1H), 4.52 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.1 Hz, 2H), 3.29-3.26 (m, 2H), 3.23 (s, 3H), 2.82-2.71 (m, 2H), 2.08-1.88 (m, 2H), 1.74-1.57 (m, 3H), 1.48 (s, 3H).
LCMS (Method E): Rt=1.61 min, m/z [M+H]+=421
Compound 116 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.79 (d, J=1.0 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 5.50 (s, 1H), 4.52 (t, J=5.8 Hz, 2H), 3.81 (t, J=5.8 Hz, 2H), 3.75 (s, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.79 min, m/z [M+H]+=420
Compound 117 (Formic Acid 0.85 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.1 Hz, 1H), 8.50-8.49 (m, 2H), 8.17 (d, J=5.2 Hz, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 6.95 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.48 (s, 1H), 4.37 (t, J=7.0 Hz, 2H), 3.87 (s, 2H), 3.41 (t, J=6.8 Hz, 2H), 2.16-2.06 (m, 2H), 1.51 (s, 6H).
LCMS (Method E): Rt=1.85 min, m/z [M+H]+=434
Compound 118
1H NMR (400 MHz, DMSO-d6, trifluoroacetic acid) δ ppm: 9.64 (s, 1H), 9.00 (s, 1H), 8.88 (s, 1H), 8.34 (s, 1H), 5.30-5.21 (m, 1H), 2.98 (t, J=7.4 Hz, 2H), 2.84 (t, J=7.4 Hz, 2H), 1.87-1.77 (m, 2H), 1.66 (d, J=6.7 Hz, 6H), 1.59 (s, 6H).
LCMS (Method E): Rt=1.70 min, m/z [M+H]+=393
Compound 119
1H NMR (400 MHz, CDCl3) δ ppm: 8.79 (d, J=1.0 Hz, 1H), 8.66 (d, J=1.0 Hz, 1H), 8.15 (d, J=3.6 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 4.42 (t, J=6.6 Hz, 2H), 3.33 (s, 3H), 3.27 (t, J=5.6 Hz, 2H), 2.18-2.09 (m, 2H), 1.73 (s, 3H), 1.33-1.25 (m, 1H), 0.80-0.51 (m, 4H).
LCMS (Method E): Rt=2.83 min, m/z [M+H]+=410
Compound 120
1H NMR (400 MHz, CDCl3) δ ppm: 8.79 (d, J=1.0 Hz, 1H), 8.66 (d, J=1.0 Hz, 1H), 8.15 (d, J=3.6 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 4.42 (t, J=6.6 Hz, 2H), 3.33 (s, 3H), 3.27 (t, J=5.6 Hz, 2H), 2.17-2.09 (m, 2H), 1.73 (s, 3H), 1.33-1.25 (m, 1H), 0.80-0.50 (m, 4H).
LCMS (Method E): Rt=2.83 min, m/z [M+H]+=410
Compound 121
1H NMR (400 MHz, CDCl3) δ ppm: 8.92 (s, 1H), 8.70 (s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.20 (d, J=3.5 Hz, 1H), 5.73-5.65 (m, 1H), 5.28 (t, J=7.5 Hz, 2H), 5.10 (t, J=6.6 Hz, 2H), 5.04 (s, 2H), 2.21 (s, 1H), 1.74 (s, 3H), 1.34-1.26 (m, 1H), 0.80-0.52 (m, 4H).
LCMS (Method E): Rt=2.62 min, m/z [M+H]+=394
Compound 122
1H NMR (400 MHz, CDCl3) δ ppm: 8.91 (s, 1H), 8.69 (d, J=1.0 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.20 (d, J=3.5 Hz, 1H), 5.73-5.65 (m, 1H), 5.28 (t, J=7.5 Hz, 2H), 5.11-5.07 (m, 2H), 5.04 (s, 2H), 2.26 (s, 1H), 1.74 (s, 3H), 1.34-1.26 (m, 1H), 0.80-0.52 (m, 4H).
LCMS (Method E): Rt=2.62 min, m/z [M+H]+=394
Compound 123 (Formic Acid 1.8 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (d, J=1.1 Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 8.42 (s, 1H), 8.19-8.16 (m, 2.8H), 6.98 (d, J=5.3 Hz, 1H), 6.56 (s, 2H), 4.52 (t, J=4.9 Hz, 2H), 3.75 (t, J=5.2 Hz, 4H), 3.23 (s, 3H), 2.68-2.57 (m, 2H), 2.26 (s, 3H), 1.99-1.90 (m, 2H), 1.87-1.77 (m, 2H).
LCMS (Method E): Rt=1.55 min, m/z [M+H]+=407
Compound 124
1H NMR (400 MHz, DMSO-d6, trifluoroacetic acid) δ ppm: 9.58 (s, 1H), 9.43 (s, 1H), 9.09 (s, 1H), 8.43 (d, J=6.8 Hz, 1H), 7.54 (d, J=6.8 Hz, 1H), 4.75 (t, J=4.8 Hz, 2H), 4.14-3.99 (m, 4H), 3.81 (t, J=4.8 Hz, 2H), 3.25 (s, 3H), 3.22-3.12 (m, 1H), 1.50 (s, 3H).
LCMS (Method E): Rt=1.59 min, m/z [M+H]+=393
Compound 125
1H NMR (400 MHz, CD3OD) δ ppm: 8.79 (s, 1H), 8.69 (s, 1H), 8.29 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.01 (d, J=5.5 Hz, 1H), 4.51 (t, J=4.9 Hz, 2H), 3.97-3.94 (m, 2H), 3.80-3.73 (m, 4H) 3.23 (s, 3H).
LCMS (Method E): Rt=1.55 min, m/z [M+H]+=365
Compound 126 (Formic Acid 0.7 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=0.9 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.26 (d, J=3.7 Hz, 1H), 8.17 (s, 0.7H), 6.63 (s, 2H), 5.34 (s, 1H), 4.70-4.60 (m, 1H), 3.48 (t, J=5.8 Hz, 2H), 3.26 (s, 3H), 3.06 (d, J=12.0 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H), 2.34-2.24 (m, 2H), 2.11-2.00 (m, 4H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.22 min, m/z [M+H]+=479
Compound 127
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.97 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.30 (d, J=2.7 Hz, 1H), 8.27 (d, J=3.8 Hz, 1H), 6.65 (s, 2H), 5.35 (s, 1H), 4.59-4.42 (m, 2H), 3.85-3.77 (m, 2H), 3.47-3.38 (m, 1H), 2.94 (d, J=10.8 Hz, 1H), 2.69-2.63 (m, 1H), 2.36-2.30 (m, 2H), 2.01-1.92 (m, 1H), 1.75 (t, J=10.5 Hz, 1H), 1.56 (s, 3H), 1.23-1.15 (m, 1H), 1.01 (t, J=7.1 Hz, 3H), 0.62-0.40 (m, 4H).
LCMS (Method E): Rt=2.17 min, m/z [M+H]+=465
Compound 128
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.26 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.36 (s, 1H), 5.13-5.06 (m, 1H), 3.79 (dd, J=7.5, 10.4 Hz, 1H), 3.69 (dd, J=4.2, 10.4 Hz, 1H), 3.21 (s, 3H), 1.56-1.53 (m, 6H), 1.22-1.14 (m, 1H), 0.60-0.39 (m, 4H).
LCMS (Method E): Rt=2.92 min, m/z [M+H]+=410
Compound 129
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 8.25 (d, J=3.7 Hz, 1H), 6.63 (s, 2H), 5.32 (s, 1H), 4.64 (s, 2H), 4.58 (d, J=6.0 Hz, 2H), 4.21 (d, J=6.0 Hz, 2H), 1.53 (s, 3H), 1.22 (s, 3H), 1.20-1.12 (m, 1H), 0.59-0.37 (m, 4H).
LCMS (Method E): Rt=2.78 min, m/z [M+H]+=422
Compound 130
