Novel compounds modulating miR-155

Field of the invention

The present invention relates to a compound according to formula (II): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, as well as pharmaceutical composition comprising the compounds of formula (I) or the compounds of formula (II) that can be used in treating and/or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155. Instant compounds are particularly useful in treating and/or preventing and/or alleviating the symptoms of systemic lupus erythematosus and scleroderma.

Background of the invention

Systemic lupus erythematosus (SLE) is an autoimmune disease that often leads to functional disorder in multiple organs, most often with symptoms related to skin lesions, cardiovascular disease and kidney damage. Although significant efforts have been made to find efficient therapies, it still remains uncured. Furthermore, the current therapy is often associated with adverse side effects and leads to a high economic burden for society. The non-coding RNA microRNA-155 (also referred to as miR-155) is upregulated in SLE patients and SLE mouse models. miRNAs (also referred to as micro RNAs), whose genes are often located within intronic regions of a genome, are located in a clustered manner and can be transcribed either as one primary transcript by a common promoter or transcribed individually using different promoters. A primary transcript of a miRNA, i.e. pri-miRNA is cleaved by Drosha in the nucleus, resulting in a small hairpin RNA, referred to as pre-miRNA that is released and exported to the cytoplasm by Exportin-5. In the cytoplasm, the apical loop of pre-miRNA is cleaved by RNase III, called Dicer. The product contains two strands of about 22 nucleotides that form a duplex that is often perturbed by small unpaired regions (bulges and 3’-ends). Other double-stranded RNA-binding proteins assist in this process as well. It results in two mature miRNA strands. Depending on their thermodynamic properties, one of the two strands is preferred to incorporate into the RNA-induced silencing complex (RISC), which contains the Argonaute (Ago) family of proteins responsible for the execution of the inhibitory function of miRNA on its target mRNA.

Silencing of mRNA transcripts at the posttranscriptional level by miRNAs belongs to one of the mechanisms in epigenetic regulation of genes. So far, more than 2000 miRNAs have been identified in humans and they may regulate the expression of approximately 60% of all human protein-coding genes as shown by computational prediction. miR-155 is one of the most widely recognized miRNAs known to be involved in autoimmune diseases through its crucial activities in innate and adaptive immunity. The expression of miR-155 is increased upon infection or injury and decreased by encountering anti-inflammatory cytokines, resolvins and glucocorticoids. For instance, miR-155 regulates polarization of macrophages in favor of a pro-inflammatory activation rather than an anti-inflammatory and repairing phenotype. It has been shown that deficiency of miR-155 reduces the levels of pro-inflammatory cytokines both in murine and in human macrophages. In dendritic cells (DCs), the crucial cell type in shaping the T cell repertoire and determining the nature of T cell response, miR-155 is known to regulate DC activation through repression of Src homology 2 domain- containing inositol-5'-phosphatase 1 (SHIP-1 ) and suppressor of cytokine signaling-1 (SOCS-1 ) in a similar manner as in macrophages. Experimentally, it has been shown that overexpression of miR-155 alone is sufficient to break selftolerance and promote a CD8- mediated autoimmune response in a diabetes model. In adaptive immunity, miR-155 is known to regulate B cell proliferation through SHIP and CCAAT enhancerbinding protein [3 (C/EBP[3). In addition, the formation of the germinal center (GC), a structure essential for antibody production, is positively supported by miR-155 via targeting Pll.1 , which reduces the expression of Pax5, an inhibitor of B cell activation. This enables plasma cell differentiation together with the expression of genes involved in B and T cell interactions, facilitating antibody production. Multiple studies have shown that miR-155 is upregulated in B cell-associated diseases including B cell malignancies and autoimmune diseases. Finally, miR-155 has been proven to be a regulator of T cell differentiation. Taken together, the mediator function of miR-155 in the human immune system, which is impaired in autoimmune diseases, including SLE, shows the rationality of targeting miR-155 in the fight against SLE. In fact, clinical trials already attempted to target miRNA dependent regulation with oligonucleotides, e.g. anti-miR-122 in hepatitis C infection and a mimic of the tumor suppressor miRNA-34 in cancer. miR-155 has been shown to be abundant in SLE patients. Its downregulation by inhibition of its maturation prevents secretion of proinflammatory cytokines.

Scleroderma, also referred to as systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterized by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. Systemic scleroderma is a rare disease, with an annual incidence that varies in different populations. Estimates of incidence (new cases per million people) range from 3.7 to 43 in the United Kingdom and Europe, 7.2 in Japan, 10.9 in Taiwan, 12.0 to 22.8 in Australia, 13.9 to 21.0 in the United States. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the torso. Visceral organs, including the kidneys, heart, lungs, and gastrointestinal tract can also be affected by the fibrotic process. Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk of cancer is increased slightly. Therapies include immunosuppressive drugs and, in some cases, glucocorticoids. It has been found that miR-155 was upregulated in lesional skin tissue from patients with either systemic or localized scleroderma, and correlated with fibrosis area. Alterations of microRNAs in lesional skin could be a new approach to treating the disease.

Despite extensive knowledge that several diseases as referred to hereinabove are characterized by the increased expression of miR-155, no compounds capable of reducing the expression of miR-155 and hence treating the diseases characterized by increased expression of miR-155 are available to the public.

Summary of the invention

The objective technical problem of the present invention was the provision of new compounds for modulating miR-155, that are useful in treating and/or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155.

The problem is solved by the embodiments described herein and as characterized by the claims.

Instant compounds have been shown to modulate miR-155 in the disease models. In particular, as demonstrated in Example 1 , representative compounds of formula (I) as well as formula (II) have been shown to effectively reduce the expression level of miR- 155 in a mouse model of miR-155-dependent disease, namely in a mouse model of scleroderma. The invention is summarized by the following embodiments.

In a first embodiment, the present invention relates to a compound according to formula (II): or its pharmaceutically acceptable salts, wherein

Ri and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, optionally substituted (C0-3 alkylene)- heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (Co- 3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-C(O)-cycloalkyl, optionally substituted (C0-3 alkylene)-C(O)-heterocycloalkyl, optionally substituted (C0-3 alkylene)- C(O)-aryl, optionally substituted (C0-3 alkylene)-C(O)-heteroaryl, optionally substituted (C0-3 alkylene)-C(O)NH-cycloalkyl, optionally substituted (C0-3 alkylene)-C(O)NH- heterocycloalkyl, optionally substituted (C0-3 alkylene)-C(O)NH-aryl, and optionally substituted (C0-3 alkylene)-C(O)NH-heteroaryl, wherein at least one of R1 and R2 is hydrogen, or R1 and R2 are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2;;

R3 and R4 are independently selected from hydrogen, optionally substituted -C(0)- (C0-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl; optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl;

Rs is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)- heteroaryl, optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (Co- 3 alkylene)-heterocycloalkyl; wherein one or more optional substituents of said alkyl, said alkenyl and said alkynyl group is selected from selected from -OH, -0(0-5 alkyl), -0(0-5 alkylene)-OH, -0(0-5 alkylene)-O(Ci- ₅ alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH-O(CI- ₅ alkyl), -N(CI- ₅ alkyl)-O(Ci- ₅ alkyl), halogen, -O-(Ci- ₅ haloalkyl), -CF ₃ , -CN, -NO ₂ , -CHO, -C(O)-(Ci- ₅ alkyl), -C(O)OH, -C(O)-O-(Ci- ₅ alkyl), -O-C(O)-(Ci- ₅ alkyl), -C(O)-NH ₂ , -C(O)-NH(CI- ₅ alkyl), -C(O)-N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-C(O)-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-(Ci- ₅ alkyl), -NH-C(O)-O-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-O-(Ci- ₅ alkyl), -O-C(O)-NH-(CI- ₅ alkyl), -O-C(O)-N(CI- ₅ alkyl)-(Ci- ₅ alkyl), -SO ₂ -NH ₂ , -SO ₂ -NH(CI- ₅ alkyl), -SO ₂ -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-SO ₂ -(CI- ₅ alkyl), -N(CI- ₅ alkyl)-SO ₂ -(Ci- ₅ alkyl), -SO ₂ -(Ci- ₅ alkyl), -SO-(Ci- ₅ alkyl) and =0; and wherein one or more optional substituents of said cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is selected from C1-5 alkyl, C ₂ -s alkenyl, C ₂ -s alkynyl, -OH, -O(Ci-s alkyl), -O(Ci- ₅ alkylene)-OH, -O(Ci- ₅ alkylene)-O(Ci- ₅ alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH-O(CI- ₅ alkyl), -N(CI- ₅ alkyl)-O(Ci- ₅ alkyl), halogen, C1-5 haloalkyl, -O-(Ci-s haloalkyl), -CF3, -CN, -N0 ₂ , -CHO, -C(O)-(Ci-s alkyl), -C(O)OH, -C(O)-O-(Ci- ₅ alkyl), -O-C(O)-(Ci- ₅ alkyl), -C(O)-NH ₂ , -C(O)-NH(CI- ₅ alkyl), -C(O)-N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-C(O)-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-(Ci- ₅ alkyl), -NH-C(O)-O-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-O-(Ci- ₅ alkyl), -O-C(O)-NH-(CI- ₅ alkyl), -O-C(O)-N(CI- ₅ alkyl)-(Ci- ₅ alkyl), -SO ₂ -NH ₂ , -SO ₂ -NH(CI- ₅ alkyl), -SO ₂ -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-SO ₂ -(CI- ₅ alkyl), -N(CI- ₅ alkyl)-SO ₂ -(Ci- ₅ alkyl), -SO ₂ -(Ci- ₅ alkyl), -S0-(Ci-5 alkyl), cycloalkyl and heterocycloalkyl.

In a particular embodiment, the present invention relates to the compound of formula (II), wherein both R1 and R ₂ are hydrogen.

In a further particular embodiment, the present invention relates to the compound of formula (II), wherein R5 is optionally substituted (C0-3 alkylene)-aryl or optionally substituted (C0-3 alkylene)-heteroaryl, preferably wherein R5 is optionally substituted aryl or optionally substituted heteroaryl. In a further particular embodiment, the present invention relates to the compound of formula (II), wherein R5 is selected from 2-benzothiazolyl, benzyl, 4-methoxyphenyl, and phenyl, preferably wherein R5 is 4-methoxyphenyl.

In a further particular embodiment, the present invention relates to the compound of formula (II), wherein R3 or R4 is optionally substituted -C(O)-heteroaryl, preferably wherein R3 or R4 is selected from 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-methoxy-3-pyridyl, and 4-pyridyl, more preferably wherein R3 or R4 is 3-pyridyl.

In a further particular embodiment, the present invention relates to the compound of formula (II), wherein the compound according to formula (II) is a compound of formula:

In a second embodiment pharmaceutical composition comprising the compound of the present invention as defined hereinabove, and a pharmaceutically acceptable carrier.

In a third embodiment, the present invention relates to the compound of the present invention as defined hereinabove, or the pharmaceutical composition of the present invention, for use as a medicament.

In a fourth embodiment, the present invention relates to the compound of the present invention as defined hereinabove, or the pharmaceutical composition of the present invention for use in treating and/or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155.

In a particular embodiment, the present invention relates to the compound for use of the present invention or the pharmaceutical composition for use of the present invention, wherein the disease characterized by the increased expression level of miR- 155 is systemic lupus erythematosus.

In a particular embodiment, the present invention relates to the compound for use of the present invention or the pharmaceutical composition for use of the present invention, wherein the disease characterized by the increased expression level of miR- 155 is scleroderma.

Definitions

The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The word “about” means plus or minus 5% of the stated number.

It is to be understood that wherever numerical ranges are provided/disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of” and “consisting of”. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non- cyclic) hydrocarbon group which may be linear or branched. As understood herein, the term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n- propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to- carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 - en-1 -yl, prop-1 -en-2-yl, or prop-2 -en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1 -yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2-4 alkynyl. As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “Ci- 5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “Co-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2- ), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(- CH2-CH3)-, -CH ₂ -CH(-CH ₃ )-, or -CH(-CH ₃ )-CH ₂ -), or butylene (e.g., -CH2-CH2-CH2- CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

As used herein, the term “arylene” refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 ,3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5-diyl, naphthalen-1 ,6-diyl, naphthalen-1 , 7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2, 7-diyl, or naphthalen-2,8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless defined otherwise, an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen-1 ,4-diyl).

As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e. , to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2- benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, [3-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or

[4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or

1 .3.4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4- thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrim idinyl (e.g., pyrazolo[1 ,5-a]pyrimidin- 3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3- c]pyridinyl or 1 ,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2- a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or

1 .4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or decalinyl (i.e., decahydronaphthyl). Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatomcontaining ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholine-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1 - dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza- bicyclo[2.2.1 ]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

As used herein, the term “heterocyclic ring” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl or heterocycloalkyl.

The term “halogen” or “Hal” covers F, Cl, Br and I, preferably F or Cl.

As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ -CH ₃ , -CH ₂ -CF ₃ , -CH ₂ -CHF ₂ , -CH ₂ -CF ₂ -CH ₃ , -CH ₂ -CF ₂ -C F ₃ , or -CH(CF ₃ ) ₂ . A particularly preferred “haloalkyl” group is -CF ₃ . The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted. The optional substituents as defined herein, are preferably those as defined in the description. Further preferably, unless otherwise stated substitution refers to replacing one or more hydrogen atoms with a substituent. An example of a substituent that replaces more than one hydrogen atoms is an =0 moiety.

A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples. Brief description of Figures

Figure 1 : Compounds of the present invention show activity in modulating the level of miR-155 in (A) blood and (B) skin in a mouse model of scleroderma.

Figure 2: Diseases where miR155 is upregulated. Result of a database search in HMDD v3.2. (Search done at Aug, 10, 2021 )

Figure 3: Secondary structure of human pre-miR-155 (a) and its constructs used in NMR screening (b) and in hit validation (c).

Figure 4. Hit-finding example for pre-miR155 by NMR screening. The structure of the hit is shown in a). The compound is an example of the family of chemical structures referred to herein as formula III. b). Resonances of two orthogonal mixtures of fragments. The aromatic region is shown. Upon addition of RNA, a small change in the chemical shift position of three proton resonances is observed. The resonances of the fragment hit shown in a) are indicated in the two mixtures by lines and c, d and e, and these signals are shown enlarged in Figures c-e. These signals correspond to the individual protons of the compound shown in a) at a concentration of 50 pM. The black signals correspond to the same compound after adding 5 pM of a pre-miR-155 as described in the Materials section. The arrow indicates the direction of change in chemical shift upon addition of RNA.

Figure 5: Follow-up investigation of the compound that was identified as a hit in the 1 D NMR screening in Figure 4. a) 2D TOCSY (2-dimensional total correlation spectroscopy) spectrum of the RNA secondary structure shown in c). The contour signals correspond to the H5 and H6 protons of Uracil and Cytidine. The signals are assigned to the nucleotides numbered in c). The gray contours correspond to 30 pM RNA at a temperature of 308 K in the absence of the hit compound in b). The black contours correspond to the RNA after adding 300 pM compound. The three signals that shift in the 2D spectrum after the addition of the compound are assigned to the four residues at or near the bulge region of the RNA. b) Chemical structure of the compound under investigation. See also Figure 4. c) Secondary structure of the RNA sequence containing the bulge region of pre-miR155. The NMR signals, which correspond to the nucleotides indicated in red, are caused by binding of the ligand.

Figure 6: Hit-finding example for pre-miR155 by NMR screening, a) chemical structure of the hit. The compound is an example of the compound family II described in this patent, b) Two selected resonances of the compound are shown. The intense signals correspond to the compound shown in a) at a concentration of 50 pM. The lower and broadened signals correspond to the same compound after adding 5 pM of a pre-miR-155 as described in Example 3 section. When RNA is added, a small change in the position of the chemical shift as indicated by arrows as well as a change in the spectral line width of these proton resonances is observed.

Figure 7. Hit-finding example for pre-miR155 by NMR screening. Compound signals are shifted and I or show line broadening after adding RNA to the compound (compare a and b (without and with RNA). The region of the 1H spectrum in which resonances of aromatic protons are found is shown left and the region where aliphatic protons are found is shown right. The chemical structure of the hit is shown on top. The resonances of the four different fragments of the compound are indicated with dotted lines. The signals of all fragments of the compound are perturbed upon binding to pre-miR155 (line broadening and/or chemical shift perturbation).

Figure 8. In vivo study, wherein 2 compounds were evaluated regarding their antitumoral potency in an in vivo Hollow Fiber model in female NMRI nude mice using the human cell lines A549 (lung), HT29 (colon), and SW480 (colon). In the hollow fiber mouse model, three cell culture lines are injected into separate hollow fibers, which are implanted into the mouse at two locations (subcutaneously and intraperitoneally). The fibers have porous membranes allowing nutrients and testing compounds to flow into the fiber, and CO2 and waste to flow out of the fiber. Tumor cells inside the fiber form aggregates. After a standard study duration of two weeks, the fibers are extracted and live cells are quantified. Further analyses of the cells are also possible. CellTiter Gio assay performed for A549, HT29 and SW480 cells from the extracted hollow fibers for FBL- 1068 compound (also referred to as compound 1.3) and compound 2 (also referred to as compound 2.7) is shown.

Figure 9. Monitoring microRNA-155 in the blood.

Figure 10. Protein urea readout in the experimental groups of Example 6. Positive effect in protein urea observed for SPC-Sav-047 (A) and Cyclophosphamide (B). Vehicle varied in protein urea levels greatly from week to week.

Figure 11. Positive effect in anti-dsDNA levels have been observed for SPC-Sav- 047 (A) and Cyclophosphamide (B) in Example 6.

Figure 12. Organ weight at the termination in Example 6.

Figure 13. Cellular activity studies showing TNFa reduction upon treatment with the compounds of the invention.

Detailed description of the invention The compounds of the present invention will be described in the following embodiments. It is to be understood that all the combinations of features are envisaged to be encompassed by the invention.

In one embodiment, the present invention relates to a compound according to formula (I): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In formula (I), Ri’ is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, optionally substituted (C0-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, or optionally substituted (C0-3 alkylene)-heteroaryl.

Preferably, R-T is optionally substituted (C0-3 alkylene)-cycloalkyl, optionally substituted (C0-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, or optionally substituted (C0-3 alkylene)-heteroaryl.

More preferably, R-T is optionally substituted (C0-3 alkylene)-heterocycloalkyl. Preferably, (C0-3 alkylene)-heterocycloalkyl is (C0-3 alkylene)-N-morpholinyl, (C0-3 alkylene)-N-thiomorpholinyl, (C0-3 alkylene)-N-piperazyl, (C0-3 alkylene)-N-piperidyl, (C0-3 alkylene)— 4— piperidyl, (C0-3 alkylene)-4-tetrahydropyranyl, (C0-3 alkylene)-3- tetrahydropyranyl, or (C0-3 alkylene)-2-tetrahydropyranyl. Preferably, (C0-3 alkylene)- heterocycloalkyl is (C0-3 alkylene)-N-morpholinyl. Preferred C0-3 alkylene is ethylene. Therefore, preferred (C0-3 alkylene)-heterocycloalkyl is ethylene-N-morpholinyl. In formula (I), R2’ is optionally substituted aryl, or optionally substituted heteroaryl.

In formula (I), X is -0- or -NH- Preferably, X is -NH-.

Said alkyl, cycloalkyl, heterocycloalkyl, and alkylene can be optionally substituted with one or more optional substituents selected from -OH, -NH2, -CN and Hal.

Said aryl and heteroaryl group can be optionally substituted with one or more optional substituents selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, -NH-C1-4 alkyl, or — N(CI-4 alkyl)2.

In one specific embodiment, R-T is (C0-3 alkylene)-heterocycloalkyl wherein (C0-3 alkylene) is absent, that is R-T is heterocycloalkyl. Suitable examples of R-T being heterocycloalkyl are 4-tetrahydropyranyl, N-morpholinyl, and 4— piperidyl.

In a further specific embodiment, R-T is optionally substituted (C0-3 alkylene)-aryl, or optionally substituted (C0-3 alkylene)-heteroaryl. Preferably, R-T is optionally substituted -CH2-aryl or optionally substituted -CH2-heteroaryl. In a particularly preferred embodiment, R1’ is optionally substituted -CH2-C6H5.

