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Definitions

• ATX Autotaxin
• ATX Pyrophosphatase/Phosphodiesterase 2 (ENPP-2 or NPP2).
• ENPP-2 or NPP2 Pyrophosphatase/Phosphodiesterase 2
• LPC Lysophosphatidylcholine
• LPA Lysophosphatidic Acid
• LPA Low-power plasma phosphatidylcholine
• IPF Idiopathic Pulmonary Fibrosis
• thrombosis thrombosis
• cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or activation of ATX.
• Fibrotic diseases are chronic, debilitating and often lethal pathologies driven by a dysregulated response to tissue or organ injury. Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids.
• ATX, LPA, and LPA Receptor (LPAR) pathways have been implicated in fibrotic disease.
• profiling studies show increased levels of ATX, LPA and LPARs in various rodent models of fibrosis and in human patient fluids and biopsy tissue.
• LPA can induce proliferative, survival, and chemotactic responses in transformed cell lines, indicating that LPA may exert pro-inflammatory and pro- fibrotic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes.
• Gene-targeted mouse models have implicated LPARs in fibrosis pathogenesis.
• Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents.
• Cell type-specific gene targeting studies have showed that ATX plays a role in the development of lung fibrosis and inflammatory arthritis.
• ATX and LPA have also been implicated in tumor progression and metastasis.
• ATX may be responsible for increased LPA levels in ascites and plasma of ovarian cancer patients since ATX converts LPC to LPA.
• Increased levels of LPA, altered receptor expression and altered responses to LPA may contribute to initiation, progression or outcome of ovarian cancer.
• LPA has also been linked to prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers.
• LPA has been shown to promote tumor cell survival, proliferation, invasion and migration into neighboring tissues, which can result in the formation of metastases. Additionally, LPA promotes cytoskeletal remodeling that may enhance migratory and invasive properties of cells, which may contribute to cancer metastasis.
• Transcriptome analyses of more than 350 normal tissues and more than 1700 malignant tissues demonstrate that ATX is expressed in a variety of carcinomas and sarcomas, underscoring the potential contribution of LPA to metastatic disease.
• LPA levels when treating patients with diseases, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX.
• ATX is expressed in tumors and affects tumor cell proliferation and invasion into neighboring tissues both of which can lead to the formation of metastases
• ATX is a target for anti-tumor therapy.
• ATX taken with other anti-angiogenetic factors, brings about blood vessel formation.
• Angiogenesis supplies tumors with nutrients during tumor growth. Therefore, inhibition of angiogenesis is a target for anti-tumor therapy, leading to starvation of a tumor.
• ATX has also been implicated in nerve injury-induced neuropathic pain.
• LPA biosynthesis, through ATX, is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis may represent a novel treatment to prevent nerve injury- induced neuropathic pain.
• ATX inhibitors having the potential to reach the clinic and obtain regulatory approval for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
• physiological and/or pathophysiological conditions such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX.
• the present invention includes certain substituted compounds described herein, their salts, preparations thereof, pharmaceutical compositions and formulations thereof, and methods of treating disease such as cancers therewith.
• the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof:
• X 2 is selected from C 1-2a
• kyl , C 0, NR 3 or O
• R 1 , R 7 , R 2a , R 4 , R 10 and R 1 1 are each independently optionally substituted; and
• m and n are each independently selected from 0, 1 or 2. Any of the above can be further substituted.
• Compounds of Formula I inhibit ATX.
• compounds of the present invention are inhibitors of ATX. In some embodiments, compounds of the present invention are selective inhibitors of ATX.
• the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
• Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical forms thereof including solvates and hydrates, preparation of the compounds, intermediates, and pharmaceutical compositions and formulations thereof.
• the present invention concerns compounds and salts thereof of Formula I, as shown below and defined herein.