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.57 (d, J=0.9 Hz, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.26 (d, J=4.0 Hz, 1H), 6.63 (s, 2H), 5.34 (s, 1H), 4.56 (dd, J=3.2, 14.4 Hz, 1H), 4.41 (dd, J=7.6, 14.4 Hz, 1H), 4.25-4.17 (m, 1H), 3.78-3.71 (m, 1H), 3.66-3.59 (m, 1H), 2.07-1.97 (m, 1H), 1.82-1.73 (m, 2H), 1.55 (s, 4H), 1.22-1.14 (m, 1H), 0.60-0.39 (m, 4H).
LCMS (Method E): Rt=2.89 min, m/z [M+H]+=422
Compound 131
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.58 (d, J=1.0 Hz, 1H), 8.27 (d, J=4.0 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 6.66 (s, 2H), 5.57-5.50 (m, 1H), 5.36 (s, 1H), 4.16-4.09 (m, 2H), 3.98 (dd, J=5.7, 10.1 Hz, 1H), 3.88-3.80 (m, 1H), 2.65-2.55 (m, 1H), 2.25-2.15 (m, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.39 (m, 4H).
LCMS (Method E): Rt=2.73 min, m/z [M+H]+=408
Compound 132
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.42 (s, 1H), 8.79 (d, J=1.1 Hz, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 6.62 (s, 2H), 5.33 (s, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.39 (m, 4H).
LCMS (Method E): Rt=2.39 min, m/z [M+H]+=338
Compound 133
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.30 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 6.16-6.09 (m, 1H), 5.34 (s, 1H), 5.09 (t, J=7.3 Hz, 2H), 4.94 (t, J=6.5 Hz, 2H), 2.79 (s, 3H), 1.53 (s, 3H), 1.21-1.13 (m, 1H), 0.58-0.37 (m, 4H).
LCMS (Method E): Rt=2.52 min, m/z [M+H]+=408
Compound 134
1H NMR (400 MHz, CDCl3) δ ppm: 8.80 (s, 1H), 8.66 (s, 1H), 8.16 (d, J=3.5 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 5.04 (s, 2H), 4.47 (t, J=5.7 Hz, 2H), 3.61 (t, J=5.8 Hz, 2H), 3.14-3.09 (m, 2H), 2.81 (d, J=8.2 Hz, 2H), 2.78 (s, 3H), 1.73 (s, 3H), 1.34-1.25 (m, 1H), 0.80-0.51 (m, 4H).
LCMS (Method E): Rt=2.56 min, m/z [M+H]+=464
Compound 135
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.02 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.37-5.31 (m, 2H), 3.78 (t, J=7.7 Hz, 2H), 3.52-3.46 (m, 2H), 2.38 (s, 3H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.09 min, m/z [M+H]+=407
Compound 136
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.40-5.30 (m, 2H), 3.77 (t, J=7.7 Hz, 2H), 3.48-3.41 (m, 2H), 2.59-2.52 (m, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.95 (t, J=7.1 Hz, 3H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.16 min, m/z [M+H]+=421
Compound 137
1H NMR (400 MHz, CDCl3) δ ppm: 8.92 (d, J=0.9 Hz, 1H), 8.72 (d, J=0.9 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.20 (d, J=3.5 Hz, 1H), 5.72-5.65 (m, 1H), 5.28 (t, J=7.5 Hz, 2H), 5.08 (dd, J=6.0, 7.4 Hz, 4H), 4.71-4.48 (m, 2H), 2.88 (s, 1H), 1.35-1.27 (m, 1H), 0.90-0.83 (m, 1H), 0.77-0.59 (m, 3H).
LCMS (Method E): Rt=2.71 min, m/z [M+H]+=412
Compound 138 (Formic Acid 1.0 Equivalents)
1H NMR (400 MHz, CDCl3) δ ppm: 8.90 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 8.14 (d, J=3.7 Hz, 1H), 5.21 (s, 2H), 4.85-4.77 (m, 1H), 3.28 (dd, J=1.3, 8.6 Hz, 1H), 2.99 (d, J=10.8 Hz, 1H), 2.65-2.53 (m, 3H), 2.38-2.30 (m, 1H), 2.23 (d, J=9.0 Hz, 1H), 1.99-1.89 (m, 3H), 1.73 (s, 3H), 1.33-1.24 (m, 1H), 1.16 (t, J=7.2 Hz, 3H), 0.79-0.50 (m, 4H).
LCMS (Method E): Rt=2.37 min, m/z [M+H]+=449
Compound 139
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.05 (d, J=1.0 Hz, 1H), 8.57 (d, J=0.9 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.41-5.32 (m, 2H), 3.76 (t, J=7.6 Hz, 2H), 3.58-3.42 (m, 2H), 2.48-2.47 (m, 2H), 1.55 (s, 3H), 1.40-1.33 (m, 2H), 1.22-1.13 (m, 1H), 0.90 (t, J=7.4 Hz, 3H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.26 min, m/z [M+H]+=435
Compound 140
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (s, 1H), 8.56 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.39-5.31 (m, 2H), 3.83 (t, J=7.5 Hz, 2H), 3.48 (dd, J=5.8, 7.6 Hz, 2H), 2.42 (d, J=6.6 Hz, 2H), 1.55 (s, 3H), 1.22-1.13 (m, 1H), 0.83-0.76 (m, 1H), 0.58-0.39 (m, 6H), 0.17-011 (m, 2H).
LCMS (Method E): Rt=2.41 min, m/z [M+H]+=447
Compound 141
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.13 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.41-5.35 (m, 1H), 5.34 (s, 1H), 3.18-3.11 (m, 2H), 2.68-2.55 (m, 4H), 2.33-2.25 (m, 1H), 2.02-1.91 (m, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 1.11 (t, J=7.2 Hz, 3H), 0.60-0.39 (m, 4H).
LCMS (Method E): Rt=2.24 min, m/z [M+H]+=435
Compound 142
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.06 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.8 Hz, 1H), 6.66 (s, 2H), 5.34 (s, 1H), 5.33-5.27 (m, 1H), 3.74 (t, J=7.6 Hz, 2H), 3.44-3.39 (m, 2H), 2.91-2.85 (m, 1H), 1.72-1.62 (m, 2H), 1.60-1.47 (m, 7H), 1.44-1.36 (m, 2H), 1.22-1.14 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=2.49 min, m/z [M+H]+=461
Compound 143
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=1.0 Hz, 1H), 8.36 (d, J=1.0 Hz, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 6.71 (s, 2H), 5.33 (s, 1H), 5.06-4.95 (m, 1H), 4.28 (s, 2H), 3.37 (s, 3H), 1.57-1.53 (m, 9H), 1.20-1.12 (m, 1H), 0.59-0.38 (m, 4H).
LCMS (Method E): Rt=2.68 min, m/z [M+H]+=406
Compound 144
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.39 (d, J=1.0 Hz, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 6.72 (s, 2H), 5.47 (s, 1H), 5.05-4.96 (m, 1H), 4.29 (s, 2H), 3.37 (s, 3H), 1.56 (d, J=6.8 Hz, 6H), 1.51 (s, 6H).