In a further specific embodiment, R-T is optionally substituted (C0-3 alkylene)-aryl, preferably R-T is optionally substituted (C0-3 alkylene)-phenyl.

In a further specific embodiment, R-T is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl. Preferably, R-T is optionally substituted C1-6 alkyl. Preferably, R-T is optionally substituted ethyl, more preferably R-T is ethyl. Alternatively, R-T is methyl.

In a further specific embodiment, R2’ is optionally substituted heteroaryl; preferably 2- furyl, 2-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 3-pyridazyl. Suitable examples of optionally substituted heteroaryl groups include but are not limited to N-methyl-4- amino-2-pyrrolyl and 2-amino-4-thiazolyl.

In a further specific embodiment, R2’ is optionally substituted aryl, preferably selected from phenyl, 4-bromophenyl, 2-iodophenyl, 3-bromo-4-fluorophenyl, 3-fluorophenyl, 2- fluorophenyl, 3-methoxyphenyl, 4-aminophenyl, 3-chlorophenyl, 3-methylphenyl, 2- methylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, and 2- trifluoromethylphenyl. Preferably, R2’ is phenyl.

In a further embodiment, the present invention relates to a compound of formula (la): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In formula (la), X is -0- or -NH-. Preferably, X is -NH-.

In formula (la), R2’ is optionally substituted aryl, or optionally substituted heteroaryl.

In one specific embodiment, R2’ is optionally substituted heteroaryl; preferably 2-furyl, 2-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 3-pyridazyl. Suitable examples of optionally substituted heteroaryl groups include but are not limited to N-methyl-4-amino-2-pyrrolyl and 2-amino-4-thiazolyl. In a further embodiment, R2’ is optionally substituted aryl, preferably selected from phenyl, 4-bromophenyl, 2-iodophenyl, 3-bromo-4-fluorophenyl, 3-fluorophenyl, 2- fluorophenyl, 3-methoxyphenyl, 4-aminophenyl, 3-chlorophenyl, 3-methylphenyl, 2- methylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, and 2- trifluoromethylphenyl. Preferably, R2’ is phenyl.

Thus, in a preferred embodiment, the present invention relates to a compound of formula (lb): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In one embodiment, the present invention relates to a compound of formula (II): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof. In formula (II), Ri and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, optionally substituted (C0-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-C(O)- cycloalkyl, optionally substituted (C0-3 alkylene)-C(O)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-C(O)-aryl, optionally substituted (C0-3 alkylene)-C(O)- heteroaryl, optionally substituted (C0-3 alkylene)-C(O)NH-cycloalkyl, optionally substituted (C0-3 alkylene)-C(O)NH-heterocycloalkyl, optionally substituted (C0-3 alkylene)-C(O)NH-aryl, and optionally substituted (C0-3 alkylene)-C(O)NH-heteroaryl, or R1 and R2 are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2.

Preferably, R1 and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, optionally substituted (C0-3 alkylene)- heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (Co- 3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-C(O)-cycloalkyl, optionally substituted (C0-3 alkylene)-C(O)-heterocycloalkyl, optionally substituted (C0-3 alkylene)- C(O)-aryl, optionally substituted (C0-3 alkylene)-C(O)-heteroaryl, or R1 and R2 are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2.

More preferably, R1 and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, and optionally substituted (Co- 3 alkylene)-heterocycloalkyl, or R1 and R2are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2.

Even more preferably, R1 and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, and optionally substituted (Co- 3 alkylene)-heterocycloalkyl.

Preferably, in the compound of formula (II), at least one of Ri and R2 is hydrogen.

In formula (II), R3 and R4 are independently selected from hydrogen, optionally substituted -C(0)-(Co-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)- heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl. More preferably, R3 and R4 are independently selected from hydrogen, optionally substituted -C(O)-aryl, optionally substituted -C(O)-heteroaryl, optionally substituted -C(O)-cycloalkyl, optionally substituted -C(O)-heterocycloalkyl. Even more preferably, R3 and R4 are independently selected from hydrogen, optionally substituted -C(O)-aryl, and optionally substituted -C(O)-heteroaryl.

Preferably R3 or R4 is hydrogen. In other words, it is preferred that one of R3 and R4 is hydrogen.

Further preferably, one of R3 and R4 is selected from optionally substituted -C(0)-(Co- 3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, and optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl. More preferably, one of R3 and R4 is selected from optionally substituted -C(O)-aryl, optionally substituted -C(O)-heteroaryl, optionally substituted -C(O)-cycloalkyl, and optionally substituted -C(O)-heterocycloalkyl. Even more preferably, one of R3 and R4 is selected from optionally substituted -C(O)-aryl, and optionally substituted -C(O)-heteroaryl.

In formula (II), R5 is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl. Optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl are each optionally substituted with one or more substituents selected from -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH- O(Ci-5 alkyl), -N(CI-5 alkyl)-O(Ci-5 alkyl), halogen, -O-(Ci-5 haloalkyl), -CF ₃ , -CN, -NO ₂ , -CHO, -C(O)-(Ci- ₅ alkyl), -C(O)OH, -C(O)-O-(Ci- ₅ alkyl), -O-C(O)-(Ci- ₅ alkyl), -C(O)-NH ₂ , -C(O)-NH(CI- ₅ alkyl), -C(O)-N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-C(O)-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-(Ci- ₅ alkyl), -NH-C(O)-O-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-O-(Ci- ₅ alkyl), -O-C(O)-NH-(CI- ₅ alkyl), -O-C(O)-N(CI- ₅ alkyl)-(Ci- ₅ alkyl), -SO ₂ -NH ₂ , -SO ₂ -NH(CI- ₅ alkyl), -SO ₂ -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-SO ₂ -(CI- ₅ alkyl), -N(CI- ₅ alkyl)-SO ₂ -(Ci- ₅ alkyl), -SO ₂ -(Ci- ₅ alkyl), -SO-(Ci- ₅ alkyl) and =0, preferably selected from -OH, -O(Ci-s alkyl), -O(Ci-s alkylene)-OH, -O(Ci- ₅ alkylene)-O(Ci- ₅ alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH-O(CI- ₅ alkyl), -N(CI- ₅ alkyl)-O(Ci- ₅ alkyl), halogen, and =0.

Optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl are each optionally substituted with one or more substituents selected from C1-5 alkyl, C ₂ -5 alkenyl, C ₂ -5 alkynyl, -OH, -0(Ci-5 alkyl), -0(Ci-5 alkylene)-OH, -0(Ci-5 alkylene)-0(Ci-5 alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH- 0(Ci-5 alkyl), -N(Ci-s alkyl)-0(Ci-5 alkyl), halogen, C1-5 haloalkyl, -O-(Ci-s haloalkyl), -CF ₃ , -CN, -N0 ₂ , -CHO, -C(O)-(Ci- ₅ alkyl), -C(O)OH, -C(O)-O-(Ci- ₅ alkyl), -O-C(O)-(Ci- ₅ alkyl), -C(O)-NH ₂ , -C(O)-NH(CI- ₅ alkyl), -C(O)-N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-C(O)-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-(Ci- ₅ alkyl), -NH-C(O)-O-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-O-(Ci- ₅ alkyl), -O-C(O)-NH-(CI- ₅ alkyl), -O-C(O)-N(CI- ₅ alkyl)-(Ci- ₅ alkyl), -SO ₂ -NH ₂ , -SO ₂ -NH(CI- ₅ alkyl), -SO ₂ -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-SO ₂ -(CI- ₅ alkyl), -N(CI- ₅ alkyl)-SO ₂ -(Ci- ₅ alkyl), -SO ₂ -(Ci- ₅ alkyl), -SO-(Ci- ₅ alkyl), cycloalkyl and heterocycloalkyl, preferably selected from C1-5 alkyl, C ₂ -s alkenyl, C2-5 alkynyl, -OH, -0(0-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH- O(Ci-5 alkyl), -N(Ci-s alkyl)-O(Ci-5 alkyl), halogen, C1-5 haloalkyl, -O-(Ci-5 haloalkyl), -CF ₃ , -CN, -NO ₂ , -CHO, -C(O)-(Ci- ₅ alkyl), -C(O)OH, -C(O)-O-(Ci- ₅ alkyl), -O-C(O)-(Ci- ₅ alkyl), -C(O)-NH ₂ , -C(O)-NH(CI- ₅ alkyl), -C(O)-N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-C(O)-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-(Ci- ₅ alkyl), -NH-C(O)-O-(CI- ₅ alkyl), -N(CI- ₅ alkyl)-C(O)-O-(Ci- ₅ alkyl), -O-C(O)-NH-(CI- ₅ alkyl), -O-C(O)-N(CI- ₅ alkyl)-(Ci- ₅ alkyl), -SO2-NH2, -SO ₂ -NH(CI- ₅ alkyl), -SO ₂ -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-SO ₂ -(CI- ₅ alkyl), -N(CI- ₅ alkyl)-SO ₂ -(Ci- ₅ alkyl), -SO ₂ -(Ci- ₅ alkyl), and -SO-(Ci-5 alkyl), more preferably selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -O(Ci-5 alkyl), -O(Ci-5 alkylene)-OH, -O(Ci-5 alkylene)-O(Ci-5 alkyl), -SH, -S(Ci- ₅ alkyl), -S(Ci- ₅ alkylene)-SH, -S(Ci- ₅ alkylene)-S(Ci- ₅ alkyl), -NH ₂ , -NH(CI- ₅ alkyl), -N(CI- ₅ alkyl)(Ci- ₅ alkyl), -NH-OH, -N(CI- ₅ alkyl)-OH, -NH- O(Ci-5 alkyl), -N(Ci-s alkyl)-O(Ci-5 alkyl), and halogen.

It is to be understood that, unless indicated to the contrary, if a reference is made to an optionally substituted group including a cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety, said cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety is meant to be optionally substituted. Preferably the remainder of said optionally substituted group beyond said cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety is not optionally substituted. For example in optionally substituted -C(0)-(Co-3 alkylene)- heteroaryl, said heteroaryl moiety is meant to be optionally substituted, as indicated herein. Preferably, C0-3 alkylene is not optionally substituted.

Preferably, said alkyl, cycloalkyl, heterocycloalkyl, and alkylene can be optionally substituted with one or more optional substituents selected from -OH, -NH2, -CN, Hal, and =0, preferably with one or more optional substituents selected from -OH, -NH2, - CN, and Hal. Preferably, said aryl and heteroaryl group can be optionally substituted with one or more optional substituents selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, -NH-C1-4 alkyl, or — N(CI-4 alkyl)2.

In a first specific embodiment of the compound of formula (II), both Ri and R2 are hydrogen.

In a second specific embodiment of the compound of formula (II), R1 or R2 is selected from optionally substituted C1-6 alkyl. Preferably, the optionally substituted C1-6 alkyl is an optionally substituted C1-4 alkyl, which may be selected from methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, 2-methyl-propyl, and tert-butyl. Even more preferably, R1 or R2 is selected from methyl, isopropyl, and n-butyl.

In a third specific embodiment of the compound of formula (II), R1 or R2 is selected from optionally substituted (C0-3 alkylene)-cycloalkyl, and optionally substituted (C0-3 alkylene)-heterocycloalkyl. Preferably, R1 or R2 is optionally substituted (C0-3 alkylene)-cycloalkyl, preferably cycloalkyl, more preferably cyclopropyl or cyclohexyl. In an alternative preferred embodiment, R1 or R2 is optionally substituted (C0-3 alkylene)-heterocycloalkyl. Preferably, R1 or R2 is 4-tetrahydropiranyl.

In a fourth specific embodiment of the compound of formula (II), R1 and R2are replaced by an =0 or =S moiety, preferably by an =0 moiety, attached to the carbon atom that otherwise carries R1 and R2.

In a fifth specific embodiment of the compound of formula (II), R1 or R2 is selected from optionally substituted (C0-3 alkylene)-C(O)NH-cycloalkyl, and optionally substituted (Co- 3 alkylene)-C(O)NH-heterocycloalkyl. Preferably, R1 or R2 is selected from optionally substituted -CH2-C(O)NH-cycloalkyl, and optionally substituted -CH2-C(0)NH- heterocycloalkyl. More preferably, R1 or R2 is optionally substituted -CH2-C(0)NH- heterocycloalkyl. In a sixth specific embodiment of the compound of formula (II), Ri or R2 is selected from optionally substituted (C0-3 alkylene)-C(O)-cycloalkyl and optionally substituted (C0-3 alkylene)-C(O)-heterocycloalkyl.

In a seventh specific embodiment of the compound of formula (II), R1 or R2 is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. Preferably, R1 or R2 is selected from optionally substituted cycloalkyl and optionally substituted aryl. More preferably, R1 or R2 is selected from optionally substituted cycloalkyl. Particularly preferred cycloalkyl is cyclopropyl. Accordingly, preferred optionally substituted cycloalkyl is cyclopropyl.

In an eighth specific embodiment of the compound of formula (II), one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(O)-aryl. Preferably one of R3 and R4 is hydrogen and one of R3 and R4 is selected from phenyl, 2-methylphenyl,

4-chlorophenyl, 3-chlorophenyl, and 2-chlorophenyl.

In a ninth specific embodiment of the compound of formula (II), one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(O)-heteroaryl. Preferably, said heteroaryl is selected from 2-pyrroryl, 2-pyridyl, 3-pyridyl, 4-methoxy-3-pyridyl, 4- pyridyl, 5-oxazyl, 5-thiazyl, 1-N-methyl-5-imidazyl, 2-pyrazyl, 3-pyridazyl, 4-pyridazyl,

5-pyrimidyl, 2-methyl-5-pyridyl, 3-amino-5-pyridyl, 3-tetrahydrofuranyl, 3-piperidyl, 3- pyrrolidyl, and N-methyl-3-pyrrolidyl. More preferably, said heteroaryl is 3-pyridyl.

In a tenth specific embodiment of the compound of formula (II), one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(O)-heterocycloalkyl. Preferably, said heterocycloalkyl is selected from pyrrolidinyl and piperidinyl.

In an eleventh specific embodiment of the compound of formula (II), R5 is optionally substituted (C0-3 alkylene)-aryl, preferably a benzyl group. In a twelfth specific embodiment of the compound of formula (II), Rs is optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)- heterocycloalkyl, preferably optionally substituted (C0-3 alkylene)-heterocycloalkyl, more preferably heterocycloalkyl. Even more preferably, Rs is N-piperidyl or N- morpholinyl.

In a thirteenth specific embodiment of the compound of formula (II), Rs is optionally substituted (C0-3 alkylene)-aryl or optionally substituted (C0-3 alkylene)-heteroaryl, preferably optionally substituted aryl or optionally substituted heteroaryl. Preferably, Rs is selected from 2-benzothiazolyl, benzyl, 4-methoxyphenyl, and phenyl, more preferably Rs is 4-methoxyphenyl.

In a fourteenth specific embodiment of the compound of formula (II) Rs is selected from 4-fluorophenyl, 4-methoxyphenyl, phenyl and 3-pirydyl.

It is preferred that in any of the specific embodiments of the compound of formula (II), as listed hereinabove, at least one of R1 and R2 is hydrogen.

Thus, in a preferred embodiment, the present invention relates to a compound according to formula (Ila): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

R1 , R2, R3 and R4 are as defined for formula (II) or for any of the specific embodiments of the compound of formula (II). Preferably, R1 or R2 are hydrogen. More preferably, each R1 and R2 are hydrogen.

Thus, in a preferred embodiment the present invention relates to a compound of formula (lib): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

R3 and R4 are as defined for formula (II) or for any of the specific embodiments of the compound of formula (II).

Preferably one of R3 and R s hydrogen.

Further preferably, one of R3 and R4 is optionally substituted -C(O)-heteroaryl. Preferably, said heteroaryl is selected from 2-pyrroryl, 2-pyridyl, 3-pyridyl, 4-methoxy-

3-pyridyl, 4-pyridyl, 5-oxazyl, 5-thiazyl, 1-N-methyl-5-imidazyl, 2-pyrazyl, 3-pyridazyl,

4-pyridazyl, 5-pyrimidyl, 2-methyl-5-pyridyl, 3-amino-5-pyridyl, 3-tetrahydrofuranyl, 3- piperidyl, 3-pyrrolidyl, and N-methyl-3-pyrrolidyl, more preferably said heteroaryl is selected from 2-pyrroryl, 2-pyridyl, 3-pyridyl, 4-methoxy-3-pyridyl, and 4-pyridyl, even more preferably said heteroaryl is 3-pyridyl.

Thus, in a particularly preferred embodiment, the present invention relates to a compound of formula (He):

and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In one particular embodiment relating to the compound of formula (II) and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, Rs is phenyl.

Thus, in one particular embodiment, the present invention relates to a compound of formula (lid):

Ri , R2, 3 and R4 are as defined for formula (II) or for any of the specific embodiments of the compound of formula (II).

Preferably, one of R1 and R2 is hydrogen.

Further preferably, one of R1 and R2 is optionally substituted C1-6 alkyl, preferably selected from methyl, ethyl, propyl, and isopropyl, more preferably isopropyl.

Thus, in one particular embodiment, the present invention relates to a compound of formula (He):

Rs and R4 are as defined for formula (II) or for any of the specific embodiments of the compound of formula (II).

Preferably one of R3 and R s hydrogen.

Further preferably, one of R3 and R4 is optionally substituted -C(O)-heteroaryl or optionally substituted -C(O)-heterocycloalkyl. Preferably, said heteroaryl is selected from 2-pyrroryl, 2-pyridyl, 3-pyridyl, 4-methoxy-3-pyridyl, 4-pyridyl, 5-oxazyl, 5-thiazyl, 1-N-methyl-5-imidazyl, 2-pyrazyl, 3-pyridazyl, 4-pyridazyl, 5-pyrimidyl, 2-methyl-5- pyridyl, 3-amino-5-pyridyl, 3-tetrahydrofuranyl, 3-piperidyl, 3-pyrrolidyl, and N-methyl- 3-pyrrolidyl, more preferably said heteroaryl is selected from 2-pyrroryl, 2-pyridyl, 3- pyridyl, 4-methoxy-3-pyridyl, and 4-pyridyl. Preferably, said heterocycloalkyl is selected from tetrahydrofuranyl, tetrahydropyrrolidyl and N-methyl- tetrahydropyrrolidyl.

In one specific embodiment, one of R3 and R4 is hydrogen and one of R3 and R4 is selected from 4-pyridyl, tetrahydrofuranyl, and N-methyl-tetrahydropyrrolidyl.

In one particular embodiment relating to the compound of formula (II) and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, R1 and R2 are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2. Preferably, R1 and R2 are replaced by an =0 moiety attached to the carbon atom that otherwise carries R1 and R2. Thus, in one particular embodiment, the present invention relates to a compound of formula (lid): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In formula (Ilf), R3 and R4 are independently selected from hydrogen, optionally substituted -C(0)-(Co-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)- heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl; optionally substituted (C0-3 alkylene)-cycloalkyl and optionally substituted (C0-3 alkylene)-heterocycloalkyl.

Preferably, one of R3 and R4 is hydrogen.

Further preferably, one of R3 and R4 is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl; optionally substituted (C0-3 alkylene)- cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl.

In formula (Ilf), R5 is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl.

Each of one or more optional substituents of said alkyl, cycloalkyl, heterocycloalkyl or alkylene group is selected from -OH, -NH2, -CN, Hal, and =0, preferably with one or more optional substituents selected from -OH, -NH2, -CN, and Hal , each of one or more optional substituents of said aryl or heteroaryl group is selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, -NH-C1-4 alkyl, or — N(CI- ₄ alkyl) ₂ .

In a first specific embodiment of the compound of formula (Ilf), one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted (C0-3 alkylene)-aryl, preferably one of R3 and R4 is hydrogen and one of R3 and R4 is benzyl.

In a second specific embodiment of the compound of formula (Ilf), one of R3 and R4 is hydrogen and one of R3 and R4 is an optionally substituted aryl or heteroaryl. Preferably, one of R3 and R4 is hydrogen and one of R3 and R4 is 3,4-dimethoxybenzyl, phenyl, 3-methylphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4- methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3- trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl, 2-aminophenyl, 3-aminophenyl, or 4-aminophenyl.

In a third specific embodiment of the compound of formula (Ilf), R5 is optionally substituted (C0-3 alkylene)-aryl, preferably a benzyl group.

In a fourth specific embodiment of the compound of formula (Ilf), R5 is optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)- heterocycloalkyl, preferably optionally substituted (C0-3 alkylene)-heterocycloalkyl, more preferably heterocycloalkyl. Even more preferably, R5 is N-piperidyl or N- morpholinyl.

In a fifth specific embodiment of the compound of formula (Ilf), R5 is optionally substituted (C0-3 alkylene)-aryl or optionally substituted (C0-3 alkylene)-heteroaryl, preferably optionally substituted aryl or optionally substituted heteroaryl. Preferably, R5 is selected from 2-benzothiazolyl, benzyl, 4-methoxyphenyl, and phenyl, more preferably R5 is 4-methoxyphenyl. As it is to be understood herein, wheren a statement is made that the present invention relates to a compound of formula (II) (or formula (Ila), (lib), (He), (lid), (He) or (Ilf), or any other formula referred to herein) and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, preferably the invention relates to a compound of said formula and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof, more preferably to a compound of said formula or its pharmaceutically acceptable salt.

Particularly preferred compound of formula (II) is selected from the following compounds or their pharmaceutically acceptable salts:

SPC-Sav-053

SPC-Sav-059

SPC-Sav-057

SPC-Sav-056

Particularly preferred is a compound according to formula: or its pharmaceutically acceptable salt.

The present invention further relates to a compound of formula (III): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

In formula (III), R3 and R4 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted -C(0)-(Co-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, and optionally substituted -C(0)-(Co-3 alkylene)- heterocycloalkyl, preferably R3 and R4 are independently selected from hydrogen, optionally substituted -C(0)-(Co-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, and optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl, more preferably R3 and R4 are independently selected from hydrogen, optionally substituted -C(O)-aryl, optionally substituted -C(O)-heteroaryl, optionally substituted -C(O)-cycloalkyl, and optionally substituted -C(O)-heterocycloalkyl.

Preferably, one of R3 and R4 is hydrogen.

Further preferably, one of R3 and R4 is optionally substituted -C(0)-(Co-3 alkylene)- aryl, optionally substituted -C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted - C(0)-(Co-3 alkylene)-cycloalkyl, or optionally substituted -C(0)-(Co-3 alkylene)- heterocycloalkyl, more preferably one of R3 and R4 is selected from optionally substituted -C(O)-aryl, optionally substituted -C(O)-heteroaryl, optionally substituted -C(O)-cycloalkyl, and optionally substituted -C(O)-heterocycloalkyl.

In formula (III), R5 is as defined for formula (II).

Each of one or more optional substituents of said alkyl, cycloalkyl, heterocycloalkyl or alkylene group are selected from -OH, -NH2, -CN, Hal, and =0, preferably with one or more optional substituents selected from -OH, -NH2, -CN, and Hal. Each of one or more optional substituents of said aryl or heteroaryl group are selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, -NH-C1-4 alkyl, or -N(CI- ₄ alkyl) ₂ .

In one specific embodiment of the present invention, one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(O)-aryl. Preferably, one of R3 and R4 is hydrogen and one of R3 and R4 is selected from -C(O)-phenyl, -C(0)-4-m ethylphenyl, -C(O)-3-methylphenyl, -C(O)-2-methylphenyl, -C(O)-4-trifluoromethylphenyl, - C(O)-3-trifluoromethylphenyl, -C(O)-2 -trifluoromethylphenyl, -C(O)-4- methoxyphenyl, -C(O)-3-methoxyphenyl, -C(O)-2-methoxyphenyl, -C(O)-4- aminophenyl, -C(O)-3-aminophenyl, -C(O)-2-aminophenyl, -C(O)-3-chlorophenyl, - C(O)-3-aminophenyl, and -C(O)-2-aminophenyl.

In a further specific embodiment of the compound of formula (III) of the present invention, one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl, preferably one of R3 and R4 is hydrogen and one of R3 and R4 is -C(O)-(ethylene)-/V-morpholinyl or -C(O)-(methylene)-/V- morpholinyl.

In a further specific embodiment of the compound of formula (III) of the present invention, one of R3 and R4 is hydrogen and one of R3 and R4 is optionally substituted -C(O)-heterocycloalkyl, preferably N-morpholinyl or N-piperidyl.

Compounds of the present invention may contain one or more asymmetrically- substituted carbon, sulfur, or phosphorus or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation. Chemical formulas used to represent compounds of the present invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

Many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present invention.

Atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

Compounds of the present invention may function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

Compounds of the present invention may be provided in form of a salt. Pharmaceutically acceptable salts are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18 ^th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

Compounds of the present invention have been shown to modulate the expression level of miR-155 in the cells. As demonstrated in Example 1 , both the compound according to formula (I), specifically compounds according to formula (lb), and the compound according to formula (II), namely the compound according to formula (He), were capable of reducing the blood miR-155 level in a scleroderma mouse model upon treatment (see Examples). Therefore, without wishing to be bound to the theory, it is noted that effectiveness of the compounds as claimed herein is, at least in part, due to their ability to regulate miR-155 expression. It is further noted that the compounds as disclosed herein are useful in treating a disease characterized by the increased expression level of miR-155.

Pharmaceutical compositions

The compounds of the present invention can be administered to a patient in the form of a pharmaceutical composition which can optionally comprise one or more pharmaceutically acceptable excipient(s) and/or carrier(s).

Pharmaceutical compositions comprise a prophylactically or therapeutically effective amount, optionally disposed in a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a particular carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

The pharmaceutical composition of the present invention can take the form of solution, suspension, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Generally, the ingredients of compositions of the invention are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. When the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. When the composition is to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

Formulations for oral use include tablets containing the active ingredient(s) (e.g., the compounds of formula (I), (II) or (III) or pharmaceutically acceptable salt(s) thereof, as described herein) in a mixture with non-toxic pharmaceutically acceptable excipients. Such formulations are known to the skilled artisan. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

Tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active drug in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material, such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.

One or more compound of the present invention can be formulated in combination with a solid or a liquid dermatologically acceptable carrier. Useful solid carriers include finely divided solids such as talc, clay, micro crystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohols, or glycols (orwater-alcohol/glycol blends), in which the present compounds can be dissolved or dispersed at effective levels.

The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical agents are described in “Remington’s Pharmaceutical Sciences”, Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

Pharmaceutical composition as defined herein will contain a prophylactically or therapeutically effective amount of the compound of the present invention, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.

It is to be understood that depending on the severity of the disease and the particular type which is treatable with one of the compounds of the invention, as well as on the respective patient to be treated, e.g., the general health status of the patient, etc., different doses of the respective compound can be required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. It is contemplated that the dosage of a compound of the invention in the therapeutic or prophylactic use of the invention should be in the range of about 0.1 mg to about 1 g of the active ingredient (i.e. compound of the invention) per kg body weight. However, in a preferred use of the present invention a compound of the invention can be administered to a subject in need thereof in an amount ranging from 1.0 to 500 mg/kg body weight, preferably ranging from 1 to 200 mg/kg body weight. The duration of therapy with a compound of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient. In one preferred embodiment of a prophylactic or therapeutic use, between 100 mg to 200 mg of the compound is orally administered to an adult per day, depending on the severity of the disease.

The formulation should suit the mode of administration, which can be oral, intravenous, intraarterial, intrabuccal, intranasal, nebulized, bronchial inhalation, intra-rectal, vaginal, topical or delivered by mechanical ventilation.

In some embodiments, administering comprises intravenous, intra-arterial, oral, intranasal, lung instillation, bronchial inhalation, topical or infusion. In some aspects, administering comprises twice daily administration, once daily administration, every other day administration, every three-day administration or weekly administration. In some embodiments, administering continues for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months.

The pharmaceutical composition of the present invention comprising the compound of the present invention can, upon administration to a subject, modulate the expression level of miR-155 in the cells. As demonstrated in Example 1 , both the compound according to formula (I), specifically compounds according to formula (lb), and the compound according to formula (II), namely the compound according to formula (He), were capable of reducing the blood miR-155 level in a scleroderma mouse model upon treatment (see Examples). Therefore, without wishing to be bound to the theory, it is noted that effectiveness of the pharmaceutical composition of the present invention comprising the compound as claimed herein is, at least in part, due to the ability of the said compounds to regulate miR-155 expression.

As understood herein, the expression of miR-155 may also refer to the local concentration of miR-155. Thus, the disease characterized by the increased expression level of miR-155 may also refer to a disease characterized by the increased local concentration of miR-155. Furthermore, it is to be understood that the ability of the compounds of the invention to regulate miR-155 expression may also refer to their ability to regulate miR-155 local concentration.

The pharmaceutical composition of the present invention is useful for treating and or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155.

Thus, in another embodiment the present invention relates to the compound of formula (I), the compound of formula (II), or the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use as a medicament. The said compound is as defined hereinabove.

In a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155. In one embodiment of the present invention, the disease characterized by the increased expression level of miR-155 is systemic lupus erythematosus. Therefore, the present invention relates to the compound of formula (I), the compound of formula

(II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of systemic lupus erythematosus.

Symptoms of systemic lupus erythematosus include pain in the joints, swelling in the joints, fever, chest pain, hair loss, mouth ulcers, swelling of the lymph nodes, fatigue, and occurrence of a red rash, in particular on the face.

In a further embodiment, the present invention relates to treating and/or preventing and/or alleviating the symptoms of complications of systemic lupus erythematosus in a subject suffering from systemic lupus erythematosus.

More than 90 percent of those affected will experience joint or muscle pain at some time during the course of their systemic lupus erythematosus illness. Complications related thereto may also be referred to as lupus arthritis. Unlike rheumatoid arthritis, lupus arthritis is less disabling and usually does not cause severe destruction of the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula

(III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of lupus arthritis. The compounds are as described hereinabove. Anemia has been described as a common complication in subjects suffering from systemic lupus erythematosus, in particular in children suffering from systemic lupus erythematosus, with about 50% of children suffering from systemic lupus erythematosus developing anemia. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound according to formula (I) or the compound according to formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of systemic lupus erythematosus-associated anemia.

Systemic lupus erythematosus has been associated with cardiological complications. Cardiological complications of systemic lupus erythematosus include pericarditis (inflammation of the outer lining surrounding the heart), myocarditis (inflammation of the heart muscle) and endocarditis (inflammation of the inner lining of the heart. It is noted that lupus-associated endocarditis is non-infectious and is also referred to as Libman-Sacks endocarditis. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of cardiological complications of systemic lupus erythematosus, in particular lupus- associated pericarditis, lupus-associated myocarditis or lupus-associated endocarditis, also referred to as Libman-Sacks endocarditis.

Systemic lupus erythematosus has been associated with complications affecting lungs. Systemic lupus erythematosus may cause pleuritic pain as well as inflammation of the pleurae, also referred to as pleurisy. Systemic lupus erythematosus may also cause pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, and pulmonary hemorrhage. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound according to formula (I) or the compound according to formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of pleuritic pain and/or pleurisy. In a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, or pulmonary hemorrhage.

Systemic lupus erythematosus has been associated with complications affecting kidneys, in particular with lupus nephritis, which may lead to acute or end-stage kidney failure in rare cases. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of lupus nephritis.

Systemic lupus erythematosus is known to affect central and/or peripheral nervous system and has been associated with neuropsychiatric complications. The most common neuropsychiatric complication of systemic lupus erythematosus is headache. The neuropsychiatric complications of systemic lupus erythematosus further may include cognitive dysfunction, mood disorder, cerebrovascular disease, seizures, polyneuropathy, anxiety disorder, psychosis, depression, and/or personality disorders. In certain rare cases, the neuropsychiatric complications of systemic lupus erythematosus further may include acute confusional state, Guillain- Barre syndrome, aseptic meningitis, autonomic disorder, demyelinating syndrome, mononeuropathy, movement disorder, in particular chorea, myasthenia gravis, myelopyathy, cranial neuropathy and/or plexopathy. Therefore, in a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of cognitive dysfunction, mood disorder, cerebrovascular disease, seizures, polyneuropathy, anxiety disorder, psychosis, depression, and/or personality disorders. In a further embodiment the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of acute confusional state, Guillain-Barre syndrome, aseptic meningitis, autonomic disorder, demyelinating syndrome, mononeuropathy, movement disorder, in particular chorea, myasthenia gravis, myelopyathy, cranial neuropathy and/or plexopathy.

In a further embodiment of the present invention, the complication of systemic lupus erythematosus is a complication affecting eye, preferably selected from dry eye syndrome, secondary Sjoegren’s syndrome, episcleritis, scleritis, retinopathy, ischemic optic neuropathy, retinal detachment and secondary angle-closure glaucoma. In a further embodiment, the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of dry eye syndrome, secondary Sjogren’s syndrome, episcleritis, scleritis, retinopathy, ischemic optic neuropathy, retinal detachment or secondary angle-closure glaucoma.

In a further embodiment of the present invention the systemic lupus erythematosus is selected from discoid lupus erythematosus, neonatal lupus, and subacute cutaneous lupus erythematosus.

In a further embodiment of the present invention, the disease characterized by the increased expression level of miR-155 is scleroderma. Therefore, in certain embodiments the present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), preferably to the compound of formula (I) or the compound of formula (II), or the pharmaceutical composition comprising the compound of formula (I), or the compound of formula (II), or the compound of formula (III), preferably the compound of formula (I) or the compound of formula (II), and a pharmaceutically acceptable carrier, for use in treating and/or preventing and/or alleviating the symptoms of scleroderma. As defined herein, scleroderma may refer to systemic scleroderma (or systemic sclerosis), or to localized scleroderma.

In a further embodiment, the present invention relates to treating and/or preventing and/or alleviating the symptoms of complications of scleroderma in a subject suffering from scleroderma. These may include a kidney disease, which may also be referred to as scleroderma renal crisis, and which may manifest itself through hypertension and/or occurrence of kidney injury. The complications of scleroderma may further include a scleroderma-related lung disease, in particular pulmonary hypertension. It is to be understood that all potential complications of scleroderma, also those not explicitly recited herein, are meant to be encompassed by the present invention.

In a further embodiment of the present invention, the disease characterized by the increased expression level of miR1 -55 is an autoimmune disorder.

In a further embodiment of the present invention, the disease characterized by the increased expression level of miR-155 is type II diabetes.

In a further embodiment of the present invention, the disease characterized by the increased expression level of miR-155 is cancer. Preferably, the cancer is colon cancer.

Further disorders and diseases where miR155 is upregulated, according to a database search of HMDD v 3.2 (as performed on August 10, 2021 ) are shown in Figure 2.

Synthesis of the compounds of the present invention

The compounds of the present invention can be synthesized in accordance with or in analogy to the synthetic routes described in the examples section.

The invention is illustrated by the following examples which, however, should not be construed as limiting.

Preparative Example 1 :

Synthesis of the compound according to formula (lb) - compound 1.3

Compound 1.3, also referred to herein as compound according to the formula (lb) has been synthesized in two steps starting from compound 1.1 , with an overall yield of 22.3% as shown in the scheme above and as described in the following.

1.2 eq.

Ethyl 5-benzamido-1,3,4-thiadiazole-2-carboxylate (1.2). To a solution of ethyl 5- amino-1 ,3,4-thiadiazole-2-carboxylate (2.36 g, 1 eq., 13.6 mmol) (1.1), in dry DCM (118 mL), at 0°C, under nitrogen, was added TEA (3.80 mL, 2 eq., 27.3 mmol), followed by slow addition of benzoyl chloride (1.90 mL, 1.2 eq., 16.4 mmol). The reaction mixture was stirred at rt. For 16h. TLC (50% EtOAc/cyclohexane) and LC-MS showed full completion of the reaction. The reaction mixture was then diluted with DCM and H2O and the two layers were separated. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in DCM and EtOAc (minimal amounts) and sonicated for 5 min.. The suspension was filtered off and washed with small amounts of DCM to afford ethyl 5-benzamido-1 ,3,4-thiadiazole-2-carboxylate (3.34 g, 12.0 mmol, 88.4%) (1.2) as a white solid which was dried under high vacuum. ¹ H NMR (400 MHz, DMSO) 5 13.54 (s, 1 H), 8.18 - 8.11 (m, 2H), 7.74 - 7.65 (m, 1 H),

7.59 (t, J = 7.6 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

5-benzamido-N-benzyl-1,3,4-thiadiazole-2-carboxamide (1.3). To a solution of ethyl 5-benzamido-1 ,3,4-thiadiazole-2-carboxylate (3.34 g, 1 eq., 12.0 mmol) (1.2) dissolved in dry MeOH (50.2 mL) was added benzylamine (13.2 mL, 10 eq., 120 mmol). The solution was heated at 100°C and stirred for 16h. TLC (30% EtOAc/DCM) and LC-MS showed full completion of the reaction. The reaction mixture was then concentrated under reduced pressure and dried under high vacuum. The obtained mixture was then dissolved in water and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 2M aq. KHSO4 was then added to the residue and vigorously stirred at rt. For 30 min.. The suspension was filtered off and washed with small amounts of water. Finally, the crude product was purified using Biotage flash chromatography on silica gel (0% to 30% EtOAc/DCM) to afford 5-benzamido-N-benzyl-1 ,3,4-thiadiazole-2- carboxamide (1.03 g, 3.04 mmol, 25.3%) (1.3) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 13.36 (s, 1 H), 9.72 (t, J = 6.3 Hz, 1 H), 8.19 - 8.11 (m, 2H), 7.77 - 7.50 (m, 3H), 7.39 - 7.19 (m, 5H), 4.48 (d, J = 6.3 Hz, 2H).

Preparative Example 2:

Synthesis of the compound according to formula (He) - compound 2.7

Compound 2.7, also referred to herein as compound according to the formula (He) has been synthesized in six steps starting from compound 2.1 , with an overall yield of 8.9% as shown in the scheme above and as described in the following.

2.1 23% yield 2.2

Methyl 3-(4-methoxyphenyl)bicyclo[1.1.1]pentane-1 -carboxylate (2.2). In a sealed tube with a stir bar, colorless gas tricyclo[1.1.1.01 ,3]pentane (1.3 g, 50 mL, 0.406 molar, 1 eq., 20 mmol) (2.1) in Et2<D was added followed by (4- methoxyphenyl)magnesium bromide (8.6 g, 2 eq., 41 mmol) following the procedure as disclosed in Angew Chem Int Ed Engl. 2017 Oct 2;56(41 ): 12774-12777. The orange suspension was stirred at 100°C for 1.5h (use face shield due to pressure build-up). Methyl carbonochloridate (chloroformate) (6.3 mL, 4 eq., 81 mmol) was then added after cooling the mixture to 0°C and the resulting mixture was stirred at rt. For 16h. The reaction was quenched with saturated aq. Solution of NH4CI which was added dropwise (exothermic). Water was added and layers were separated. The aqueous layer was extracted with Et20 (3x). The combined organic layers was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 15% ether/n-hexane) to afford mixed fractions of the desired product and the side product. Then, the crude mixture was placed in a Kugelrohr distillation apparatus and heated to 140°C at 0.5 mbar for 30 min to remove the side product. Finally, the remaining crude mixture was heated at 160°C at 0.5 mbar for 30 min to distill out the desired product methyl 3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentane-1 - carboxylate (1.10 g, 4.74 mmol, 23%) (2.2) as a yellow transparent oil that solidified on standing. ¹ H NMR (400 MHz, CDCI3) 6 2.29 (s, 6H), 3.71 (s, 3H), 3.79 (s, 3H), 6.81 - 6.89 (m, 2H), 7.10 - 7.18 (m, 2H).