LCMS (Method E): Rt=2.42 min, m/z [M+H]+=380
Compound 145
1H NMR (400 MHz, DMSO-d6) δ ppm: d 9.06 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 8.30 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.48 (tt, J=6.4, 6.5 Hz, 1H), 5.35 (s, 1H), 4.02 (t, J=7.7 Hz, 2H), 3.79-3.74 (m, 2H), 3.44 (q, J=10.1 Hz, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.60-0.38 (m, 4H).
LCMS (Method E): Rt=3.41 min, m/z [M+H]+=475
Compound 146
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.07 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 6.65 (s, 2H), 5.33 (s, 2H), 3.76 (t, J=7.6 Hz, 2H), 3.48-3.43 (m, 2H), 2.47-2.44 (m, 2H), 1.93-1.80 (m, 1H), 1.75-1.65 (m, 2H), 1.59-1.44 (m, 7H), 1.25-1.12 (m, 3H), 0.59-0.37 (m, 4H).
LCMS (Method E): Rt=2.73 min, m/z [M+H]+=475
Compound 147
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.89 (d, J=0.9 Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 8.48 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.88-7.82 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.48 (s, 1H), 4.35 (t, J=6.9 Hz, 2H), 3.07 (q, J=6.3 Hz, 2H), 2.07 (t, J=7.5 Hz, 2H), 2.02-1.93 (m, 2H), 1.52 (s, 6H), 1.51-1.42 (m, 2H), 1.29-1.22 (m, 2H), 0.86 (t, J=7.4 Hz, 3H).
LCMS (Method E): Rt=2.32 min, m/z [M+H]+=435
Compound 148 (Formic Acid 0.6 Equivalents)
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (d, J=1.0 Hz, 1H), 8.50 (d, J=1.1 Hz, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.17 (s, 0.6H), 7.95-7.89 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57 (s, 2H), 5.48-5.48 (m, 1H), 4.36 (t, J=6.9 Hz, 2H), 3.05 (q, J=6.4 Hz, 2H), 2.02-1.92 (m, 2H), 1.81 (s, 3H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.81 min, m/z [M+H]+=393
Compound 149
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.96 (d, J=0.9 Hz, 1H), 8.68 (d, J=1.0 Hz, 1H), 8.48 (s, 1H), 8.22 (s, 0.5H), 8.11 (s, 1H), 6.16 (s, 2H), 5.32-5.32 (m, 1H), 5.05-4.94 (m, 1H), 3.90 (s, 3H), 1.57 (s, 3H), 1.55 (d, J=1.7 Hz, 6H), 1.22-1.14 (m, 1H), 0.62-0.48 (m, 2H), 0.47-0.36 (m, 2H).
LCMS (Method E): Rt=2.61 min, m/z [M+H]+=392
Compound 150
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (d, J=0.9 Hz, 1H), 8.64 (d, J=1.0 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 6.64 (s, 2H), 6.43 (s, 1H), 5.09-5.00 (m, 1H), 3.42-3.36 (m, 3H), 2.82 (s, 2H), 2.55-2.52 (m, 1H), 2.26-2.17 (m, 1H), 1.57 (d, J=6.7 Hz, 6H).
LCMS (Method E): Rt=2.58 min, m/z [M+H]+=409
Compound 151
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.12 (d, J=0.9 Hz, 1H), 8.60 (d, J=0.9 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.25 (d, J=3.8 Hz, 1H), 6.64 (s, 2H), 5.48 (s, 1H), 5.43-5.36 (m, 1H), 4.65 (t, J=4.9 Hz, 1H), 4.54 (t, J=4.9 Hz, 1H), 3.23-3.16 (m, 2H), 2.95-2.74 (m, 3H), 2.56-2.53 (m, 1H), 2.47-2.38 (m, 1H), 2.03-1.93 (m, 1H), 1.52 (s, 6H).
LCMS (Method E): Rt=1.98 min, m/z [M+H]+=427
Compound 152
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.10 (d, J=0.9 Hz, 1H), 8.58 (d, J=0.9 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.26 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.43-5.38 (m, 1H), 5.34 (s, 1H), 3.23-3.18 (m, 2H), 2.81-2.67 (m, 3H), 2.62-2.52 (m, 3H), 2.38-2.29 (m, 1H), 2.03-1.92 (m, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.62-0.49 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.11 min, m/z [M+H]+=503
Compound 153
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.12 (d, J=0.9 Hz, 1H), 8.58 (d, J=0.9 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.26 (d, J=3.8 Hz, 1H), 6.63 (s, 2H), 5.43-5.36 (m, 1H), 5.34 (s, 1H), 4.66 (t, J=4.9 Hz, 1H), 4.54 (t, J=4.9 Hz, 1H), 3.24-3.16 (m, 2H), 2.93-2.76 (m, 3H), 2.60-2.52 (m, 1H), 2.43 (q, J=8.5 Hz, 1H), 2.03-1.93 (m, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.62-0.49 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.24 min, m/z [M+H]+=453
Compound 154
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.30 (d, J=3.7 Hz, 1H), 6.68 (s, 2H), 5.73-5.64 (m, 1H), 5.35 (s, 1H), 4.70 (t, J=8.8 Hz, 1H), 4.64-4.59 (m, 1H), 4.44 (t, J=9.4 Hz, 1H), 4.28-4.22 (m, 1H), 1.88 (s, 3H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.48 (m, 2H), 0.48-0.37 (m, 2H).
LCMS (Method E): Rt=2.53 min, m/z [M+H]+=435
Compound 155
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.39-5.33 (m, 2H), 3.83 (t, J=7.7 Hz, 2H), 3.55-3.49 (m, 2H), 3.38 (t, J=5.7 Hz, 2H), 3.26 (s, 3H), 2.72 (t, J=5.7 Hz, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.48 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.27 min, m/z [M+H]+=451
Compound 156
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (d, J=0.9 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.37-5.34 (m, 2H), 3.77 (t, J=7.3 Hz, 2H), 3.48-3.42 (m, 2H), 3.38 (t, J=6.4 Hz, 2H), 3.24 (s, 3H), 2.60-2.54 (m, 2H), 1.61-1.54 (m, 5H), 1.22-1.14 (m, 1H), 0.62-0.49 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.32 min, m/z [M+H]+=465
Compound 157
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=0.9 Hz, 1H), 8.56 (d, J=0.9 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.6 Hz, 1H), 6.66 (s, 2H), 5.37-5.29 (m, 2H), 3.87 (t, J=7.6 Hz, 2H), 3.62-3.57 (m, 2H), 2.13-2.06 (m, 1H), 1.54 (s, 3H), 1.21-1.13 (m, 1H), 0.61-0.48 (m, 2H), 0.47-0.34 (m, 4H), 0.34-0.28 (m, 2H).