(3-(4-methoxyphenyl)bicyclo[1.1.1]pentan-1-yl)methanol (2.3). To a solution in a round-bottomed flask containing methyl 3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentane-1 - carboxy late (1.91 g, 1 eq., 8.22 mmol) (2.2) dissolved in dry THF (41 .1 mL) and cooled to 0 °C, was added UAIH4 in THF (6.17 mL, 2 molar, 1.5 eq., 12.3 mmol) dropwise. The reaction mixture was stirred at rt for 30 min. TLC (20% EtOAc/cyclohexane) showed full completion of the reaction. Fieser work-up was then performed. The resulting filtrate was evaporated to afford the desired product (3-(4- methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methanol (1 .397 g, 6.839 mmol, 83.2%) (2.3) as a yellow transparent oil. ¹ H NMR (400 MHz, CDCI3) 6 1.96 (s, 6H), 3.69 (s, 2H), 3.79 (s, 3H), 6.79 - 6.93 (m, 2H), 7.09 - 7.20 (m, 2H).

(3-(4-methoxyphenyl)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate (2.4).

To a solution in a round-bottomed flask containing (3-(4- methoxyphenyl)bicyclo[1 .1 ,1]pentan-1 -yl)methanol (210 mg, 1 eq., 1.03 mmol) (2.3) dissolved in dry DCM (5.14 mL) and cooled to 0 °C, was added TEA (430 pL, 3 eq., 3.08 mmol) and methanesulfonyl chloride (95.5 pL, 1.2 eq., 1.23 mmol) dropwise. The reaction mixture was stirred at rt for 1 h. TLC (25% EtOAc/cyclohexane) showed full completion of the reaction. Water was added and layers were separated. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (3-(4-methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methyl methanesulfonate (356 mg, 1.26 mmol, quant.) (2.4) as an off-white solid. ¹ H NMR (400 MHz, CDCI ₃ ) 6 2.05 (s, 6H), 3.03 (s, 3H), 3.79 (s, 3H), 4.29 (s, 2H), 6.80 - 6.89 (m, 2H), 7.09 - 7.17 (m, 2H).

1-(azidomethyl)-3-(4-methoxyphenyl)bicyclo[1.1.1]pentane (2.5). To a solution in a round-bottomed flask containing (3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentan-1 - yl)methyl methanesulfonate (356 mg, 1 eq., 1.26 mmol) (2.4) dissolved in dry DMF (2.52 mL), was added sodium azide (123 mg, 1.5 eq., 1.89 mmol) portionwise. The reaction mixture was stirred at rt. For 1 h. TLC (25% EtOAc/cyclohexane) showed full completion of the reaction. Water was added and layers were separated. The aqueous layer was extracted with Et20 (3x). The combined organic layers were washed again with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford (1-(azidomethyl)-3-(4-methoxyphenyl)bicyclo[1.1.1 ]pentane (227 mg, 990 pmol, 78.5%) (2.5) as an off-white solid. ¹ H NMR (400 MHz, CDCI ₃ ) 62.04 (s, 6H), 3.35 (s, 2H), 3.79 (s, 3H), 6.80 - 6.89 (m, 2H), 7.09 - 7.18 (m, 2H).

1) PPh ₃ , 3 eq.

76.7% yield

2.5 2.6

(3-(4-methoxyphenyl)bicyclo[1.1.1]pentan-1-yl)methanamine hydrochloride

(2.6). To a solution in a round-bottomed flask containing 1-(azidomethyl)-3-(4- methoxyphenyl)bicyclo[1 .1 ,1]pentane (227 mg, 1 eq., 990 pmol) (2.5) dissolved in THF (19.8 mL) and water (0.990 mL), was added triphenylphosphine (779 mg, 3 eq., 2.97 mmol). The reaction mixture was stirred at 60°C for 5h. TLC/TLC-MS (10% EtOAc/cyclohexane) showed full completion of the reaction. The reaction mixture was then concentrated. The remaining water was co-evaporated with toluene and the residue was further dried under high vacuum. Finally, HCI in dioxane (990 pL, 4.00 molar, 4 eq., 3.96 mmol) was added to the crude mixture dissolved in Et20 and stirred at rt. For 15 min.. The precipitate was filtered off and washed with Et20 to afford the desired product (3-(4-methoxyphenyl)bicyclo[1 .1 .1]pentan-1 -yl)methanamine hydrochloride (182 mg, 759 pmol, 76.7%) (2.6) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 1 .97 (s, 6H), 2.97 (q, J = 5.7 Hz, 2H), 3.72 (s, 3H), 6.82 - 6.90 (m, 2H), 7.07 - 7.15 (m, 2H), 8.07 (s, 3H).

N-((3-(4-methoxyphenyl)bicyclo[1.1.1]pentan-1-yl)methyl)n icotinamide (2.7). To a solution in a sealed tube containing (3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentan-1 - yl)methanamine hydrochloride (100 mg, 1 eq., 362 pmol) (2.6), nicotinic acid (53.5 mg, 1.2 eq., 434 pmol), EDC Hydrochloride (83.3 mg, 1.2 eq., 434 pmol), and HOBt (58.7 mg, 1 .2 eq., 434 pmol) in THF (1 .81 mL) and DMF (0.905 mL), was added DIPEA (189 pL, 3 eq., 1.09 mmol). The reaction mixture was stirred at rt. for 16h. LC-MS showed full completion of the reaction. The crude mixture was then concentrated to remove THF. Then, the crude residue was directly loaded on a C-18 column and chromatographed (5% to 95% MeOH/H2O (0.1 % HCOOH)) to afford the desired product N-((3-(4-methoxyphenyl)bicyclo[1.1 .1 ]pentan-1 -yl)methyl)nicotinamide (89 mg, 0.29 mmol, 80%) (2.7) as a beige solid after solvent evaporation under high vacuum. ¹ H NMR (400 MHz, DMSO) 5 1 .89 (s, 6H), 3.45 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 6.80 - 6.88 (m, 2H), 7.06 - 7.15 (m, 2H), 7.51 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 8.19 (ddd, J = 7.9, 2.3, 1 .7 Hz, 1 H), 8.67 - 8.76 (m, 2H), 9.01 (dd, J = 2.3, 0.9 Hz, 1 H).

Example 1 - compounds of the present invention reduce expression of miR-155 in mouse model of scleroderma

The results are summarized in Figure 1.

Example 2 - Cellular assays

The human monocyte THP-1 is a suspension cell line (ATCC, TIB-202) with a monocytic phenotype, including the ability to differentiate to macrophages. The cells are suitable for studying monocytes and macrophages, as a standardized surrogate cell line for peripheral blood mononuclear cells (PBMCs) (Aldo et al., ARJI, 2013). The cells can be differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) before exposing them to stimulations, in order to study polarization phenotype post treatments (Forrester et al., Cell Immunology, 2018, doi: 10.1016/j.cellimm.2018.07.008).

The cells are cultivated in cell culture flasks and then seeded on 96-well plates, 100.000 cells per well. On the plate, the cells are differentiated into macrophages using PMA (10 ng/ml). After two days differentiation, the non-differentiated, non-adhered cells are removed and new medium (RPMI with 10% FBS) is added to the wells. Test compounds are added and the cells are incubated with the compounds for 72 h. Next LPS (100 ng/ml) is added to the wells to stimulate the cells. The cells are incubated further for 24 h with LPS. Thereafter, the cytokine TNFa is measured from the supernatant using the Human TNF-alpha ELISA Max Standard Set (BioLegend). Viability of the cells is measured using FACS using CD206 as the marker for macrophag and CTLA-4 as the intracellular marker. RNA is isolated from the cells using miRNeasy Mini Kit (Qiagen). The RNA is reverse transcribed to generate cDNA using the microRNA-specific miRCURY LNA SYBR Green PCR kit (Qiagen). Levels of miR-155 are measured using qPCR and the Taqman assay microRNA - hsa-miR-155- 5p 000479 (Thermo Scientific).

Figure 13 shows relevant experiments in the cells.

Example 3 - NMR ligand binding studies.

The molecules described in this patent downregulate miR155 and can be used as therapeutics in diseases in which miR155 is upregulated. miR155 regulates the expression of key proteins in various biochemical signaling pathways, such as the NFKB signaling pathway, which is important in inflammation. Thus, a drug that downregulates this signaling miRNA will downregulate cytokine excretion and the (auto) inflammatory response. Since miR155 is upregulated in many diseases, it can be assumed that such a drug molecule can find broad application. The most obvious therapeutic options are autoimmune diseases and cancer, but there are many other diseases in which inflammation plays a role (Huang, Z.; Shi, J.; Gao, Y.; Cui, C.; Zhang, S.; Li, J.; Zhou, Y.; Cui, Q. HMDD v3.0: A database for experimentally supported human microRNA-disease associations. Nucleic Acids Res. 2019, 47, D1013-D1017). An overview is given in Figure 2.

The proposed mechanism of down-regulation of miR-155 is the inhibition of the maturation of pre-miR-155 by Dicer. Therefore, the strategy in small molecule screening has been aimed at finding small molecules that bind close to the Dicer cleavage site in the bulge region near the apical loop. The structure of human pre- miR155 is shown in Figure 3a. It should be noted that this potential binding site for small molecules is also present in pri-miRNA and it cannot be ruled out that small molecules in addition down-regulate the interaction of pri-miRNA during transport, maturation, loading into Ago2 or inhibit interaction with mRNA in the silencing complex.

Since the target binding site was chosen to be the bulge region near the apical loop, we decided to use a construct for screening that includes the bulge and apical loop (Figure 3b) and to validate binding to a construct that contains the bulge and a stable tetraloop (Figure 3c). The advantage of the latter construct are the well-structured areas around the bulge, which allow the resonance assignment of the fingerprint in the 2D TOCSY spectrum. This 2D spectrum is of high quality and could be assigned, while the spectrum of the construct with the natural apical loop contains many signals that are broadened due to conformational exchange.

Fragment library

All fragments were selected from SpiroChem's available drug library, available in January 2019, based on the following criteria: compounds were selected using a machine learning model that recognizes chemical features which may binds to microRNAs and having a good solubility. Stock solutions of 50 mM compound in 90% d6-DMSO; 10% D2O were prepared and stored at 4 °C. The library used for screening was checked for inconsistencies by running 1 D ¹ H spectra of each compound. Spectra were analyzed by hand and compounds with incorrect or additional signals were excluded. Orthogonal mixes were created from sets of 144 compounds. In these mixtures, the compound solutions were distributed in a matrix of 12 x 12 vials. Mixtures of 12 compounds each were made by pipetting 1 pl of each matrix row and by pipetting 1 pl of each matrix column. This results in 24 mixtures.

RNA preparation

All RNA preparations were made by chemical synthesis on an RNA synthesizer, followed by desalting. RNA samples were dissolved in 50 mM sodium phosphate buffer pH 6.0. Before the NMR measurements, each RNA sample was heated to 90 °C for 1 minute and cooled on ice.

Screening sample preparation

Each fragment mixture contained 12 fragments at a concentration of 4.17 mM in 90% -d6-DMSO with 10% D2O. The final sample volume was 170 pL with 10% D2O as the locking solvent and 3 mm NMR tubes were used. For each target, two samples (with and without target) were prepared per mixture. ¹ H NMR screening was performed at a 10: 1 ratio for fragments and RNA. The concentration of the fragments was 50 pM in 50 mM phosphate buffer pH 6.0 in H2O. The hits were validated under the same conditions as the single compound.

Several hits from the screening were selected for follow-up experiments. Samples of these fragments with the corresponding RNA were prepared in the same way, to confirm the binding of the individual fragment. For 2D-TOCSY experiments, the samples were prepared with a concentration of 300 pM compound and 30 pM RNA in 50 mM phosphate buffer pH 6.0 in D2O.

NMR spectroscopy

The spectra were recorded on a Broker AVIIIHD-600 NMR spectrometer, which was equipped with a 5 mm 1 H / 19F [13C, 15N] -TCI cryoprobe and a “sample case” sample changer for 24 samples. For the screening process, 1 H spectra with water suppression were recorded using excitation sculpting. 2D TOCSY experiments were recorded at 308 K with spin lock times of 50 ms. The 2D-TOCSY spectrum of the pre-miRNA construct (Figure 5c) was assigned by combining it with various 2D-NOESY spectra obtained with a mixing time of 300 ms for a H2O and for a D2O sample for a 200 pM RNA sample. These 2D spectra were recorded at a temperature of 278 K, 298 K and 308 K. The NOESY spectra were recorded using excitation sculpting as a method for water suppression.

The screening data were analyzed with Topspin 3.2 (Broker Biospin). Hits were identified by comparing mixtures of fragments with and without RNA. Fragments were assigned as hits if the chemical shift perturbation was greater than 1 Hz. In addition, line broadening effects on binding were found in the event of hits. The chemical structure of the hit was identified as follows: First, the spectra of the Tow” mixtures were examined for resonances that changed when RNA was added. The 12 spectra of “column” mixtures were then displayed above the “row” mixture spectrum and the disturbed signals could be located in one of the “column” mixture spectra. This can usually be identified for several resonances of the same fragment. In this case the hit is observed twice and the mixture number of the row and the column refers to the compound solution in the corresponding vial. Screening hits can therefore be assigned to the chemical structure without having to know the 1 D spectra.

Example experiments are shown in Figures 4 to 7.

Example 4 - MicroRNA-155 is overexpressed in cancer cell lines

In vivo study, wherein 2 compounds were evaluated regarding their antitumoral potency in an in vivo Hollow Fiber model in female NMRI nude mice using the human cell lines A549 (lung), HT29 (colon), and SW480 (colon). In the hollow fiber mouse model, three cell culture lines are injected into separate hollow fibers, which are implanted into the mouse at two locations (subcutaneously and intraperitoneally). The fibers have porous membranes allowing nutrients and testing compounds to flow into the fiber, and CO2 and waste to flow out of the fiber. Tumor cells inside the fiber form aggregates. After a standard study duration of two weeks, the fibers are extracted and live cells are quantified. Further analyses of the cells are also possible.

Figure 8 shows Cel ITiter Gio assay performed for A549, HT29 and SW480 cells from the extracted hollow fibers for FBL-1068 compound (also referred to as compound 1.3) and compound 2 (also referred to as compound 2.7).

Example 5 - Monitoring microRNA-155 in the blood

Figure 9 shows monitoring microRNA-155 in the blood.

Example 6 - Studies in the mouse model of SLE (mSLE)

The aim of this study was to evaluate the possible beneficial effect on miR-155 and disease parameters using compounds of the invention, in particular SPC-Sav-047 in the model for spontaneous SLE in mice. 50 female MRL/lpr mice subjected to daily compound treatment (5x per week). Study duration was set to 11 weeks (from week 8 to 19). Basic study setup was set as follows:

- 8 weeks of age at start

- Experiment running 8-12 weeks (based on disease development).

- Treated daily (50mg/kg), s.c, 5 days/week

- Weight twice per week

- Urine collection every week

- Blood is collected at week 8, 10, 12, 14 and 16 and at termination. anti-dsDNA analysis.

- Collection upon termination: blood serum (cytokines), blood RNA (mir155), spleen (FACS), kidney/liver tissue (staining). Spleen, thymus, mandibular glands and lymph nodes (mandible and axillary) are weighed.

Table 1 . Summary of the study

Gradual increase in weight has been observed in all three groups throughout the study.

Figure 10 shows protein urea readout in the experimental groups. Positive effect in protein urea observed for SPC-Sav-047 (A) and Cyclophosphamide (B). Vehicle varied in protein urea levels greatly from week to week.

Positive effect in anti-dsDNA levels have been observed for SPC-Sav-047 (A) and Cyclophosphamide (B), as shown in Figure 11.

Figure 12 summarizes the information on organ weight at the termination.

Further analyses include the FACS analysis, RNA isolation on blood taken at termination and qPCR , Luminex/ELISA on IFN-gamma, TNF-alpha in plasma and histology work to be performed on kidneys - C3 and IgG staining.

Further preparative examples methyl 3-(4-methoxyphenyl)bicvclo[ 1.1.1 lpentane-1 -carboxylate

To a solution of 3-(4-methoxyphenyl)bicyclo[1.1.1 ]pentane-1 -carboxylic acid (0.950 g, 1 Eq, 4.35 mmol), in MeOH (20.0 mL), was added H2SO4 (128 mg, 69.6 pL, 0.3 Eq, 1 .31 mmol). The mixture was stirred at 70 °C overnight. The mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in Et20 and washed with saturated NaHCOs solution (2x). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give methyl 3-(4- methoxyphenyl)bicyclo[1 .1 ,1]pentane-1 -carboxylate (1.00 g, 4.31 mmol, 98.9 %), as a white solid. TLC: Hexane/AcOEt 1 :1 ; Rf = 0.7; Stain: KMnO ₄ (UV visible)

¹ H NMR (400 MHz, Chloroform-d) 5 7.18 - 7.08 (m, 2H), 6.91 - 6.80 (m, 2H), 3.79 (s, 4H), 3.71 (s, 3H), 2.29 (s, 6H).

3-(4-methoxyphenyl)bicvclo[ 1.1.1 lpentane-1 -carbaldehyde

To a solution of methyl 3-(4-methoxyphenyl)bicyclo[1.1.1 ]pentane-1 -carboxylate (1.06 g, 1 Eq, 4.56 mmol), in dry DCM (50.0 mL), at -78 °C under inert atmosphere, was added dropwise a 1 M solution of DIBAL-H (974 mg, 6.85 mL, 1.0 molar, 1.5 Eq, 6.85 mmol) in DCM. The mixture was stirred at -78°C for 2h. The reaction was quenched by addition of methanol and water 1 :1 (6mL) at -78°C. The mixture was stirred at the same temperature for 10 min and then brought to rt. Mixture was diluted with 1 M HCI and the two layers separated. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure to give 3-(4-methoxyphenyl)bicyclo[1.1.1 ]pentane-1 -carbaldehyde (0.870 g, 4.30 mmol, 94.3 %), as a colorless oil.

TLC: Hexane/EtOAc 1 :1 ; Rf = 0.7; Stain: KMnCU

¹ H NMR (400 MHz, Chloroform-d) 5 9.68 (s, 1 H), 7.21 - 7.08 (m, 2H), 6.92 - 6.78 (m, 2H), 3.79 (s, 3H), 2.28 (s, 6H).

E)-N-((3-(4-methoxyphenyl)bicvclo[1.1 .1 ]pentan-1 -yl)methylene)-2-methylpropane-2- sulfinamide

To a solution of 3-(4-methoxyphenyl)bicyclo[1.1.1 ]pentane-1 -carbaldehyde (0.870 g, 99.0% Wt, 1.0 Eq, 4.26 mmol), in THF (35.5 mL), under inert atmosphere, was consecutively added 2-methylpropane-2-sulfinamide (559 mg, 97.0% Wt, 1.05 Eq, 4.47 mmol) and titanium(IV) isopropoxide (2.42 g, 2.58 mL, 2.0 Eq, 8.52 mmol). The mixture was stirred at room temperature overnight. Brine was added to the reaction mixture which was stirred for 30 minutes. The suspension was filtered through a pad of celite which was well washed with EtOAc. The two layers were separated and the aqueous layer further extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica (gradient: Hexane/EtOAc 95% for 2CV, then to Hexane/EtOAc 70% in 12CV, and at Hexane/EtOAc 70% for 3CV) to give (E)-N-((3-(4- methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methylene)-2-methylpropane-2-sulfinamide (0.59 g, 1 .9 mmol, 45 %), as a colorless oil that solidifies on standing.

TLC: Hexane/EtOAc 1 :1 ; Rf = 0.8; Stain: KMnO4 (UV visible)

¹ H NMR (400 MHz, CDCI ₃ ) 6 8.08 (s, 1 H), 7.20 - 7.12 (m, 2H), 6.89 - 6.82 (m, 2H), 3.80 (s, 3H), 2.27 (s, 6H), 1.21 (s, 9H).

N-(cvclopropyl(3-(4-methoxyphenyl)bicvclo[ 1.1.1 lpentan-1 -yl)methyl)-2- methylpropane-2-sulfinamide

To a suspension of (E)-N-((3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentan-1-yl)methylene)- 2-methylpropane-2-sulfinamide (920 mg, 1 eq., 3.01 mmol) dissolved in dry THF (30.1 mL) was slowly added a solution of cyclopropylmagnesium bromide (1.75 g, 13.6 mL, 0.886 molar, 4 eq., 12.0 mmol) in THF under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 16h. After cooling to rt, TLC was performed (20% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was cooled to 0°C and quenched with saturated NH4CI (543 pL, 10 eq., 30.1 mmol) and the resulting white suspension was stirred at rt for 15 min and concentrated. The mixture was then diluted in water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 90% EtOAc/cyclohexane) to afford N-(cyclopropyl(3-(4- methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2-methylpropane-2-sulfinamide (1.05 g, 3.02 mmol, >99%) as a colorless oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification.

TLC-MS APCI+ m/z = 348.5 [M+H] ⁺ .

N-(cyclopropyl(3-(4-methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2- methylpropane-2-sulfinamide (1.05 g, 1 Eq, 3.02 mmol) was dissolved in MeOH (20.1 mL) and then HCI 4 M in dioxane (3.78 mL, 4.0 molar, 5 Eq, 15.1 mmol) was added drop-wise to the flask which is sealed by a septum under nitrogen.. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude mixture is then triturated with diethyl ether and filtered to give cyclopropyl(3-(4-methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methanamine hydrochloride, HCI (666 mg, 2.11 mmol, 69.7 %) as a white solid.

¹ H NMR (400 MHz, CDCI ₃ ) 6 8.14 (s, 3H), 7.16 - 7.09 (m, 2H), 6.90 - 6.82 (m, 2H), 3.72 (s, 3H), 2.45 (m, J = 10.1 , 5.0 Hz, 1 H), 2.11 - 1.93 (m, 6H), 0.88 (dddd, J = 12.7, 9.9, 8.3, 4.7 Hz, 1 H), 0.66 - 0.40 (m, 3H), 0.35 - 0.24 (m, 1 H).

SPC-Sav-047

To a suspension of cyclopropyl(3-(4-methoxyphenyl)bicyclo[1 .1 ,1 ]pentan-1 - yl)methanamine hydrochloride, HCI (600.0 mg, 1 Eq, 1.90 mmol), EDC Hydrochloride (436.4 mg, 1 .2 Eq, 2.28 mmol), HOBt (307.6 mg, 1 .2 Eq, 2.28 mmol) and nicotinic acid (280.3 mg, 1.2 Eq, 2.28 mmol), in DMF (9.50 mL), at room temperature, was added DIPEA (991 pL, 3 Eq, 5.691 mmol). The mixture was stirred at room temperature overnight. The mixture turned into a transparent pale white color. The residue was purified by reverse phase (C-18, gradient = 5-95% MeOH/water, 0.1 % formic acid) to afford N-(cyclopropyl(3-(4-methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 - yl)methyl)nicotinamide (670.00 mg, 1.92 mmol, >99%, 100% purity by HPLC) as a white solid.

¹ H NMR (400 MHz, DMSO) 5 9.02 (dd, J = 2.3, 0.9 Hz, 1 H), 8.70 (dd, J = 4.8, 1 .6 Hz, 1 H), 8.52 (d, J = 8.7 Hz, 1 H), 8.20 (ddd, J = 7.9, 2.3, 1 .7 Hz, 1 H), 7.50 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.16 - 7.08 (m, 2H), 6.88 - 6.80 (m, 2H), 3.71 (s, 3H), 3.46 (t, J = 9.0 Hz, 1 H), 1 .98 - 1 .87 (m, 6H), 1 .01 (dtt, J = 9.5, 8.0, 4.9 Hz, 1 H), 0.60 - 0.55 (m, 1 H), 0.44 - 0.33 (m, 1 H), 0.30 - 0.16 (m, 2H).

General Procedure A for acylation:

To a suspension in a rond bottom flask containing the acid dissolved in DCM (0.2 M) was added oxalyl chloride and 2 drops of DMF under inert conditions. The reaction mixture is stirred at rt for 1 h. TLC is performed to check the formation of the acyl chloride. The crude mixture is then concentrated under reduced pressure and used as crude.

General Procedure B for amide coupling:

1.2 eq. THF, rt, 16h

To a suspension in a microwave vial containing the amine as an HCI salt, acyl chloride (1 .2 eq.) in THF (0.085 M) was added DIPEA (6 eq.). The reaction mixture was stirred at rt for 16h. TLC-MS was performed (80% EtOAc/Cy) to confirm the formation of the product. The crude mixture was then concentrated under reduced pressure. The crude product was purified using Biotage flash chromatography on silica gel (0% to 80% EtOAc/cyclohexane) to afford the pure product as a solid.

General Procedure C for amide coupling

DMF, rt, 16h

1.1 eq.

To a suspension in a microwave vial containing the carboxylic acid in DMF (0.15 M) was added DIPEA (5 eq.) and HBTU (1.2 eq.). The reaction mixture was stirred at rt for 30 min. The amine was added and the mixture was stirred at rt for 16h. . LC-MS was performed to confirm the formation of the product and the completion of the reaction. The crude reaction mixture was directly loaded on a C-18 column and chromatographed (5% to 95% MeOH/H2O (0.1 % HCOOH)) to afford the targeted amide as a solid after the evaporation of the solvent by freeze drying.

General Procedure D for Boc deprotection:

Dioxane, rt, th

To a suspension in a round-bottomed flask containing the amide dissolved in MeOH (0.10 M) was added 4M HCI in Dioxane (20 eq.) dropwise under inert conditions. The reaction mixture was stirred at rt for 1 h. TLC is performed to check the formation of the salt. The crude reaction mixture is then concentrated under reduced pressure and triturated with ether to remove impurities to afford the pure product as a solid or an oil.

Further synthetic procedures

BAS-SAV-38

1 g Quantitative yield

Compound BAS-SAV-38 was prepared following General Procedure A using nicotinic acid (1 g, 1 Eq, 8 mmol) to afford nicotinoyl chloride as a white solid.

Quantitative yield

Compound BAS-SAV-39 was prepared following General procedure B using nicotinoyl chloride hydrochloride (374 mg, 1.2 Eq, 2.10 mmol) and ethyl 3-amino-3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)propanoate hydrochloride, HCI (613 mg, 1 Eq, 1.75 mmol) to afford ethyl 3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3- (nicotinamido)propanoate (725.5 mg, 1.897 mmol, 108 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (dt, J = 2.2, 1.1 Hz, 1 H), 8.69 (dd, J = 4.9, 1 .6 Hz, 1 H), 8.23 (ddd, J = 8.0, 2.3, 1 .6 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.24 - 7.16 (m, 2H), 7.03 - 6.94 (m, 2H), 4.71 (ddd, J = 9.3, 5.7, 3.8 Hz, 1 H), 4.19 - 4.06 (m, 2H), 3.69 (s, 1 H), 2.76 - 2.55 (m, 2H), 1 .98 (s, J = 0.9 Hz, 6H), 1 .24 (td, J = 7.2, 2.6 Hz, 3H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.59 (tt, J = 9.1 , 5.4 Hz). 74 % yield

In a round-bottomed flask, ethyl 3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3- (nicotinamido)propanoate (669 mg, 1 Eq, 1.75 mmol) was dissolved in a mixture of THF (8.75 mL) and water (1.75 mL) in a 5:1 ratio. Lithium hydroxide monohydrate (220 mg, 3 Eq, 5.25 mmol) was added and the resulting mixture was stirred for 16h at room temperature. Upon confirmation of the completion of the reaction via LC-MS and TLC- MS, the THF was evaporated. Then, the aqueous phase was extracted with DCM (10 mL, 3 times) to remove any impurities. The mixture was then acidified with 2M aq. KHSO4 (0.20 mL) to pH <2 and extracted with DCM (10 mL, 3 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuo. The crude product was purified using Biotage flash chromatography on silica gel (0% to 80% EtOAc/cyclohexane) to afford the desired product 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (34.4 mg, 97.1 pmol, 74%) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (dd, J = 2.3, 0.9 Hz, 1 H), 8.68 (dd, J = 4.9, 1 .7 Hz, 1 H), 8.23 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.24 - 7.16 (m, 2H), 7.04 - 6.93 (m, 2H), 4.70 (ddd, J = 8.4, 5.9, 2.5 Hz, 1 H), 2.76 - 2.53 (m, 3H), 1 .99 (s, 6H).

62 % yield

Compound BAS-SAV-36 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and 4-Amino-1 -methylpiperidine (4.962 mg, 5.5 pL, 1.1 Eq, 43.46 pmol) to afford N-(1-(3-(4-fluorophenyl)bicyclo[1.1.1 ]pentan-1 -yl)-3-((1 - methylpiperidin-4-yl)amino)-3-oxopropyl)nicotinamide (11.1 mg, 24.6 pmol, 62.4 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (dd, J = 2.2, 0.9 Hz, 1 H), 8.69 (dd, J = 4.9, 1 .7 Hz, 1 H), 8.49 (s, 1 H), 8.23 (ddd, J = 8.0, 2.3, 1 .6 Hz, 1 H), 7.55 (ddd, J = 8.0, 5.0, 0.9 Hz, 1 H), 7.25 - 7.16 (m, 2H), 7.02 - 6.94 (m, 2H), 4.69 (dd, J = 8.8, 5.5 Hz, 2H), 3.80 (d, J = 11 .2 Hz, 2H), 3.21 (d, J = 12.1 Hz, 3H), 2.74 (s, 3H), 2.61 (m, J = 6.1 , 5.6 Hz, 4H), 2.44 (dd, J = 14.3, 8.8 Hz, 2H), 2.00 (s, 6H). LC-MS (ESI+), [M+H] ⁺ = 451 Da.

67 % yield

Compound BAS-SAV-45 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and N,N-dimethylpyrrolidin-3-amine (4.511 mg, 1 Eq, 39.51 pmol) to afford N-(3-(3-(dimethylamino)pyrrolidin-1 -yl)-1 -(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-oxopropyl)nicotinamide (12 mg, 27 pmol, 67 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.95 (dd, J = 2.3, 1 .2 Hz, 1 H), 8.68 (ddd, J = 5.0, 1 .6, 0.8 Hz, 1 H), 8.23 (dt, J = 8.1 , 2.0 Hz, 1 H), 7.58 - 7.52 (m, 1 H), 7.21 (ddt, J = 7.5, 5.1 , 1.4 Hz, 2H), 7.03 - 6.94 (m, 2H), 4.74 (m, J = 5.5, 3.1 Hz, 1 H), 3.97 - 3.56 (m, 3H), 3.37 (t, J = 9.0 Hz, 1 H), 3.25 - 3.18 (m, 1 H), 2.96 (dt, J = 16.4, 8.4 Hz, 1 H), 2.67 (dddd, J = 17.9, 15.5, 11.5, 6.7 Hz, 2H), 2.38 (d, J = 6.3 Hz, 6H), 2.24 (ddt, J = 38.4, 13.2, 6.2 Hz, 1 H), 2.05 - 1.89 (m, 7H). LC-MS (ESI+), [M+H] ⁺ = 451 Da.

Compound BAS-SAV-46 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and 4-(piperidin-4-yl)morpholine (6.726 mg, 1 Eq, 39.51 pmol) to afford N-(1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(4-morpholinopiperidin-1 - yl)-3-oxopropyl)nicotinamide (12 mg, 24 pmol, 60 %), as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (ddd, J = 4.2, 2.2, 0.9 Hz, 1 H), 8.69 (dt, J = 4.8, 1 .3 Hz, 1 H), 8.25 - 8.20 (m, 1 H), 7.58 - 7.52 (m, 1 H), 7.25 - 7.17 (m, 2H), 7.03 - 6.93 (m, 2H), 4.70 (td, J = 8.8, 8.3, 5.5 Hz, 1 H), 4.54 (t, J = 9.9 Hz, 1 H), 4.10 (d, J = 13.8 Hz, 1 H), 3.70 (dt, J = 6.5, 4.5 Hz, 4H), 3.25 - 3.06 (m, 1 H), 2.87 - 2.47 (m, 9H), 2.00 (d, J = 2.3 Hz, 8H), 1.61 (qd, J = 12.2, 4.1 Hz, 1 H), 1.51 - 1.40 (m, 1 H). LC-MS (ESI+), [M+H] ⁺ = 507 Da.

Compound BAS-SAV-48 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and N,N-dimethylpiperidin-4-amine (6.0 mg, 1.1 Eq, 47 pmol) to afford N-(3-(4-(dimethylamino)piperidin-1 -y l)-1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)- 3-oxopropyl)nicotinamide (11.5 mg, 24.8 pmol, 58 %), as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.98 - 8.93 (m, 1 H), 8.69 (dd, J = 4.9, 1 .6 Hz, 1 H), 8.52 (s, 1 H), 8.23 (dt, J = 8.0, 1 .8 Hz, 1 H), 7.55 (dd, J = 8.0, 4.9 Hz, 1 H), 7.22 (ddd, J = 8.7, 5.4, 1 .8 Hz, 2H), 6.99 (td, J = 8.8, 1 .3 Hz, 2H), 4.72 - 4.59 (m, 2H), 4.18 (d, J = 13.8 Hz, 1 H), 3.26 - 3.11 (m, 2H), 3.08 - 2.98 (m, 1 H), 2.85 (ddd, J = 26.0, 15.0, 5.1 Hz, 1 H), 2.76 - 2.56 (m, 8H), 2.11 (d, J = 12.3 Hz, 1 H), 2.01 (d, J = 1 .7 Hz, 6H), 1 .87 (qd, J = 12.1 , 4.3 Hz, 1 H), 1 .59 (tt, J = 12.3, 6.2 Hz, 1 H), 1 .50 - 1 .38 (m, 1 H). LC-MS (ESI+), [M+H] ⁺ = 465 Da.

Compound BAS-SAV-55 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and 1 -methylpiperazine (4.353 mg, 1.1 Eq, 43.46 pmol) to afford N- (1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(4-methylpiperazin-1 -y I )-3- oxopropyl)nicotinamide (7.3 mg, 17 pmol, 42 %), as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.95 (dd, J = 2.3, 0.9 Hz, 1 H), 8.69 (dd, J = 5.0, 1 .6 Hz, 1 H), 8.22 (ddd, J = 8.0, 2.3, 1 .6 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.25 - 7.16 (m, 2H), 7.03 - 6.96 (m, 2H), 4.70 (dd, J = 8.9, 5.2 Hz, 1 H), 3.63 (dt, J = 33.3, 6.8 Hz, 5H), 2.80 (dd, J = 15.3, 5.2 Hz, 1 H), 2.74 - 2.59 (m, 4H), 2.54 (t, J = 5.3 Hz, 2H), 2.41 (s, 3H), 2.01 (s, 6H). LC-MS (ESI+), [M+H] ⁺ = 437 Da.

Compound BAS-SAV-62 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and 1 -(2-methoxyethyl)piperazine (6.7 mg, 1.1 Eq, 47 pmol) to afford N-(1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(4-(2-methoxyethyl)piperazin-1 - yl)-3-oxopropyl)nicotinamide (6.5 mg, 14 pmol, 32 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 9.29 (s, 1 H), 9.06 - 8.92 (m, 2H), 8.16 (q, J = 7.0 Hz, 1 H), 7.25 - 7.16 (m, 2H), 7.04 - 6.95 (m, 2H), 4.73 (t, J = 6.6 Hz, 1 H), 4.59 (m, 1 H), 4.27 (s, 1 H), 3.78 (s, 2H), 3.72 - 3.50 (m, 4H), 3.48 - 3.40 (m, 5H), 3.10 (s, 2H), 2.83 (m, 2H), 2.04 (s, 6H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.77. Compound BAS-SAV-56 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (14.00 mg, 1 Eq, 39.51 pmol) and 1 ,4'-bipiperidine (6.648 mg, 1 Eq, 39.51 pmol) to afford N-(3-([1 ,4'- bipiperid in]-1 '-y l)-1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -y l)-3- oxopropyl)nicotinamide (8.3 mg, 16 pmol, 42 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (ddd, J = 5.3, 2.2, 0.9 Hz, 1 H), 8.69 (dd, J = 5.0, 1 .6 Hz, 1 H), 8.23 (ddd, J = 7.9, 3.5, 1 .8 Hz, 1 H), 7.55 (q, 1 H), 7.25 - 7.17 (m, 2H), 7.03 - 6.93 (q, 2H), 4.73 - 4.55 (m, 2H), 4.16 (d, J = 13.9 Hz, 1 H), 3.19 (t, J = 12.9 Hz, 1 H), 3.07 - 2.53 (m, 8H), 2.01 (s, 8H), 1.89 - 1.67 (m, 4H), 1.57 (m, 2H), 1.49 - 1.35 (m, 1 H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.83. y

1.2 eq

Compound BAS-SAV-68 was prepared following General procedure B using nicotinoyl chloride hydrochloride (92.7 mg, 1.2 Eq, 521 pmol) and 2-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)propan-2-amine hydrochloride (11 1 mg, 1 Eq, 434 pmol) to afford N-(2-(3-(4-fluorophenyl)bicyclo[1.1.1 ]pentan-1 -yl)propan-2- yl)nicotinamide (47 mg, 0.14 mmol, 33 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.88 (dd, J = 2.2, 0.9 Hz, 1 H), 8.65 (dd, J = 4.9, 1 .6 Hz, 1 H), 8.15 (ddd, J = 7.9, 2.3, 1.6 Hz, 1 H), 7.52 (ddd, J = 8.0, 5.0, 0.9 Hz, 1 H), 7.26 - 7.18 (m, 2H), 7.03 - 6.93 (m, 2H), 2.02 (s, 6H), 1.48 (s, 6H). ¹⁹ F NMR (376 MHz, MeOD) 5 -119.13.

Compound BAS-SAV-65 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (15 mg, 1 Eq, 42 pmol) and 2-(piperazin-1 -yl)ethan-1 -ol (6.1 mg, 1.1 Eq, 47 pmol) to afford N-(1-(3- (4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(4-(2-hydroxyethyl)piperazin-1 -y l)-3- oxopropyl)nicotinamide (14.9 mg, 31.9 pmol, 75 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (d, J = 2.2 Hz, 1 H), 8.68 (dd, J = 5.0, 1.6 Hz, 1 H), 8.23 (dt, J = 8.0, 1.9 Hz, 1 H), 7.55 (dd, J = 8.0, 4.9 Hz, 1 H), 7.26 - 7.15 (m, 2H), 7.03 - 6.95 (m, 2H), 4.71 (dd, J = 8.9, 5.2 Hz, 1 H), 3.79 - 3.51 (m, 6H), 2.87 - 2.63 (m, 8H), 2.01 (s, 6H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.56 (qt, J = 8.9, 4.4 Hz).

Compound BAS-SAV-52 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (15 mg, 1 Eq, 42 pmol) and tert-butyl 3-(l1 -azaneyl)pyrrolidine-1 -carboxylate (7.279 mg, 1 Eq, 39.51 pmol) followed by General procedure D using HCI in dioxane 4M (155 pL, 20 Eq) and tert-butyl 3-(3-(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-

(nicotinamido)propanamido)pyrrolidine-1 -carboxylate (16.2 mg, 1 Eq, 31.0 pmol) to afford N-(1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-oxo-3-(pyrrolidin-3- ylamino)propyl)nicotinamide (4.8 mg, 11 pmol, 37 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 9.19 (s, 1 H), 8.89 (s, 1 H), 8.74 (t, J = 7.7 Hz, 1 H), 8.00 - 7.90 (m, 1 H), 7.21 (ddt, J = 7.1 , 5.5, 1.7 Hz, 2H), 7.03 - 6.94 (m, 2H), 4.72 (m, 3.3 Hz, 1 H), 4.42 - 4.33 (m, 1 H), 3.48 (m, 2H), 3.23 (dd, J = 12.2, 4.4 Hz, 1 H), 2.66 (ddd, J = 14.3, 5.3, 2.1 Hz, 1 H), 2.58 - 2.43 (m, 1 H), 2.36 - 2.22 (m, 1 H), 2.02 (d, J = 2.0 Hz, 7H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.49 (dt, J = 14.6, 7.0 Hz).