LCMS (Method E): Rt=2.28 min, m/z [M+H]+=433
Compound 158
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.41-5.32 (m, 2H), 3.83 (t, J=7.6 Hz, 2H), 3.54-3.50 (m, 2H), 3.47-3.38 (m, 4H), 2.71 (t, J=5.7 Hz, 2H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 1.11 (t, J=7.0 Hz, 3H), 0.61-0.48 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.42 min, m/z [M+H]+=465
Compound 159
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (d, J=0.9 Hz, 1H), 8.57 (d, J=0.9 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.34 (s, 1H), 5.32-5.24 (m, 1H), 3.78 (t, J=7.6 Hz, 2H), 3.44-3.39 (m, 2H), 2.48-2.43 (m, 1H), 1.55 (s, 3H), 1.22-1.13 (m, 1H), 0.93 (d, J=6.3 Hz, 6H), 0.55 (d, J=50.2 Hz, 2H), 0.42 (d, J=39.5 Hz, 2H).
LCMS (Method E): Rt=2.25 min, m/z [M+H]+=435
Compound 160
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.47 (s, 1H), 5.38-5.29 (m, 1H), 3.87 (t, J=7.7 Hz, 2H), 3.62-3.57 (m, 2H), 2.13-2.07 (m, 1H), 0.44-0.38 (m, 2H), 0.34-0.30 (m, 2H).
LCMS (Method E): Rt=2.05 min, m/z [M+H]+=413
Compound 161
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.64 (d, J=1.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.68 (s, 2H), 5.95 (s, 1H), 5.38-5.30 (m, 1H), 4.48-4.42 (m, 1H), 4.36-4.30 (m, 1H), 3.90-3.85 (m, 2H), 3.63-3.58 (m, 2H), 2.14-2.08 (m, 1H), 1.52 (d, J=1.9 Hz, 3H), 0.44-0.38 (m, 2H), 0.34-0.30 (m, 2H).
LCMS (Method E): Rt=2.04 min, m/z [M+H]+=425
Compound 162
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=1.0 Hz, 1H), 8.56 (d, J=1.0 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.29 (d, J=3.7 Hz, 1H), 6.66 (s, 2H), 5.35 (s, 1H), 5.34-5.27 (m, 1H), 3.84 (t, J=7.5 Hz, 2H), 3.52-3.46 (m, 2H), 3.30-3.28 (m, 1H), 3.26 (s, 3H), 3.15 (dd, J=5.4, 9.6 Hz, 1H), 2.66-2.59 (m, 1H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.91 (d, J=6.3 Hz, 3H), 0.62-0.48 (m, 2H), 0.48-0.37 (m, 2H).
LCMS (Method E): Rt=2.35 min, m/z [M+H]+=465
Compound 163
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.04 (d, J=1.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 6.63 (s, 2H), 5.34 (s, 1H), 4.70-4.62 (m, 2H), 4.52 (t, J=4.8 Hz, 1H), 3.10-3.03 (m, 2H), 2.76 (t, J=4.8 Hz, 1H), 2.68 (t, J=5.0 Hz, 1H), 2.40-2.30 (m, 2H), 2.14-2.01 (m, 4H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.49 (m, 2H), 0.48-0.36 (m, 2H).
LCMS (Method E): Rt=2.19 min, m/z [M+H]+=467
Compound 164
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.54 (s, 2H), 5.34 (s, 1H), 4.70-4.60 (m, 1H), 3.09 (d, J=11.4 Hz, 2H), 2.48-2.43 (m, 1H), 2.06-1.97 (m, 4H), 1.76-1.69 (m, 1H), 1.54 (s, 3H), 1.22-1.13 (m, 1H), 0.61-0.37 (m, 7H), 0.36-0.32 (m, 2H).
LCMS (Method E): Rt=1.89 min, m/z [M+H]+=443
Compound 165
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=0.9 Hz, 1H), 8.57 (d, J=0.9 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 6.63 (s, 2H), 5.34 (s, 1H), 4.70-4.60 (m, 1H), 3.18-3.11 (m, 2H), 2.29-2.19 (m, 4H), 2.13-2.06 (m, 4H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.92-0.84 (m, 1H), 0.59-0.38 (m, 6H), 0.14-0.08 (m, 2H).
LCMS (Method E): Rt=2.32 min, m/z [M+H]+=475
Compound 166
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.01 (d, J=1.0 Hz, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.28 (d, J=3.7 Hz, 1H), 6.67 (s, 2H), 5.49 (s, 1H), 5.37-5.29 (m, 1H), 3.87 (t, J=7.7 Hz, 2H), 3.62-3.57 (m, 2H), 2.13-2.07 (m, 1H), 1.52 (s, 6H), 0.44-0.38 (m, 2H), 0.34-0.30 (m, 2H).
LCMS (Method E): Rt=2.00 min, m/z [M+H]+=407
Compound 167
1H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=0.9 Hz, 1H), 8.57 (d, J=0.9 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.27 (d, J=3.7 Hz, 1H), 6.64 (s, 2H), 5.34 (s, 1H), 4.73-4.63 (m, 1H), 3.06 (d, J=11.5 Hz, 2H), 2.68-2.54 (m, 4H), 2.34-2.23 (m, 2H), 2.11-2.03 (m, 4H), 1.55 (s, 3H), 1.22-1.14 (m, 1H), 0.61-0.48 (m, 2H), 0.48-0.37 (m, 2H).
LCMS (Method E): Rt=2.42 min, m/z [M+H]+=517
Compound 168
1H NMR (400 MHz, DMSO-d6) δ ppm: 8.95 (d, J=0.9 Hz, 1H), 8.71-8.69 (m, 2H), 8.12 (s, 1H), 6.22 (s, 2H), 5.33 (s, 1H), 5.04-4.96 (m, 1H), 4.20-4.17 (m, 2H), 3.78-3.74 (m, 2H), 3.39 (s, 3H), 1.55 (s, 6H), 1.53 (s, 3H), 1.22-1.14 (m, 1H), 0.62-0.49 (m, 2H), 0.47-0.36 (m, 2H).
LCMS (Method E): Rt=2.73 min, m/z [M+H]+=436
Pharmacological Part
Biological Assay A
Inhibition of Recombinant Human NF-kappaB-Inducing Kinase (NIK/MAP3K14) Activity
Assay buffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na3VO4, 5 mM MgCl2, 0.01% Tween 20. Assays were carried out in 384 well Mesoscale high binding plates which had been coated with myelin basic protein (MBP) and blocked with bovine serum albumin to prevent non-specific protein binding. All compounds tested were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. Final DMSO concentration was 1% (v/v) in assays. Incubations consisted of compound (1% DMSO in control and blank wells), 25 μM Adenosine-5′-triphosphate (ATP), and 10 nM NIK/MAP3K14 substituting enzyme with buffer in the blank wells. Incubations were carried out for 1 h at 25° C. and were followed by washing and sequential incubation with rabbit anti-phospho-MBP and anti-rabbit Ig Sulfotag antibody before reading bound Sulfotag on a Mesoscale Discovery. Signal obtained in the wells containing blank samples was subtracted from all other wells and IC50's were determined by fitting a sigmoidal curve to % inhibition of control versus Log10 compound concentration.