Compound BAS-SAV-70 was prepared following General procedure C using 3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3-(nicotinamido)propanoic acid (15 mg, 1 Eq, 42 pmol) and tert-butyl 3-(l1 -azaneyl)pyrrolidine-1 -carboxylate (7.279 mg, 1 Eq, 39.51 pmol) followed by General procedure D using HCI in dioxane 4M (0.155 mL, 20 Eq) and tert-butyl 3-(3-(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-

(nicotinamido)propanamido)pyrrolidine-1 -carboxylate (16.2 mg, 1 Eq, 31.0 pmol) to afford N-(1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-oxo-3-(pyrrolidin-3- ylamino)propyl)nicotinamide (4.8 mg, 11 pmol, 37 %) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 9.30 (s, 1 H), 9.01 (t, J = 6.9 Hz, 2H), 8.19 (dd, J = 8.0, 5.7 Hz, 1 H), 7.22 (dd, J = 8.4, 5.4 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.73 (dd, J = 9.7, 4.2 Hz, 1 H), 3.88 (m, 3H), 3.75 (d, J = 15.1 Hz, 1 H), 3.39 (d, J = 6.0 Hz, 2H), 3.24 (d, J = 15.2 Hz, 2H), 2.96 - 2.74 (m, 2H), 2.04 (s, 6H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.76 (d, J = 2.4 Hz).

General Procedure A for sulfinamide deprotection:

To a suspension in a round-bottomed flask containing the sulfinamide dissolved in MeOH (0.15 M) was added 4M HCI (5 eq.) in Dioxane dropwise under inert conditions. The reaction mixture was stirred at rt for 1 h. TLC is performed to check the formation of the salt. The crude reaction mixture is then concentrated under reduced pressure and triturated with ether to remove impurities to afford the pure product as a solid.

General Procedure B for amide coupling:

To a suspension in a microwave vial containing the amine as an HCI salt, carboxylic acid (1 .2 eq.), EDC (1 .2 eq.), and HOBt (1 .2 eq.) in DMF (0.085 M) was added DIPEA (3 eq.). The reaction mixture was stirred at rt for 16h. LC-MS was performed to confirm the formation of the product. The crude reaction mixture was directly loaded on a C-18 column and chromatographed (5% to 95% MeOH/FhO (0.1 % HCOOH)) to afford the targeted amide as a solid after solvent evaporation under high vacuum.

General Procedure C for amide coupling:

To a suspension in a microwave vial containing the amine as an HCI salt, carboxylic acid (1 .2 eq.), EDC (1 .2 eq.), and HOBt (1 .2 eq.) in DMF (0.085 M) was added DIPEA (3 eq.). The reaction mixture was stirred at rt for 16h. The mixture was diluted with DCM and washed with saturated aq. NaHCOs, H2O, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using Biotage flash chromatography on silica gel (0% to 20%

EtOAc/cyclohexane) to afford the targeted amide as a solid after solvent evaporation under high vacuum. General Procedure D for Boc deprotection:

To a suspension in a round-bottomed flask containing the amide dissolved in MeOH (0.15 M) was added 4M HCI in Dioxane (5 eq.) dropwise under inert conditions. The reaction mixture was stirred at rt for 1 h. TLC is performed to check the formation of the salt. The crude reaction mixture is then concentrated under reduced pressure and triturated with ether to remove impurities to afford the pure product as a solid or an oil.

General Procedure E for HCI salt formation:

To a suspension in a round-bottomed flask containing the amide dissolved in MeOH (0.15 M) was added 4M HCI in Dioxane (5 eq.) dropwise under inert conditions. The reaction mixture was stirred at rt for 1 h. TLC is performed to check the formation of the salt The reaction mixture is then concentrated under reduced pressure to afford the product as a solid with some traces of MeOH. Lyophilization is finally performed to give the desired pure product as a powdered solid. . y e

Compound SPC-Sav-024_ELC-1-132 was prepared following General Procedure C using 1 -Methyl-3-bromopyrazole (18.38 mg, 1.2 eq., 145.7 pmol) (25.83 mg, 1.2 eq., 208.1 pmol) and 2-methyl-1 -(3-phenylbicyclo[1.1.1 ]pentan-1 -yl)propan-1 -amine hydrochloride (35.00 mg, 1 eq., 121.4 pmol) to afford 1 -methyl-N-(2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propyl)-1 H-imidazole-5-carboxamide (38.9 mg, 120 pmol, 99.1 %) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 7.81 (d, J = 9.6 Hz, 1 H), 7.72 (s, 1 H), 7.66 (d, J = 1 .0 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.19 (ddt, J = 7.0, 3.0, 1 .5 Hz, 3H), 3.87 (dd, J = 9.5, 7.5 Hz, 1 H), 3.79 (s, 2H), 2.01 - 1 .92 (m, 6H), 1 .85 (dt, J = 13.6, 6.8 Hz, 1 H), 0.98 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H).

Compound SPC-Sav-025_ELC-1-134 was prepared following General Procedure C using pyrazine-2 -carboxylic acid (18.08 mg, 1.2 eq., 145.7 pmol) and 2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (35.00 mg, 1 eq., 121.4 pmol) to afford N-(2-methyl-1-(3-phenylbicyclo[1 .1 ,1 ]pentan-1-yl)propyl)pyrazine-2- carboxamide (29.1 mg, 90.5 pmol, 74.6%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.20 (d, J = 1 .5 Hz, 1 H), 8.89 (d, J = 2.5 Hz, 1 H), 8.76 (dd, J = 2.5, 1 .5 Hz, 1 H), 8.28 (d, J = 10.0 Hz, 1 H), 7.32 - 7.23 (m, 2H), 7.22 - 7.16 (m, 3H), 3.98 (dd, J = 9.9, 6.6 Hz, 1 H), 2.06 - 1 .92 (m, 7H), 0.99 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H).

Compound SPC-Sav-026_ELC-1-135 was prepared following General Procedure C using pyridazine-3-carboxylic acid (18.08 mg, 1.2 eq., 145.7 pmol) and 2-methyl-1-(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (35.00 mg, 1 eq., 121.4 pmol) to afford N-(2-methyl-1-(3-phenylbicyclo[1 .1 ,1 ]pentan-1-yl)propyl)pyridazine-3- carboxamide (28.8 mg, 89.6 pmol, 73.8%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.43 (dd, J = 5.0, 1.7 Hz, 1 H), 8.65 (d, J = 10.0 Hz, 1 H), 8.22 (dd, J = 8.4, 1.7 Hz, 1 H), 7.93 (dd, J = 8.4, 5.0 Hz, 1 H), 7.28 (dd, J = 7.8, 6.8 Hz, 2H), 7.23 - 7.14 (m, 3H), 4.01 (dd, J = 9.9, 6.8 Hz, 1 H), 2.10 - 1 .94 (m, 7H), 1 .01 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H).

Compound SPC-Sav-027_KABH1-02 was prepared following General Procedure B using pyrimidine-5-carboxylic acid (25.83 mg, 1.2 eq., 208.1 pmol) and 2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (50.00 mg, 1.0 eq., 173.5 pmol) to afford N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)pyrimidine-5-carboxamide (55.6 mg, 173 pmol, 99.7%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.31 (s, 1 H), 9.16 (s, 2H), 8.43 (d, J = 9.5 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.24 - 7.15 (m, 3H), 3.98 (dd, J = 9.4, 7.1 Hz, 1 H), 2.05 - 1.93 (m, 6H), 1.95 - 1 .84 (m, 1 H), 1 .01 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).

Compound SPC-Sav-028_KABH1-03 was prepared following General Procedure B using 6-methylnicotinic acid (28.55 mg, 1.2 eq., 208.1 pmol) and 2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (50.00 mg, 1 eq., 173.5 pmol) to afford 6-methyl-N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)nicotinamide (46.7 mg, 140 pmol, 80.5%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.89 (dd, J = 2.3, 0.8 Hz, 1 H), 8.15 (d, J = 9.5 Hz, 1 H), 8.10 (dd, J = 8.0, 2.4 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.30 - 7.24 (m, 2H), 7.19 (ddq, J = 6.9, 3.4, 1.8, 1.4 Hz, 3H), 3.96 (dd, J = 9.4, 7.3 Hz, 1 H), 2.52 (s, 3H), 2.02 - 1 .93 (m, 6H), 1 .89 (p, J = 6.9 Hz, 1 H), 1 .00 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H). y e

Compound SPC-Sav-029_KABH1-04 was prepared following General Procedure B using tetrahydrofuran-3-carboxylic acid (24.17 mg, 19.91 pL, 1.2 eq., 208.1 pmol)and 2-methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)propan-1 -amine hydrochloride (50.00 mg, 1 eq., 173.5 pmol) to afford N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1- yl)propyl)tetrahydrofuran-3-carboxamide (53 mg, 0.17 mmol, 97%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 7.59 (d, J = 9.6 Hz, 1 H), 7.37 - 7.23 (m, 2H), 7.20 (dddd, J = 6.5, 5.7, 1 .5, 0.8 Hz, 3H), 3.87 (q, J = 8.0 Hz, 1 H), 3.80 - 3.55 (m, 4H), 3.05 (p, J = 7.7 Hz, 1 H), 2.08 - 1 .94 (m, 2H), 1 .93 - 1 .86 (m, 6H), 1.83 - 1 .70 (m, 1 H), 0.95 - 0.82 (m, 6H).

Compound KABH1-05 was prepared following General Procedure B using 1 -(tertbutoxycarbonyl)piperidine-3-carboxylic acid (47.72 mg, 1.2 eq., 208.1 pmol) and 2- methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)propan-1 -am ine hydrochloride (50.00 mg,

1 eq., 173.5 pmol) to afford tert-butyl 3-((2-methyl-1 -(3-phenylbicyclo[1 .1 ,1 ]pentan-1- yl)propyl)carbamoyl)piperidine-1 -carboxylate (73.9 mg, 173 pmol, 99.9%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 7.58 (dd, J = 9.5, 3.4 Hz, 1 H), 7.33 - 7.25 (m, 2H), 7.24 - 7.15 (m, 3H), 3.88 (d, J = 12.5 Hz, 2H), 3.73 (dd, J = 9.6, 6.1 Hz, 1 H), 2.75 (s, 1 H), 2.38 (ddt, J = 11 .2, 7.5, 3.7 Hz, 1 H), 1 .91 (h, J = 5.6, 4.9 Hz, 6H), 1.84 - 1 .71 (m, 2H), 1 .69 - 1 .47 (m, 2H), 1 .39 (d, J = 2.3 Hz, 9H), 1.35 - 1 .25 (m, 1 H), 0.88 (ddd, J = 14.3, 6.7, 4.6 Hz, 6H).

Compound SPC-Sav-030_KABH1-09 was prepared following General Procedure D using tert-butyl 3-((2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)carbamoyl)piperidine-1 -carboxylate (50 mg, 1 eq., 0.12 mmol) to afford N-(2- methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)propyl)piperidine-3-carboxamide hydrochloride (41 .1 mg, 113 pmol, 97%) as a yellow solid. ¹ H NMR (400 MHz, DMSO) 5 8.89 (d, J = 93.3 Hz, 2H), 7.86 (dd, J = 9.6, 2.2 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 2H), 7.19 (dd, J = 8.1 , 1 .4 Hz, 3H), 3.75 (ddd, J = 9.9, 5.9, 4.2 Hz, 1 H), 3.12 (d, J = 12.6 Hz, 2H), 2.97 (q, J = 10.6 Hz, 1 H), 2.89 - 2.74 (m, 2H), 1.91 (d, J = 3.2 Hz, 6H), 1.77 (dq, J = 13.3, 6.7 Hz, 3H), 1.65 - 1.51 (m, 1 H), 0.94 - 0.83 (m, 6H).

Compound SPC-Sav-031_KABH1-12 was prepared following General Procedure B using pyridazine-3-carboxylic acid (18.15 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford N-((3-phenylbicyclo[1 .1 .1]pentan-1 -yl)methyl)pyridazine-3- carboxamide (23.2 mg, 83.1 pmol, 68.2%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.31 (s, 1 H), 9.16 (s, 2H), 8.43 (d, J = 9.5 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.24 - 7.15 (m, 3H), 3.98 (dd, J = 9.4, 7.1 Hz, 1 H), 2.05 - 1.93 (m, 6H), 1.95 - 1.84 (m, 1 H), 1.01 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). ¹ H NMR (400 MHz, DMSO) 5 9.41 (dd, J = 5.0, 1 .7 Hz, 1 H), 9.32 (t, J = 6.3 Hz, 1 H), 8.22 (dd, J = 8.4, 1 .7 Hz, 1 H), 7.92 (dd, J = 8.5, 5.0 Hz, 1 H), 7.32 - 7.23 (m, 2H), 7.19 (dtd, J = 6.9, 3.7, 3.3, 1 .6 Hz, 3H), 3.54 (d, J = 6.3 Hz, 2H), 1.92 (s, 6H).

Compound SPC-Sav-032_KABH1-13 was prepared following General Procedure B using pyrazine-2-carboxylic acid (18.15 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford N-((3-phenylbicyclo[1.1 .1 ]pentan-1 -yl)methyl)pyrazine-2-carboxamide (27.5 mg, 98.4 pmol, 80.8%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.20 (d, J = 1 .5 Hz, 1 H), 8.96 (t, J = 6.2 Hz, 1 H), 8.88 (d, J = 2.5 Hz, 1 H), 8.75 (dd, J = 2.5, 1 .5 Hz, 1 H), 7.28 (ddd, J = 8.8, 6.5, 0.9 Hz, 2H), 7.22 - 7.14 (m, 3H), 3.50 (d, J = 6.3 Hz, 2H), 1.91 (s, 6H).

Compound SPC-Sav-033_KABH1-14 was prepared following General Procedure B using pyridazine-4-carboxylic acid (18.15 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford N-((3-phenylbicyclo[1 .1 .1]pentan-1 -yl)methyl)pyridazine-4- carboxamide (27.2 mg, 97.4 pmol, 79.9%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.55 (dd, J = 2.3, 1 .3 Hz, 1 H), 9.44 (dd, J = 5.3, 1 .3 Hz, 1 H), 9.07 (t, J = 5.8 Hz, 1 H), 8.01 (dd, J = 5.3, 2.3 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.20 (ddt, J = 7.0, 4.0, 1 .5 Hz, 3H), 3.49 (d, J = 6.0 Hz, 2H), 1 .94 (s, 6H). . y e

Compound SPC-Sav-034_KABH1-18 was prepared following General Procedure B using 6-methylnicotinic acid (20.05 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford 6-methyl-N-((3-phenylbicyclo[1.1.1 ]pentan-1 -yl)methyl)nicotinamide (31 .4 mg, 107 pmol, 88.1 %) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.90 (dd, J = 2.4, 0.9 Hz, 1 H), 8.65 (t, J = 6.0 Hz, 1 H), 8.09 (dd, J = 8.1 , 2.3 Hz, 1 H), 7.35 (dt, J = 8.1 , 0.7 Hz, 1 H), 7.32 - 7.24 (m, 2H), 7.19 (ddt, J = 7.0, 3.4, 1.4 Hz, 3H), 3.45 (d, J = 6.0 Hz, 2H), 2.52 (s, 3H), 1.92 (s, 6H).

Compound SPC-Sav-035_KABH1-19 was prepared following General Procedure B using pyrimidine-5-carboxylic acid (18.15 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford 6N-((3-phenylbicyclo[1 .1 .1 ]pentan-1-yl)methyl)pyrimidine-5- carboxamide (23.9 mg, 85.6 pmol, 70.2%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.32 (s, 1 H), 9.17 (s, 2H), 8.91 (t, J = 6.0 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.20 (ddt, J = 8.4, 3.5, 1.5 Hz, 3H), 3.49 (d, J = 5.9 Hz, 2H), 1.94 (s, 6H).

Compound SPC-Sav-036_KABH1-20 was prepared following General Procedure B using thiazole-5-carboxylic acid (18.88 mg, 1.2 eq., 146.2 pmol) and (3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)methanamine hydrochloride (30.00 mg, 1 eq., 121.9 pmol) to afford N-((3-phenylbicyclo[1 .1 .1]pentan-1 -yl)methyl)thiazole-5-carboxamide (29.1 mg, 102 pmol, 84%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.21 (s, 1 H), 8.78 (t, J = 6.1 Hz, 1 H), 8.50 (s, 1 H), 7.33 - 7.24 (m, 2H), 7.23 - 7.15 (m, 3H), 3.43 (d, J = 6.0 Hz, 2H), 1.92 (s, 6H).

Compound KABH1-10 was prepared following General Procedure B using 1 -(tert- butoxycarbonyl)pyrrolidine-3-carboxylic acid (44.80 mg, 1.2 eq., 208.1 pmol) and 2- methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)propan-1 -am ine hydrochloride (50.00 mg, 1 eq., 173.5 pmol) to afford tert-butyl 3-((2-methyl-1 -(3-phenylbicyclo[1 .1 ,1 ]pentan-1- yl)propyl)carbamoyl)pyrrolidine-1 -carboxylate (64.1 mg, 155 pmol, 89.6%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 7.66 - 7.59 (m, 1 H), 7.33 - 7.23 (m, 2H), 7.20 (tt, J = 6.8, 1 .3 Hz, 3H), 3.75 (dd, J = 9.6, 6.1 Hz, 1 H), 3.42 (t, J = 9.5 Hz, 1 H), 3.38 - 3.33 (m, 1 H), 3.28 (d, J = 9.4 Hz, 1 H), 3.18 (q, J = 9.3 Hz, 1 H), 3.10 - 2.94 (m, 1 H), 2.10 - 1.84 (m, 8H), 1.84 - 1.70 (m, 1 H), 1.41 - 1.35 (m, 9H), 0.88 (ddd, J = 13.8, 6.8, 1.9 Hz, 6H). 95% yield

Compound SPC-Sav-037_KABH1-24 was prepared following General Procedure D using tert-butyl 3-((2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)carbamoyl)pyrrolidine-1 -carboxylate (56.5 mg, 1 eq., 137 pmol) to afford N- (2-methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)propyl)pyrrolidine-3-carboxamide hydrochloride (45.4 mg, 130 pmol, 95.0%) as a colorless oil. ¹ H NMR (400 MHz, MeOD) 5 8.01 (d, J = 9.7 Hz, 1 H), 7.31 - 7.22 (m, 2H), 7.19 (ddt, J = 7.9, 1.8, 1.0 Hz, 3H), 3.85 (ddd, J = 9.7, 6.2, 2.5 Hz, 1 H), 3.55 - 3.33 (m, 5H), 2.38 (dp, J = 14.6, 7.4 Hz, 1 H), 2.14 (dq, J = 13.4, 6.3 Hz, 1 H), 2.05 - 1.95 (m, 6H), 1.88 (dtd, J = 13.4, 6.7, 4.6 Hz, 1 H), 1.03 - 0.93 (m, 6H). y e

Compound SPC-Sav-038_KABH1-08 was prepared following General Procedure B using 5-aminonicotinic acid (8.6 mg, 1.2 eq., 62 pmol) and 2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (15 mg, 1 eq., 52 pmol) to afford 5-amino-N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)nicotinamide (12.8 mg, 38.2 pmol, 73%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) 5 8.24 - 8.14 (m, 2H), 8.07 (d, J = 2.5 Hz, 1 H), 7.42 (dd, J = 2.6, 1 .9 Hz, 1 H), 7.30 - 7.22 (m, 2H), 7.22 - 7.12 (m, 3H), 4.06 - 3.97 (m, 1 H), 2.09 - 2.01 (m, 6H), 2.00 - 1 .91 (m, 1 H), 1 .08 (d, J = 6.7 Hz, 3H), 1 .00 (d, J = 6.8 Hz, 3H).

NaBH(OAc) ₃ , 1.5 eq.

Compound SPC-Sav-039_KABH1-31 was prepared using the following procedure. To a suspension of N-(2-methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -y l)propy l)pyrrol id ine-3- carboxamide hydrochloride (16 mg, 1 eq., 46 pmol) dissolved in DCM/MeOH (2:1 ) was added acetic acid (3.9 pL, 1.5 eq., 69 pmol) and formaldehyde (7.4 mg, 6.8 pL, 37% wt., 2 eq., 92 pmol). Then, sodium triacetoxyborohydride (15 mg, 1 .5 eq., 69 pmol) was slowly added in portions over 15 min. while stirring. The reaction mixture was stirred at rt for 2h. TLC-MS was performed (5% MeOH/DCM). After completion, the reaction mixture was quenched with water, adjusted to pH 9 with 2M aq. NaOH, and concentrated to remove DCM. The aqueous layer was extracted with EtOAc (3x2 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was directly loaded on a C-18 column and chromatographed (5% to 95% MeOH/H2O (0.1 % HCOOH)) to afford 1- methyl-N-(2-methyl-1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -y l)propy l)py rrol id ine-3- carboxamide (8.3 mg, 25 pmol, 55%) as a colorless oil after solvent evaporation under high vacuum. ¹ H NMR (400 MHz, MeOD) 5 8.52 (s, 1 H), 7.31 - 7.22 (m, 2H), 7.21 - 7.14 (m, 3H), 3.85 (dd, J = 6.2, 1.5 Hz, 1 H), 3.46 - 3.40 (m, 2H), 3.40 - 3.26 (m, J = 1.5 Hz, 6H), 2.87 (d, J = 1.9 Hz, 3H), 2.42 (ddq, J = 13.3, 8.9, 7.5 Hz, 1 H), 2.23 - 2.10 (m, 1 H), 2.04 - 1.94 (m, 6H), 1.88 (dqd, J = 13.4, 6.7, 4.0 Hz, 1 H), 1.03 - 0.92 (m, 6H).

Compound SPC-FBL-0719_KABH1-111 was prepared following General Procedure B using nicotinic acid (42.54 mg, 1.2 eq., 345.5 pmol) and 2-methyl-1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (83.00 mg, 1 eq., 287.9 pmol) to afford N-(2-methyl-1-(3-phenylbicyclo[1.1 ,1 ]pentan-1 -yl)propyl)nicotinamide (92 mg, 0.29 mmol, >99%) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.97 (dd, J = 2.3, 0.9 Hz, 1 H), 8.69 (dd, J = 5.0, 1 .6 Hz, 1 H), 8.24 (ddd, J = 8.0, 2.3, 1 .7 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.28 - 7.23 (m, 2H), 7.22 - 7.14 (m, 3H), 4.05 (dd, J = 7.3, 2.7 Hz, 1 H), 2.11 - 2.01 (m, 6H), 2.01 - 1.93 (m, 1 H), 1.09 (d, J = 6.7 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H).

Compound SPC-Sav-040_KABH1-117 was prepared following General Procedure E using N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1 ]pentan-1-yl)propyl)nicotinamide (90 mg, 1 eq., 0.28 mmol) to afford N-(2-methyl-1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)propyl)nicotinamide hydrochloride (80.3 mg, 204 pmol, 73%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.21 (s, 1 H), 8.90 (d, J = 5.1 Hz, 1 H), 8.64 (d, J = 7.5 Hz, 1 H), 8.54 (d, J = 9.2 Hz, 1 H), 7.87 (d, J = 6.9 Hz, 1 H), 7.33 - 7.25 (m, 2H), 7.20 (dtd, J = 6.8, 4.2, 1.9 Hz, 3H), 3.99 (dd, J = 9.4, 7.2 Hz, 1 H), 2.04 - 1.96 (m, 6H), 1.96 - 1 .86 (m, 1 H), 1 .01 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). . y e

Compound SPC-Sav-042_KABH1-34 was prepared following General Procedure B using pyridazine-4-carboxylic acid (20.66 mg, 1.2 eq., 166.5 pmol) and 2-methyl-1-(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)propan-1 -amine hydrochloride (40.00 mg, 1 eq., 138.8 pmol) to afford N-(2-methyl-1-(3-phenylbicyclo[1 .1 ,1 ]pentan-1-yl)propyl)pyridazine-4- carboxamide (28.6 mg, 89.0 pmol, 64.1 %) as a orange solid. ¹ H NMR (400 MHz, DMSO) 5 9.53 (dd, J = 2.4, 1 .3 Hz, 1 H), 9.42 (dd, J = 5.3, 1 .3 Hz, 1 H), 8.58 (d, J = 9.5 Hz, 1 H), 8.01 (dd, J = 5.3, 2.3 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.20 (dtd, J = 8.2, 3.2, 2.8, 1.8 Hz, 3H), 3.97 (dd, J = 9.4, 7.2 Hz, 1 H), 2.05 - 1.94 (m, 6H), 1.90 (p, J = 6.8 Hz, 1 H), 1 .01 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). y e

Compound KABH1-38 was prepared using the following procedure. To a suspension of (E)-2-methyl-N-((3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methylene)propane-2- sulfinamide (100 mg, 1 eq., 363 pmol) dissolved in dry THF (3.63 mL) was slowly added a 3M solution of phenylmagnesium bromide (263 mg, 484 pL, 3 molar, 4 eq., 1.45 mmol) in diethyl ether under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (50% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was then cooled to 0°C and quenched with water (65.4 pL, 10 eq., 3.63 mmol). The resulting white suspension mixture was stirred at rt for 15 min and concentrated. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 50% EtOAc/cyclohexane) to afford 2-methyl-N-(phenyl(3-phenylbicyclo[1 .1 ,1 ]pentan-1- yl)methyl)propane-2-sulfinamide (79 mg, 0.22 mmol, 62%) as a colorless oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 354.5 [M+H] ⁺ .

Compound KABH1-39 was prepared following General Procedure A using 2-methyl- N-(phenyl(3-phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)methyl)propane-2-sulfinamide (79 mg, 1 eq., 0.22 mmol) to afford phenyl(3-phenylbicyclo[1 .1 .1]pentan-1 -yl)methanamine hydrochloride (61.5 mg, 191 pmol, 85%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.75 (s, 3H), 7.45 (d, J = 4.3 Hz, 4H), 7.42 - 7.36 (m, 1 H), 7.31 - 7.24 (m, 2H), 7.24 - 7.12 (m, 3H), 4.47 (d, J = 5.5 Hz, 1 H), 2.00 - 1 .86 (m, 6H).

Compound SPC-Sav-043_KABH1-40 was prepared following General Procedure B using nicotinic acid (18.34 mg, 1.2 eq., 148.9 pmol) and phenyl(3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (40.00 mg, 1 eq., 124.1 pmol) to afford N-(phenyl(3-phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methyl)nicotinamide (40.9 mg, 115 pmol, 93%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.03 (dd, J = 2.3, 0.9 Hz, 1 H), 8.91 (d, J = 8.8 Hz, 1 H), 8.72 (dd, J = 4.8, 1 .7 Hz, 1 H), 8.21 (dt, J = 7.9, 2.0 Hz, 1 H), 7.52 (ddd, J = 7.9, 4.9, 0.9 Hz, 1 H), 7.45 - 7.32 (m, 4H), 7.32 - 7.23 (m, 3H), 7.24 - 7.14 (m, 3H), 5.30 (d, J = 8.8 Hz, 1 H), 1 .90 (m, 6H).

Compound KABH1-48 was prepared using the following procedure. To a suspension of (E)-2-methyl-N-((3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methylene)propane-2- sulfinamide (113 mg, 1 eq., 410 pmol) dissolved in dry THF (4.10 mL) was slowly added a solution of cyclohexylmagnesium bromide (461 mg, 6 eq., 2.46 mmol) in THF under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (50% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was then cooled to 0°C and quenched with water (73 pL, 10 eq., 4.10 mmol). The resulting white suspension mixture was stirred at rt for 15 min and concentrated. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 50% EtOAc/cyclohexane) to afford N-(cyclohexyl(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2-methylpropane-2- sulfinamide (133.4 mg, 371 .0 pmol, 90.4%) as a colorless oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 360.6 [M+H] ⁺ . y e

Compound KABH1-49 was prepared following General Procedure A using N- (cyclohexyl(3-phenylbicyclo[1 .1 .1 ]pentan-1-yl)methyl)-2-methylpropane-2 -sulfinamide (133.4 mg, 1 eq., 371.0 pmol) to afford cyclohexyl(3-phenylbicyclo[1 .1 ,1]pentan-1 - yl)methanamine hydrochloride (46.3 mg, 141 pmol, 38%) as a white solid. TLC-MS APCI+ m/z = 256.4 [M+H] ⁺ .

Compound SPC-Sav-044_KABH1-52 was prepared following General Procedure B using nicotinic acid (18.00 mg, 1.2 Eq, 146.2 pmol) and cyclohexyl(3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (40.00 mg, 1 eq., 121.8 pmol) to afford N-(cyclohexyl(3-phenylbicyclo[1 .1 .1 ]pentan-1-yl)methyl)nicotinamide (42.8 mg, 119 pmol, 97.4%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.00 (dd, J = 2.3, 0.9 Hz, 1 H), 8.70 (dd, J = 4.8, 1.6 Hz, 1 H), 8.25 (d, J = 9.5 Hz, 1 H), 8.19 (ddd, J = 7.9, 2.3, 1 .7 Hz, 1 H), 7.50 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.24 - 7.15 (m, 3H), 4.01 (dd, J = 9.5, 7.5 Hz, 1 H), 2.04 - 1 .92 (m, 6H), 1 .93 - 1 .53 (m, 6H), 1.33 - 0.93 (m, 5H).

Compound KABH1-51 was prepared using the following procedure. To a suspension of (E)-2-methyl-N-((3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methylene)propane-2- sulfinamide (73 mg, 1 eq., 0.27 mmol) dissolved in dry THF (2.7 mL) was slowly added a solution of (4-methoxyphenyl)magnesium bromide (0.22 g, 4 eq., 1.1 mmol) in THF under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (50% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was then cooled to 0°C and quenched with water (48 pL, 10 eq., 2.7 mmol). The resulting white suspension mixture was stirred at rt for 15 min and concentrated. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 50% EtOAc/cyclohexane) to afford N-((4-methoxyphenyl)(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2-methylpropane-2- sulfinamide (89.5 mg, 233 pmol, 88%) as a colorless oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 384.6 [M+H] ⁺ . . y e

Compound KABH1-56 was prepared following General Procedure A using N-((4- methoxyphenyl)(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2-methylpropane-2- sulfinamide (87.1 mg, 1 eq., 227 pmol) to afford (4-methoxyphenyl)(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)methanamine hydrochloride (47.4 mg, 135 pmol, 59.2%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.62 - 8.57 (m, 3H), 7.41 - 7.33 (m, 2H), 7.33 - 7.13 (m, 5H), 7.04 - 6.96 (m, 2H), 4.41 (s, 1 H), 3.77 (s, 3H), 1 .96 - 1.85 (m, 6H). . y e

Compound SPC-Sav-045_KABH1-57 was prepared following General Procedure B using nicotinic acid (16.35 mg, 1.2 eq., 132.8 pmol) and (4-methoxyphenyl)(3- phenylbicyclo[1 .1 .1 ]pentan-1 -yl)methanamine hydrochloride (39.00 mg, 1 eq., 110.7 pmol) to afford N-((4-methoxyphenyl)(3-phenylbicyclo[1.1.1 ]pentan-1- yl)methyl)nicotinamide (41.8 mg, 109 pmol, 98.2%) as a yellow solid. ¹ H NMR (400 MHz, DMSO) 5 9.02 (dd, J = 2.3, 0.9 Hz, 1 H), 8.85 (d, J = 8.9 Hz, 1 H), 8.72 (dd, J = 4.8, 1.7 Hz, 1 H), 8.20 (dt, J = 7.9, 2.0 Hz, 1 H), 7.52 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.39 - 7.30 (m, 2H), 7.30 - 7.24 (m, 2H), 7.22 - 7.14 (m, 3H), 6.96 - 6.88 (m, 2H),

5.25 (d, J = 8.9 Hz, 1 H), 3.75 (s, 3H), 1 .89 (m, 6H).

Compound KABH1-76 was prepared using the following procedure. In a sealed microwave tube with a stirring bar, colorless gas tricyclo[1 .1 .1 .01 ,3]pentane (4.666 g, 204.000 mL, 0.346 molar, 1 eq., 70.5840 mmol) in Et20 was added followed by (4- fluorophenyl)magnesium bromide (28.136 g, 70.5840 mL, 2.000 molar, 2 eq., 141.168 mmol). The orange suspension mixture was stirred at 100°C for 1 ,5h (use face shield due to pressure build-up). Methyl chloroformate (21 .900 mL, 4 eq., 282.336 mmol) was then added after cooling the mixture to 0°C and the resulting mixture was stirred for 16h at rt. The reaction was quenched with saturated aq. solution of NH4CI which was added dropwise (exothermic). Water was added and layers were separated. The aqueous layer was extracted with Et20 (3x). The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 15% ether/hexane) to afford methyl 3-(4- fluorophenyl)bicyclo[1.1.1 ]pentane-1 -carboxylate (5.141 g, 23.34 mmol, 33.7%) as a yellow transparent oil. ¹ H NMR (400 MHz, CDCI3) 6 7.22 - 7.11 (m, 2H), 7.04 - 6.94 (m, 2H), 3.71 (s, 3H), 2.31 (s, 6H).

Compound KABH1-79 was prepared using the following procedure. To a suspension in a round-bottomed flask containing methyl 3-(4-fluorophenyl)bicyclo[1.1.1 ]pentane- 1 -carboxylate (1.51 g, 1 eq., 6.86 mmol) dissolved in dry THF (34.3 mL) and cooled to 0 °C, was added LiALH4 in THF (390 mg, 5.14 mL, 2 molar, 1.5 eq., 10.3 mmol) dropwise. The reaction mixture was stirred at rt for 30 min. TLC is done to confirm the completion of the reaction (20% EtOAc/cyclohexane). Fieser work-up was then performed. The resulting filtrate was evaporated to afford (3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)methanol (1.318 g, 6.856 mmol, >99%) as a yellow transparent oil. ¹ H NMR (400 MHz, CDCI ₃ ) 6 7.22 - 7.12 (m, 1 H), 7.05 - 6.93 (m, 2H), 3.70 (s, 2H), 1 .97 (s, 6H), 1 .44 - 1 .39 (s, 1 H).

Compound KABH1-80 was prepared using the following procedure. To a suspension in a round-bottomed flask containing (3-(4-fluorophenyl)bicyclo[1.1.1 ]pentan-1 - yl)methanol (1.30 g, 1 eq., 6.76 mmol) dissolved in DCM (13.5 mL) and cooled to 0°C, was added DMP (3.62 g, 2.65 mL, 95% wt., 1.2 eq., 8.12 mmol) portion-wise. The reaction mixture was stirred at rt for 3h. TLC is done to confirm the completion of the reaction (20% EtOAc/cyclohexane). Excess Et20 was then added and the mixture was stirred for 30 min further. The suspension was filtered to remove any excess DMP and the filtrate was concentrated. The crude residue was diluted in Et20 and washed with a 1 :1 mixture of saturated aq. NaHCOs and 10% Na2SOs (3x). Layers were separated and the combined organic layers was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentane-1-carbaldehyde (1.29 g, 6.78 mmol, >99%) as a yellow transparent oil. Used in the next step without any further purification. TLC-MS APCI+ m/z = 191.2 [M+H] ⁺ . Compound KABH1-81 was prepared using the following procedure. To a suspension in a round-bottomed flask containing 3-(4-fluorophenyl)bicyclo[1.1.1 ]pentane-1 - carbaldehyde (1.292 g, 1.0 eq., 6.792 mmol) dissolved in anhydrous THF (56.6 mL) were consecutively added 2-methylpropane-2-sulfinamide (933.5 mg, 97.0% wt., 1.1 eq., 7.471 mmol) followed by titanium(IV) isopropoxide (3.861 g, 14.15 mL, 0.96 molar, 2.0 eq., 13.58 mmol) at rt. under inert atmosphere. The reaction mixture was stirred at rt for 2h. The suspension was filtered to remove any excess titanium salts and the filtrate was concentrated. The crude residue was diluted in water and extracted with EtOAc (3x). Layers were separated and the combined organic layers was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 20% EtOAc/cyclohexane) to afford (E)-N-((3-(4-fluorophenyl)bicyclo[1 .1 ,1 ]pentan-1- yl)methylene)-2-methylpropane-2-sulfinamide (961 mg, 3.28 mmol, 48.2%) as a yellow transparent oil. ¹ H N MR (400 MHz, CDCI ₃ ) 6 8.08 (s, 1 H), 7.24 - 7.13 (m, 2H), 7.05 - 6.95 (m, 2H), 2.28 (s, 6H), 1.21 (s, 9H).

Compound KABH1-82 was prepared using the following procedure. To a suspension of f (E)-N-((3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methylene)-2-methylpropane- 2-sulfinamide (454 mg, 1 eq., 1.55 mmol) dissolved in dry THF (3.63 mL) was slowly added a isopropyl magnesium chloride in THF (637 mg, 3.09 mL, 2 molar, 4 eq., 6.19 mmol) under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (20% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was then cooled to 0°C and quenched with water (279 pL, 10 eq., 15.5 mmol). The resulting white suspension mixture was stirred at rt for 15 min and concentrated. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 90% EtOAc/cyclohexane) to afford N-(1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-2-methylpropyl)-2- methylpropane-2-sulfinamide (171 mg, 507 pmol, 32.7%) as a colorless oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 338.5 [M+H] ⁺ .

Compound KABH1-83 was prepared following General Procedure A using N-(1 -(3- (4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-2-methylpropyl)-2-methylpropane-2- sulfinamide (167 mg, 1 eq., 495 pmol) to afford 1-(3-(4- fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-2-methylpropan-1 -amine hydrochloride (91 mg, 0.30 mmol, 60%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.08 - 8.04 (m, 3H), 7.23 (ddd, J = 8.6, 5.4, 2.6 Hz, 2H), 7.18 - 7.07 (m, 2H), 3.06 (q, J = 5.4 Hz, 1 H), 2.08 (s, 6H), 2.02 - 1.88 (m, 1 H), 1.00 (dd, J = 18.1 , 6.9 Hz, 6H).

Compound SPC-Sav-046_KABH1-109 was prepared following General Procedure B using nicotinic acid (25.08 mg, 1.2 eq., 203.8 pmol) and 1 -(3-(4- fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-2-methylpropan-1 -amine hydrochloride (52.00 mg, 1 eq., 169.8 pmol) (39.00 mg, 1 eq., 110.7 pmol) to afford N-(1 -(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-2-methylpropyl)nicotinamide (50.8 mg, 150 pmol, 88.4%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.00 (dd, J = 2.3, 0.9 Hz, 1 H), 8.70 (dd, J = 4.9, 1.7 Hz, 1 H), 8.26 (d, J = 9.5 Hz, 1 H), 8.19 (dt, J = 7.9, 2.0 Hz, 1 H), 7.50 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.23 (ddd, J = 8.6, 5.5, 2.6 Hz, 2H), 7.15 - 7.04 (m, 2H), 3.96 (dd, J = 9.5, 7.3 Hz, 1 H), 2.06 - 1 .93 (m, 6H), 1 .89 (p, J = 6.9 Hz, 1 H), 1 .00 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO) 5 - 116.69.

Compound SPC-Sav-049_KABH1-140 was prepared following General Procedure E using N-(cyclopropyl(3-(4-methoxyphenyl)bicyclo[1 .1.1 ]pentan-1 - yl)methyl)nicotinamide (300 mg, 1 eq., 861 pmol) to afford N-(cyclopropyl(3-(4- methoxyphenyl)bicyclo[1 .1 ,1]pentan-1 -yl)methyl)nicotinamide hydrochloride (250 mg, 650 pmol, 75.4%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.14 (dd, J = 2.2, 0.9 Hz, 1 H), 8.83 (dd, J = 5.1 , 1.6 Hz, 1 H), 8.71 (d, J = 8.6 Hz, 1 H), 8.50 (dt, J = 8.0, 1.9 Hz, 1 H), 7.76 (ddd, J = 8.1 , 5.1 , 0.8 Hz, 1 H), 7.16 - 7.07 (m, 2H), 6.89 - 6.80 (m, 2H), 3.71 (s, 3H), 3.46 (t, J = 9.1 Hz, 1 H), 1.98 - 1.88 (m, 6H), 1.02 (dddd, J = 12.9, 9.5, 8.0, 4.8 Hz, 1 H), 0.59 (tdd, J = 8.2, 5.2, 3.6 Hz, 1 H), 0.45 - 0.34 (m, 1 H), 0.25 (dtd, J = 15.6, 9.2, 4.6 Hz, 2H).