Biological Assay A2
Inhibition of Auto-Phosphorylation of Recombinant Human NF-kappaB-Inducing Kinase (NIK/MAP3K14) Activity (AlphaScreen®)
NIK/MAP3K14 auto-phosphorylation activity was measured using the AlphaScreen® (αscreen) format (Perkin Elmer). All compounds tested were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. Final DMSO concentration was 1% (v/v) in assays. Assay buffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM Na3VO4, 5 mM MgCl2, 0.01% Tween 20. Assays were carried out in 384 well Alphaplates (Perkin Elmer). Incubations consisted of compound, 25 microM Adenosine-5′-triphosphate (ATP), and 0.2 nM NIK/MAP3K14. Incubations were initiated by addition of GST-tagged NIK/MAP3K14 enzyme, carried out for 1 h at 25° C. and terminated by addition of stop buffer containing anti-phospho-IKK Ser176/180 antibody. Protein A Acceptor and Glutathione-Donor beads were added before reading using an EnVision® Multilabel Plate Reader (Perkin Elmer). Signal obtained in the wells containing blank samples was subtracted from all other wells and IC50's were determined by fitting a sigmoidal curve to % inhibition of control versus Log10 compound concentration.
Biological Assay B
Effect of Compounds on P-IKKα Levels in L363 Cells
All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 1% (v/v) in cell assays. The human L363 cells (ATCC) were cultured in RPMI 1640 medium supplemented with GlutaMax and 10% fetal calf serum (PAA). Cells were routinely maintained at densities of 0.2×106 cells per ml-1×106 cells per ml at 37° C. in a humidified 5% CO2 atmosphere. Cells were passaged twice a week splitting back to obtain the low density. Cells were seeded in 96 well plates (Nunc 167008) at 2×106 per ml media in a volume of 75 μl per well plus 25 μl 1 μg/ml recombinant human B-cell activating factor BAFF/B1YS/TNFSF13B. Seeded cells were incubated at 37° C. in a humidified 5% CO2 atmosphere for 24 hr. Drugs and/or solvents were added (20 μl) to a final volume of 120 μl. Following 2 hr treatment plates were removed from the incubator and cell lysis was achieved by the addition of 30 μl 5× lysis buffer followed by shaking on a plate shaker at 4° C. for 10 min. At the end of this incubation lysed cells were centrifuged at 800×g for 20 min at 4° C. and the lysate was assessed for P-IKKα levels by sandwich immuno-assay carried out in anti-rabbit antibody coated Mesoscale plates. Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using an 8 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing MG132 and BAFF but no test drug) and a blank incubation (containing MG132 and BAFF and 10 μM ADS125117, a test concentration known to give full inhibition) were run in parallel. The blank incubation value was subtracted from all control and sample values. To determine the IC50 a sigmoidal curve was fitted to the plot of % inhibition of control P-IKKα levels versus Log10 compound concentration.
Biological Assay C
Determination of Antiproliferative Activity on LP-1, L-363 and JJN-3 Cells
All compounds tested were dissolved in DMSO and further dilutions were made in culture medium. Final DMSO concentration was 0.3% (v/v) in cell proliferation assays. Viability was assessed using CellTiter-Glo cell viability assay kit (Promega). The human LP-1, L-363 and JJN-3 cells (DSMZ) were cultured in RPMI 1640 medium supplemented with 2 mM L-glutamine, and 10% fetal calf serum (PAA). Cells were routinely kept as suspension cells at 37° C. in a humidified 5% CO2 atmosphere. Cells were passaged at a seeding density of 0.2×106/ml twice a week. Cells were seeded in black tissue culture treated 96-well plates (Perkin Elmer). Densities used for plating ranged from 2,000 to 6,000 cells per well in a total volume of 75 μl medium. After twenty four hours, drugs and/or solvents were added (25 μl) to a final volume of 100 μl. Following 72 hr of treatment plates were removed from the incubator and allowed to equilibrate to room temperature for approx 10 min. 100 μl CellTiter-Glo reagent was added to each well that was then covered (Perkin Elmer Topseal) and shaken on plate shaker for 10 min. Luminescence was measured on a HTS Topcount (Perkin Elmer). Within an experiment, the results for each treatment were the mean of 2 replicate wells. For initial screening purposes, compounds were tested using a 9 point dilution curve (serial 1:3 dilutions). For each experiment, controls (containing no drug) and a blank incubation (containing cells read at the time of compound addition) were run in parallel. The blank value was subtracted from all control and sample values. For each sample, the mean value for cell growth (in relative light units) was expressed as a percentage of the mean value for cell growth of the control.
Data for the compounds (Co.) of the invention in the above assays are provided in Table 25 (the values in Table 25 are averaged values over all measurements on all batches of a compound).













TABLE 25






Biochemical

IKKα






(MSD MBP)
αscreen
Cellular
JJN-3
L-363
LP-1



IC50
IC50
IC50
EC50
EC50
EC50


Co.
(nM)
(nM)
(nM)
(nM)
(nM)
(nM)





















1
6.9
4.0
93
200
180
3200


2
9.7
48
82
220
210
1900


3
15
34
75
500
230
11000


4
46
21
130
420
400
5300


5
1.6
8.0
30
160
94
320


6
2.3
11
68
860
790
3000


7
15
210
540
1900
1900
3200


8
3.3
1.0
8
94
250
2700


9
1.1
2.0
37
74
120
1200


10
9.2
29
100
80
46
230


11
8.0
27
300
41
130
600


12
7.4
3.0
150
1300
1200
12000


13
30
150
n.c.
150
36
710


14
0.9
0.4
11
75
75
390


15
4.8
12
16
120
44
370


16
4.3
2.0
7.3
35
57
92


17
4.9
6.0
17
460
810
8000


18
3.7
8.0
47
340
450
1500


19
5.3
16
18
160
430
1200


20
9.4
15
30
1000
5000
11000


21
18
3.0
13
66
74
2800


22
20
9.0
75
280
190
1600


23
30
9.0
89
2500
9900
7700


24
8.7
15
13
140
96
760


25
9.9
20
11
110
63
190


26
49
19
120
5600
11000
15000


27
25
70
360
9700
>10000
>10000


28
17
49
84
1200
810
5800


29
140
110
6300
>10000
>10000
>10000


30
120
930
1700
12000
24000
>10000


31
36
79
110
1900
6400
>10000


32
59
40
89
460
740
1500


33
4.2
16
53
150
1100
4100


34
76
42
160
330
240
4100


35
120
150
470
2000
3000
3800


36
17
86
900
1700
7900
12000


37
45
100
330
3600
16000
>10000


38
21
56
370
1900
15000
>10000


39
930
1600
n.c.
n.c.
n.c.
n.c.


40
43
110
530
2300
4500
25000


41
3.5
9.0
43
240
290
2200


42
5.7
24
84
330
1500
16000


43
29
38
280
650
4100
>10000


44
25
21
36
250
400
1700


45
3.9
2.0
12
22
90
590


46
60
55
180
1100
3600
>10000


47
2900
9200
n.c.
>10000
>10000
>10000


48
65
16
260
380
650
3900


49
150
360
5900
32000
>10000
>10000


50
140
230
650
2700
7500
>10000


51
48
23
83
990
2400
>10000


52
29
33
99
1200
3200
30000


53
45
57
370
450
>10000
>10000


54
27
17
21
89
59
330


55
84
180
140
380
980
11000


56
25
18
140
840
840
14000


57
17
23
180
1300
910
31000


58
430
700
110
550
500
2000


59
71
230
5000
17000
>10000
>10000


60
8.4
11
19
170
150
14000


61
3.8
5.0
23
260
340
4600


62
250
680
n.c.
970
880
18000


63
600
780
n.c.
n.c.
n.c.
n.c.