Compound KABH1-86 was prepared using the following procedure. To a suspension of (E)-2-methyl-N-((3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)methylene)propane-2- sulfinamide (999 mg, 1 eq., 3.63 mmol) dissolved in dry THF (36.3 mL) was slowly added allylmagnesium bromide in THF (2.11 g, 14.5 mL, 1 molar, 4 eq., 14.5 mmol) under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (20% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was then cooled to 0°C and quenched with water (654 pL, 10 eq., 36.3 mmol). The resulting white suspension mixture was stirred at rt for 15 min and concentrated. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 90% EtOAc/cyclohexane) to 2-methyl-N-(1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)but-3-en-1 -yl)propane-2-sulfinamide (800 mg, 2.52 mmol, 69.5%) as a transparent yellow oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 318.5 [M+H] ⁺ .

Compound KABH1-154 was prepared following General Procedure A using 2- methyl-N-(1 -(3-phenylbicyclo[1 .1.1 ]pentan-1 -yl)but-3-en-1 -yl)propane-2-sulfinam ide (800 mg, 1 eq., 2.52 mmol) to afford 1 -(3-phenylbicyclo[1 .1 ,1]pentan-1 -yl)but-3-en-1- amine hydrochloride (600 mg, 2.10 mmol, 83.2%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.15 (s, 3H), 7.35 - 7.26 (m, 2H), 7.26 - 7.16 (m, 3H), 5.86 (ddt, J = 17.1 , 10.1 , 6.9 Hz, 1 H), 5.27 - 5.11 (m, 2H), 3.30 (s, 1 H), 2.37 (tt, J = 6.8, 1.4 Hz, 2H), 2.08 - 1.96 (m, 6H).

Compound SPC-Sav-051_KABH-01-160 was prepared following General Procedure B nicotinic acid (26 mg, 1.2 eq., 0.21 mmol) and 1 -(3-phenylbicyclo[1 .1 ,1]pentan-1- yl)but-3-en-1 -amine hydrochloride, HCI (50 mg, 1 eq., 0.17 mmol) to afford N-(1 -(3- phenylbicyclo[1 .1 ,1 ]pentan-1 -yl)but-3-en-1 -yl)nicotinamide (46.5 mg, 146 pmol, 84%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 9.00 (dd, J = 2.3, 0.9 Hz, 1 H), 8.70 (dd, J = 4.8, 1.7 Hz, 1 H), 8.36 (d, J = 8.9 Hz, 1 H), 8.18 (ddd, J = 7.9, 2.3, 1.7 Hz, 1 H), 7.50 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 7.33 - 7.24 (m, 2H), 7.24 - 7.16 (m, 3H), 5.82 (ddt, J = 17.0, 10.2, 6.8 Hz, 1 H), 5.18 - 5.07 (m, 1 H), 5.01 (ddt, J = 10.2, 2.3, 1.1 Hz, 1 H), 4.21 (ddd, J = 9.9, 8.8, 4.6 Hz, 1 H), 2.42 - 2.20 (m, 2H), 1 .98 - 1 .87 (m, 6H).

Compound KABH-01-182 was prepared using the following procedure. To a suspension of (E)-N-((3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methylene)-2- methylpropane-2-sulfinamide (254 mg, 1 eq., 866 pmol) dissolved in dry THF (8.7 mL) was slowly added a solution of cyclopropylmagnesium bromide (503 mg, 3.54 mL, 0.979 molar, 4 eq., 3.46 mmol) in THF under inert atmosphere at rt. The yellow reaction mixture was heated at 70°C and stirred for 3h. After cooling to rt, TLC was performed (20% EtOAc/cyclohexane) to confirm the completion of the reaction. The mixture was cooled to 0°C and quenched with water (156 pL, 10 eq., 8.66 mmol) and the resulting white suspension was stirred at rt for 15 min and concentrated. The mixture was then diluted in water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 90% EtOAc/cyclohexane) to afford N-(cyclopropyl(3-(4-fluorophenyl)bicyclo[1 .1 ,1 ]pentan- 1 -yl)methyl)-2-methylpropane-2-sulfinamide (257 mg, 766 pmol, 88.5%) as a yellow transparent oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 336.5

Compound KABH-01-183 was prepared following General Procedure A using N- (cyclopropyl(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methyl)-2-methylpropane-2- sulfinamide (255 mg, 1 eq., 760 pmol) to afford cyclopropyl(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)methanamine hydrochloride (181 mg, 595 pmol, 78.3%) as a white solid. ¹ H NMR (400 MHz, DMSO) 5 8.18 (s, 3H), 7.32 - 7.19 (m, 2H), 7.18 - 7.08 (m, 2H), 2.45 (dt, J = 10.7, 5.4 Hz, 1 H), 2.10 - 1.97 (m, 6H), 0.89 (dddd, J = 12.7, 9.8, 8.0, 4.8 Hz, 1 H), 0.66 - 0.41 (m, 3H), 0.30 (ddt, J = 9.0, 5.7, 4.3 Hz, 1 H). . y e

Compound SPC-Sav-052_KABH-01-185 was prepared following General Procedure B using nicotinic acid (41.28 mg, 1.2 eq., 335.3 pmol) and cyclopropyl(3-(4- fluorophenyl)bicyclo[1 .1 .1]pentan-1 -yl)methanamine hydrochloride (85.0 mg, 1 eq., 279.4 pmol) to afford N-(cyclopropyl(3-(4-fluorophenyl)bicyclo[1 .1 ,1 ]pentan-1- yl)methyl)nicotinamide (87.3 mg, 260 pmol, 92.9%) as a white solid. ¹ H NMR (400 MHz, MeOD) 5 8.99 (dd, J = 2.2, 0.9 Hz, 1 H), 8.69 (dd, J = 4.9, 1 .6 Hz, 1 H), 8.26 (ddd, J = 8.0, 2.3, 1.6 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.27 - 7.17 (m, 2H), 7.04 - 6.93 (m, 2H), 3.51 - 3.42 (m, 1 H), 2.09 - 1 .94 (m, 6H), 1 .07 (dtt, J = 9.8, 8.1 , 4.8 Hz, 1 H), 0.67 (tdd, J = 8.0, 4.9, 3.6 Hz, 1 H), 0.56 - 0.45 (m, 1 H), 0.40 - 0.25 (m, 2H).

Compound KABH-01-202 was prepared using the following procedure. To a solution of ethyl 5-amino-1 ,3,4-thiadiazole-2-carboxylate (2.36 g, 1 eq., 13.6 mmol), in dry DCM (118 mL), at 0°C, under inert atmosphere, was added TEA (2.76 g, 3.80 mL, 2 eq., 27.3 mmol), followed by slow addition of benzoyl chloride (2.30 g, 1.90 mL, 1.2 eq., 16.4 mmol). The reaction mixture was stirred at rt for 16h. TLC (50% EtOAc/cyclohexane) and LC-MS were performed to confirm the completion of reaction. The reaction mixture was then diluted with DCM and H2O and the two layers were separated. The aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in DCM and EtOAc (minimal amounts) and sonicated for 5 minutes. The suspension was filtered off and washed with small amounts of DCM to afford ethyl 5- benzamido-1 ,3,4-thiadiazole-2-carboxylate (3.34 g, 12.0 mmol, 88.4%) as a white solid which was dried under high vacuum. ¹ H NMR (400 MHz, DMSO) 5 13.54 (s, 1 H), 8.18 - 8.11 (m, 2H), 7.74 - 7.65 (m, 1 H), 7.59 (t, J = 7.6 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).

Compound KABH-01-169 was prepared using the following procedure. To a 2-necked flask with a large stir-bar, oven-dried and under nitrogen, were added zinc (134 mg, 3 eq., 2.04 mmol) and copper(l) chloride (67.5 mg, 1 eq., 682 pmol). The solid mixture was stirred at 60°C for 30 min. After cooling to rt, dry THF (3.41 mL) was added and the reaction mixture was stirred at 60°C for 30 min again. Then, a solution of ethyl bromoacetate (285 mg, 189 pL, 2.5 eq., 1.70 mmol) in dry THF (1.14 mL) was slowly added at rt and the reaction mixture was stirred at rt for 30 min. Finally, a solution of (E)-N-((3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)methylene)-2-methylpropane-2- sulfinamide (200 mg, 1 eq., 682 pmol) in dry THF (1.14 mL) was added at 0°C and the reaction mixture was stirred at 60°C for 16h. TLC was performed (60% EtOAc/cyclohexane) to confirm the completion of the reaction. The reaction mixture was then quenched with a solution of saturated aq. NH4CI and brine (1 :1 ) and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using Biotage flash chromatography on silica gel (0% to 60% EtOAc/cyclohexane) to afford ethyl 3- ((tert-butylsulfinyl)amino)-3-(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)propanoate (71.8 mg, 188 pmol, 27.6%) as a yellow transparent oil after solvent evaporation under high vacuum that solidifies on standing. Used in the next step without any further purification. TLC-MS APCI+ m/z = 382.2 [M+H] ⁺ .

Compound KABH-01-172 was prepared following General Procedure A using ethyl 3-((tert-butylsulfinyl)amino)-3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1 ]pentan-1-yl)propanoate (71 mg, 1 eq., 0.19 mmol) to afford ethyl 3-amino-3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)propanoate hydrochloride (65 mg, 0.19 mmol,

>99%) as a sticky beige solid. The reaction was considered quantitative and the resulting product was used in the next step without further purifications. TLC-MS APCI+ m/z = 278.3 [M+H] ⁺ .

Compound KABH-01-174 was prepared following General Procedure B using nicotinic acid (28 mg, 1.2 eq., 0.23 mmol) and f ethyl 3-amino-3-(3-(4- fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)propanoate hydrochloride, HCI (66 mg, 1 Eq, 0.19 mmol) to afford ethyl 3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3- (nicotinamido)propanoate (57.4 mg, 150 pmol, 80%) as a sticky yellow solid. ¹ H NMR (400 MHz, MeOD) 6 8.96 (dd, J = 2.3, 0.9 Hz, 1 H), 8.69 (dd, J = 5.0, 1 .7 Hz, 1 H), 8.23 (ddd, J = 8.0, 2.3, 1 .6 Hz, 1 H), 7.55 (ddd, J = 8.0, 4.9, 0.9 Hz, 1 H), 7.26 - 7.15 (m, 2H), 7.04 - 6.93 (m, 2H), 4.71 (dd, J = 9.1 , 5.6 Hz, 1 H), 4.14 (qd, J = 7.1 , 2.2 Hz, 2H), 2.78 - 2.55 (m, 2H), 1 .98 (s, 6H), 1 .23 (t, J = 7.1 Hz, 3H).

Compound KABH-01-177 was prepared using the following procedure. In a round- bottomed flask, ethyl 3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3- (nicotinamido)propanoate (50 mg, 1 eq., 0.13 mmol) was dissolved in a mixture of THF (0.65 mL) and water (0.13 mL) in a 5:1 ratio. Lithium hydroxide monohydrate (16 mg, 3 eq., 0.39 mmol) was added and the resulting mixture was stirred for 16h at room temperature. Upon confirmation of the completion of the reaction via LC-MS and TLC- MS, the THF was evaporated. Then, the aqueous phase was extracted with DCM (3x) to remove any impurities. The mixture was then acidified with 2M aq. KHSO4 (53 mg, 0.20 mL, 2 molar, 3 eq., 0.39 mmol) to pH <2 and extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuo to afford the desired product 3-(3-(4-fluorophenyl)bicyclo[1 .1 ,1]pentan-1 -yl)-3- (nicotinamido)propanoic acid (34.4 mg, 97.1 pmol, 74%) as a sticky yellow solid. ¹ H NMR (400 MHz, MeOD) 5 8.96 (d, J = 2.3 Hz, 1 H), 8.68 (dd, J = 4.9, 1 .7 Hz, 1 H), 8.23 (dt, J = 8.0, 2.0 Hz, 1 H), 7.55 (dd, J = 8.1 , 4.9 Hz, 1 H), 7.25 - 7.16 (m, 2H), 7.04 - 6.93 (m, 2H), 4.70 (dd, J = 8.7, 5.9 Hz, 1 H), 2.64 (qd, J = 15.6, 7.2 Hz, 2H), 1.99 (s, 6H). Compound KABH-01-186 was prepared using the following procedure. To a suspension in a microwave vial containing 3-(3-(4-fluorophenyl)bicyclo[1.1.1 ]pentan- 1 -yl)-3 (nicotinamido)propanoic acid (20.0 mg, 1 eq., 56.4 pmol), di-tert-butyl piperidine-3,5-diyldicarbamate (17.8 mg, 1 eq., 56.4 pmol), HOAT (9.22 mg, 67.7 pL, 1 molar, 1.2 eq., 67.7 pmol), and HATU (23.6 mg, 1.1 eq., 62.1 pmol) in DMF (0.3 mL) was added TEA (17.1 mg, 23.6 pL, 3 eq., 169 pmol). The reaction mixture was stirred at rt for 16h. LC-MS was performed to confirm the formation of the product. The crude reaction mixture was directly loaded on a C-18 column and chromatographed (5% to 95% MeOH/H ₂ O (0.1 % HCOOH)) to afford the targeted amide di-tert-butyl (1-(3-(3-(4- fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(nicotinamido)propanoyl)piperidine-3,5- diyl)dicarbamate (30 mg, 40.7 pmol, 82%) as a yellow solid after solvent evaporation under high vacuum. Used in the next step without any further purification. TLC-MS APCI+ m/z = 652.8 [M+H] ⁺ .

Compound SPC-Sav-053_KABH-01-189 was prepared using the following procedure. To a suspension in a round-bottomed flask containing di-tert-butyl (1 -(3-(3-(4- fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -yl)-3-(nicotinamido)propanoyl)piperidine-3,5- diyl)dicarbamate (30 mg, 1 eq., 46 pmol) dissolved in dry MeOH (0.31 mL) was added 4M HCI in Dioxane (17 mg, 0.12 mL, 4.0 molar, 10 eq., 0.46 mmol) dropwise under inert conditions. The reaction mixture was stirred at rt for 4h. TLC-MS and LC-MS are performed to check the formation of the salt. The reaction mixture is then concentrated under reduced pressure to afford the product as a yellow solid with some traces of MeOH. Lyophilization is finally performed to give the desired pure product N-(3-(3,5- diaminopiperidin-1 -y l)-1 -(3-(4-fluorophenyl)bicyclo[1 .1.1 ]pentan-1 -y l)-3- oxopropyl)nicotinamide trihydrochloride (25.2 mg, 44.9 pmol, 98%) as a powdered yellow solid. ¹ H NMR (400 MHz, MeOD) 5 9.40 - 8.88 (m, 3H), 8.16 (s, 1 H), 7.21 (dt, J = 8.9, 4.5 Hz, 2H), 6.99 (t, J = 8.4 Hz, 2H), 4.75 (s, 2H), 4.41 (s, 1 H), 3.76 - 3.56 (m, 1 H), 3.14 (s, 2H), 2.87 (d, J = 57.3 Hz, 2H), 2.62 (s, 2H), 2.05 (d, J = 10.9 Hz, 6H), 1.83 (s, 1 H). ¹⁹ F NMR (376 MHz, MeOD) 5 -118.40.

Further examples and embodiments of the present invention are disclosed in the following numbered items.

1 . A compound according to formula (I): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, wherein

Ri’ is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)- cycloalkyl, optionally substituted (C0-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, or optionally substituted (C0-3 alkylene)- heteroaryl;

R2’ is optionally substituted aryl, or optionally substituted heteroaryl; and

X is -0- or -NH-; wherein each of one or more optional substituents of said alkyl, cycloalkyl, heterocycloalkyl or alkylene group are selected from -OH, -NH2, -CN and Hal; wherein each of one or more optional substituents of said aryl or heteroaryl group are selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, -NH-C1-4 alkyl, or -N(CI-4 alkyl)2. The compound of item 1 , wherein Ri ’ is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-e alkynyl. The compound of item 1 or 2, wherein R1’ is optionally substituted C1-6 alkyl, preferably wherein R-T is ethyl or methyl. The compound of item 1 , wherein R-T is optionally substituted (C0-3 alkylene)- aryl, or optionally substituted (C0-3 alkylene)-heteroaryl, preferably wherein R-T is optionally substituted -CH2-C6H5, more preferably wherein R-T is -CH2-C6H5. The compound of any one of items 1 to 4, wherein R2’ is optionally substituted aryl. The compound of any one of items 1 to 4, wherein X is -NH-. The compound of any one of items 1 to 6, wherein the compound according to formula (I) is a compound according to formula: A compound according to formula (II): (II) and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, wherein

Ri and R2 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted (C0-3 alkylene)-cycloalkyl, and optionally substituted (C0-3 alkylene)-heterocycloalkyl, wherein at least one of R1 and R2 is hydrogen; or wherein R1 and R2 are replaced by an =0 or =S moiety attached to the carbon atom that otherwise carries R1 and R2;

R3 and R4 are independently selected from hydrogen, optionally substituted - C(0)-(Co-3 alkylene)-aryl, optionally substituted -C(0)-(Co-3 alkylene)- heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)-cycloalkyl, optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl, optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl; optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)- heterocycloalkyl;

Rs is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl; wherein each of one or more optional substituents of said alkyl, cycloalkyl, heterocycloalkyl or alkylene group is selected from -OH, -NH2, -CN, Hal and =0; wherein each of one or more optional substituents of said aryl or heteroaryl group is selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, - NH-C1-4 alkyl, or — N(CI-4 alkyl)2. The compound of item 8, wherein both R1 and R2 are hydrogen. The compound of item 7 or 8, wherein R5 is optionally substituted (C0-3 alkylene)- aryl or optionally substituted (C0-3 alkylene)-heteroaryl, preferably wherein R5 is optionally substituted aryl or optionally substituted heteroaryl. The compound of item 10, wherein Rs is selected from 2-benzothiazolyl, benzyl, 4-methoxyphenyl, and phenyl, preferably wherein Rs is 4-methoxyphenyl. The compound of any one of items 8 to 11 , wherein R3 or R4 is optionally substituted -C(O)-heteroaryl, preferably wherein R3 or R4 is selected from 2- pyrroryl, 2-pyridyl, 3-pyridyl, 4-methoxy-3-pyridyl, and 4-pyridyl, more preferably wherein R3 or R4 is 3-pyridyl. The compound of any one of items 8 to 12, wherein the compound according to formula (II) is a compound of formula: A compound of formula (III): and all stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, wherein:

R3 and R4 are independently selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted -C(0)-(Co-3 alkylene)-aryl, optionally substituted - C(0)-(Co-3 alkylene)-heteroaryl, optionally substituted -C(0)-(Co-3 alkylene)- cycloalkyl, and optionally substituted -C(0)-(Co-3 alkylene)-heterocycloalkyl; and Rs is optionally substituted (C0-3 alkylene)-aryl, optionally substituted (C0-3 alkylene)-heteroaryl, optionally substituted (C0-3 alkylene)-cycloalkyl or optionally substituted (C0-3 alkylene)-heterocycloalkyl; wherein each of one or more optional substituents of said alkyl, cycloalkyl, heterocycloalkyl or alkylene group is selected from -OH, -NH2, -CN, Hal and =0; wherein each of one or more optional substituents of said aryl or heteroaryl group is selected from -OH, -NH2, -CN, Hal, C1-4 alkyl, C1-4 haloalkyl, -O-C1-4 alkyl, - NH-C1-4 alkyl, or — N(CI-4 alkyl)2. A pharmaceutical composition comprising the compound of any one of items 1 to 14, and a pharmaceutically acceptable carrier. The compound of any one of items 1 to 14 or the pharmaceutical composition of item 15 for use as a medicament. The compound of any one of items 1 to 14 or the pharmaceutical composition of item 15 for use in treating and/or preventing and/or alleviating the symptoms of a disease characterized by the increased expression level of miR-155. The compound for use or the pharmaceutical composition for use of item 17, wherein the disease characterized by the increased expression level of miR-155 is systemic lupus erythematosus. The compound for use or the pharmaceutical composition for use of item 17, wherein the disease characterized by the increased expression level of miR-155 is scleroderma.