64
5.2
29
20
81
51
2000


65
15
54
140
470
400
7000


66
5.8
52
240
250
270
7600


67
57
30
880
2400
2400
>10000


68
130
47
360
1500
960
16000


69
250
89
600
1800
870
16000


70
28
130
51
210
120
3000


71
26
61
n.c.
550
520
2600


72
6.3
38
n.c.
320
190
7200


73
56
71
n.c.
190
140
1600


74
17
43
n.c.
76
45
1100


75
n.c.
35
n.c.
540
670
>10000


76
n.c.
16
12
140
110
300


77
n.c.
88
n.c.
570
320
4000


78
n.c.
130
n.c.
580
410
2000


79
n.c.
47
n.c.
160
61
2000


80
n.c.
76
n.c.
310
160
2500


81
n.c.
100
n.c.
5700
5900
28000


82
n.c.
35
n.c.
1100
890
13000


83
n.c.
86
n.c.
670
550
4700


84
n.c.
68
n.c.
67
22
250


85
n.c.
33
n.c.
44
15
190


86
n.c.
11
n.c.
9.2
5.9
16


87
n.c.
9.0
n.c.
530
450
1200


88
n.c.
15
n.c.
130
110
220


89
n.c.
130
n.c.
3700
4200
7600


90
n.c.
44
n.c.
720
510
740


91
n.c.
12
n.c.
1100
470
4900


92
n.c.
47
n.c.
54
32
86


93
n.c.
10
n.c.
310
250
860


94
n.c.
31
n.c.
300
200
2700


95
n.c.
7.0
n.c.
150
95
470


96
n.c.
170
n.c.
>10000
6600
>10000


97
n.c.
21
70
170
100
1200


98
n.c.
220
110
78
42
210


99
n.c.
110
n.c.
1100
1100
2000


100
n.c.
61
n.c.
1400
1500
3000


101
n.c.
38
n.c.
160
160
220


102
n.c.
900
32
35
21
65


103
n.c.
13
49
91
48
680


104
n.c.
53
n.c.
260
180
470


105
n.c.
190
n.c.
200
140
530


106
n.c.
95
n.c.
120
90
340


107
n.c.
88
n.c.
78
57
150


108
n.c.
140
n.c.
270
280
640


109
n.c.
120
n.c.
460
360
1200


110
n.c.
17
n.c.
170
140
580


111
220
190
290
640
1300
7500


112
6.3
17
140
440
1300
14000


113
52
38
660
1400
4600
24000


114
160
190
3800
1600
1500
5500


115
n.c.
4900
n.c.
>10000
>10000
>10000


116
120
170
5300
5600
11000
>10000


117
100
14
3400
3300
9000
>10000


118
240
740
1700
330
1600
3800


119
n.c.
230
n.c.
700
900
2100


120
n.c.
17
20
95
74
200


121
n.c.
680
n.c.
1400
1300
3400


122
n.c.
26
36
100
69
310


123
23%a
27%a
n.c.
n.c.
n.c.
n.c.


124
40%a
33%a
n.c.
n.c.
n.c.
n.c.


125
18%a
24%a
n.c.
n.c.
n.c.
n.c.


126
n.c.
140
n.c.
270
280
640


127
n.c.
180
n.c.
240
190
420


128
n.c.
76
n.c.
130
120
310


129
n.c.
23
n.c.
210
150
920


130
n.c.
28
n.c.
300
190
640


131
n.c.
21
n.c.
150
89
440


132
n.c.
6.5
n.c.
77
30
410


133
n.c.
50
n.c.
140
66
330


134
n.c.
110
n.c.
4100
3000
24000


135
n.c.
68
n.c.
180
64
410


136
n.c.
120
n.c.
240
140
450


137
n.c.
53
n.c.
550
380
1990


138
n.c.
110
n.c.
94
80
250


139
n.c.
98
n.c.
220
160
340


140
n.c.
100
n.c.
170
140
320


141
n.c.
66
n.c.
96
56
320


142
n.c.
210
n.c.
150
190
410


143
n.c.
74
n.c.
270
170
n.c.


144
n.c.
37
n.c.
35
16
n.c.


145
n.c.
140
n.c.
260
340
n.c.


146
n.c.
200
n.c.
450
580
n.c.


147
n.c.
130
n.c.
1400
530
n.c.


148
n.c.
64
n.c.
9100
7600
n.c.


149
n.c.
22
n.c.
38
22
n.c.


150
n.c.
210
n.c.
1600
1500
n.c.


151
n.c.
54
n.c.
46
45
n.c.


152
n.c.
47
n.c.
48
75
n.c.


153
n.c.
74
n.c.
130
150
n.c.


154
n.c.
190
n.c.
4700
2800
n.c.


155
n.c.
140
n.c.
400
380
n.c.


156
n.c.
190
n.c.
320
360
n.c.


157
n.c.
46
n.c.
180
140
n.c.


158
n.c.
180
n.c
440
390
740


159
n.c.
270
n.c
230
180
320


160
n.c.
82
n.c
110
93
210


161
n.c.
40
n.c
150
110
340


162
n.c.
340
n.c
370
350
790


163
n.c.
73
n.c
110
59
110


164
n.c.
89
n.c
390
270
680


165
n.c.
46
n.c
220
200
460


166
n.c.
76
n.c
96
60
180


167
n.c.
58
n.c
390
390
1000


168
n.c.
36
n.c
27
23
93





n.c.: not calculated


aMax % Inhib @ 10 μM (Average)






Prophetic Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or a solvate thereof; in particular to any one of the exemplified compounds.
Typical examples of recipes for the formulation of the invention are as follows:
1. Tablets

















Active ingredient
5 to 50
mg



Di-calcium phosphate
20
mg



Lactose
30
mg



Talcum
10
mg



Magnesium stearate
5
mg



Potato starch
ad 200
mg










2. Suspension

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
3. Injectable
A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution or in 10% by volume propylene glycol in water.
4. Ointment

















Active ingredient
5 to 1000
mg



Stearyl alcohol
3
g



Lanoline
5
g



White petroleum
15
g



Water
ad 100
g










In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

## Claims

1. A compound of formula (I):



or a tautomer or a stereoisomeric form thereof, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het1, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein
the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;
Het1 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein
Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
or Het3 is 2-oxo-3-pyrrolidinyl optionally substituted with one C1-4alkyl;
R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;
R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;
R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein
R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;
Het4 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het5 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or
R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl; —OC1-4alkyl; and C1-4alkyl substituted with one —OH;
R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein
R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or
R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;
R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein
R7a and R7b are each independently selected from hydrogen and C1-4alkyl;
R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(i) fluoro,
(ii) —NR8aR8b,
(iii) —NR8cC(═O)R8d,
(iv) —NR8cC(═O)NR8aR8b,
(v) —NR8cC(═O)OR8e,
(vi) —NR8cS(═O)2NR8aR8b,
(vii) —NR8cS(═O)2R8d,
(viii) —OR8f,
(ix) —OC(═O)NR8aR8b,
(x) —C(═O)NR8aR8b,
(xi) —SR8e,
(xii) —S(O)2R8d, and
(xiii) —S(O)2NR8aR8b; wherein
R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;
R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;
R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;
and
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of




Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het11 is selected from the group of




Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;
R9 is hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1 wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het1, Het2 and phenyl; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein
the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
R1a, R1b, R2a, and R2b are each independently selected from hydrogen and C1-4alkyl;
Het1 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein
Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R3 is selected from the group of hydrogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;
R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano;
R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein
R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;
Het4 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or
R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and C1-4alkyl substituted with one —OH;
R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein
R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or
R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;
R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein
R7a and R7b are each independently selected from hydrogen and C1-4alkyl;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with Het9; and C2-6alkyl substituted with one or more substituents independently selected from the group of
(i) fluoro,
(ii) —NR8aR8b,
(iii) —NR8cC(═O)R8d,
(iv) —NR8cC(═O)NR8aR8b,
(v) —NR8cC(═O)OR8e,
(vi) —NR8cS(═O)2NR8aR8b,
(vii) —NR8cS(═O)2R8d,
(viii) —OR8f,
(ix) —OC(═O)NR8aR8b,
(x) —C(═O)NR8aR8b,
(xi) —SR8e,
(xii) —S(O)2R8d, and
(xiii) —S(O)2NR8aR8b; wherein
R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl, Het10 and Het11; and C3-6cycloalkyl;
R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl;
wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl;
and
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het10 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het11 is selected from the group of




R9 is hydrogen or C1-4alkyl.

3. The compound according to claim 1, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het2; and phenyl; wherein
the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl;
Het2 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents;
R4 is hydrogen;
R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein
R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl;
R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl;
R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; and —OC2-6alkyl substituted with one —OC1-4alkyl;
R7 is selected from the group of hydrogen, C1-4alkyl, —OC1-4alkyl, and —NHC1-4alkyl;
R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and
C2-6alkyl substituted with one or more substituents independently selected from the group of (i), (ii), (iii), (viii), (ix), (x), and (xii); wherein
R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;
R8d is C1-6alkyl;
R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl;
and
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of




Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl;
R9 is hydrogen or C1-4alkyl.

4. The compound according to claim 1, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —OC1-4alkyl and C3-6cycloalkyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het1; Het2; and phenyl;
R2c and R2d are each independently selected from C1-4alkyl;
Het1 is a heterocyclyl selected from the group of piperidinyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
Het2 is a heteroaryl selected from the group of thiazolyl, oxazolyl, isoxazolyl and pyridinyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl or a Het3 group; wherein
Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydrofuranyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl;
or Het3 is 2-oxo-3-pyrrolidinyl substituted with one C1-4alkyl on the nitrogen atom;
R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents;
R4 is hydrogen;
R5 is selected from the group of hydrogen; C1-6alkyl; and —C(═O)—NR5cR5d; wherein
R5c and R5d are each independently selected from the group of hydrogen; and C2-6alkyl substituted with one —OC1-4alkyl;
R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —O—C1-6alkyl; and —OC2-6alkyl substituted with one —OC1-4alkyl;
R7 is selected from the group of hydrogen, and C1-4alkyl;
R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with one Het9; —C(═O)—Het12; C1-4alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (ii), (iii), (viii), (x), (xii); wherein
R8a, R8b, R8c, and R8f are each independently selected from the group of hydrogen; C1-6alkyl; and C2-6alkyl substituted with one substituent selected from —OH, and —OC1-4alkyl;
R8d is C1-6alkyl;
R8g and R8h are each independently selected from C1-4alkyl;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, —C(═O)—C1-4alkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
or Het9 is pyrazolyl which may be optionally substituted with one C1-4alkyl; or Het9 is




Het12 is 1-piperazinyl which may be optionally substituted with one C1-4alkyl substituent; R9 is hydrogen or C1-4alkyl.

5. The compound according to claim 1, wherein
R1 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b, —OH and —OC1-4alkyl;
R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, —OC1-4alkyl, C3-6cycloalkyl, Het2 and phenyl;
C3-6cycloalkyl; Het2; and phenyl; wherein the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and
C1-4alkyloxy substituted with one or more fluoro substituents;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl.

6. The compound according to claim 1, wherein
R1 is selected from the group of C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents;
R2 is selected from the group of C1-6alkyl and C3-6cycloalkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R3 is selected from the group of hydrogen; C3-6cycloalkyl; and C1-4alkyl;
R4 is hydrogen;
R5 is hydrogen;
R6 is selected from the group of hydrogen; halogen; C1-6alkyl; and —OC1-6alkyl;
R7 is hydrogen;
R8 is selected from the group of hydrogen; Het8; C1-6alkyl optionally substituted with one Het9; and C2-6alkyl substituted with one or more —OR8f substituents;
R8f is C1-4alkyl;
Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl;
Het9 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, each of which may be optionally substituted with one C1-4alkyl;
R9 is hydrogen.

7. The compound according to claim 1, wherein
R1 is C1-4alkyl;
R2 is C1-4alkyl;
or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl;
R6 is chloro, fluoro, methyl, or methoxy.

8. The compound according to claim 1, wherein R8 is selected from hydrogen, —CH(CH3)2,

9. The compound according to claim 1 wherein R6 is fluoro.

10. The compound according to claim 1, wherein the compound is selected from




























tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts and the solvates thereof.

11. A pharmaceutical composition comprising a compound as claimed in any of claims 1-10 and a pharmaceutically acceptable carrier or diluent.

12. A compound as claimed in any of claims 1-10 use in the treatment of cancer.

13. A pharmaceutical composition as claimed in claim 11 for use in the treatment of cancer.

14. A method of treating cancer in a human which comprises administering to said human an effective amount of a compound as claimed in any of claims 1-10.

15. A method of treating cancer in a human which comprises administering to said human an effective amount of a compound as claimed in claim 11.