• n are each independently selected from 0, 1 or 2;
• R 1 is selected from Co-i 2 alkyl-, C 3 . 12 cycloalkyl-C 0 -i2alkyl-, C3_i2heterocycloalkyl-C 0 . 12 alkyl- aryl- C 0 -i 2 alkyl-, aryl-C ⁇ cycloalkyl- aryl-C 3 .i 2 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl- heteroaryl-C 3 _ i 2 cycloalkyl- or heteroaryl-C 3 _i 2 heterocycloalkyl- any of which is optionally substituted with one or more independent G 1 substituents;
• R 2 is selected from Co-i 2 alkyl- C 3 . 12 cycloalkyl-C 0 -i 2 alkyl-, C 3 -i 2 heterocycloalkyl-C 0 -i 2 alkyl- aryl- C 0 -i 2 alkyl- aryl-C 3 .i 2 cycloalkyl- aryl-C 3 _ 12 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl- heteroaryl-C 3 _ , 2 cycloalkyl- or heteroaryl-C 3 _ 12 heterocycloalkyl- any of which is optionally substituted with one or more independent G 2 substituents;
• R 2a is selected from Co. 12 alkyi- C 3 . 12 cycloalkyl-Co-i2alkyl-, Ci ⁇ eterocycloalkyl-Co. ⁇ alkyl- aryl-
• R 2 and R a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m1 ;
• R 3 is selected from C 0 -i 2 alkyi-, C 3 . 12 cycloalkyl-Co-i 2 alkyl- C 3 . t2 heterocycloalkyl-C 0 _ 12 alkyl-, aryl-
• R 4 is selected from C 0 -i 2 alkyl- C 3 - 12 cycloalkyl-Co_ 12 alkyl- C 3 . 12 heterocycloalkyl-C 0 . 12 alkyl-, aryl— C 0 -i 2 alkyl-, aryl-C 3 . 12 cycloalkyl-, aryl-C 3 . 12 heterocycloalkyl- heteroaryl-C 0 -i 2 alkyl-, heteroaryl-C 3 _ 2cycloalkyl- heteroaryl-C 3 . 2 heterocycloalkyl-, or pyridine-N-oxide, any of which is optionally substituted with one or more independent G 4 substituents;
• G 1 , G 2 , G a , G 3 , and G 4 are each independently selected from one or more of H, D, halo, -CN, -
• Q 1 is selected from H, ⁇ , halo, -CN , -CD 3l -OCD 3 , -0x0-, -CF 3 , -OCF 3l -OCHF 2 , -N0 2 , -
• Q 2 is selected from one or more of H, D, halo, -CN, -0x0-, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -
• R 5 , R e , R 10 , R 11 , R 12 , R 13 R 14 , R 15 , and R 16 are each independently selected from one or more of H, d-salkyl-, C 3 _ 8 cycloalkyl-Co_ 6 alkyl- C 3 . 8 heterocycloalkyl-C 0 - 6 alkyl-, aryl-Co. e alkyl-, aryl-C 3 _ acycloalkyl-, aryl-C 3 . 8 heterocycloalkyl-, heteroaryl-Ci. 6 alkyl-, heteroaryl-C 3 .
• B cycloalkyl- or heteroaryl- C 3 . 8 heterocycloalkyl-, any of which may be optionally substituted;
• R 17 , R 18 , R 9 , R 20 , R 21 , R 27 R 28 , R 29 , and R 30 are each independently selected from H, C 1-6 alkyl-
• R 6 and -NR 12 R 13 are each independently a linear structure, or, R 6 and R 6 , or R 12 and R 13 , respectively, are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m2 ;
• -CR 0 R 11 and -CR 14 R 15 are each independently a linear structure, or, R 0 and R 11 , or R 14 and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(0) m3 ;
• R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m4 ;
• -NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m5 ;
• -CR 29 R 30 is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m6 ;
• -NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m7 ;
• nl , m2, m3, m4, m5, m6, m7, n1 , n2, n3, n4, n5 and n6 are each independently selected from 0, 1 or 2;
• R 1 is selected from one of C 3 . 8 cycloalkyl-Co-_alkyl-, C 3 - 8 heterocycloalkyl-C 0 - 8 alkyl-, aryl-C 0 . s alky I— , or heteroaryl-C 0 - 8 alkyl-;
• G is selected from one of H, halo, -CN, -oxo- -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R e , -N0 2 , -OC 0 _ a alkyl, -S(0) n1 R 12 -B(OH) 2 , -C 0 . 8 alkyl, -C 2 _ a alkenyl, -C 2 - 8 alkynyl, C 3 _ 8 cycloalkyl-C 0 . 8 alkyl-,C 3 _ sheterocycloalkyl-Co-aalkyl-, aryl-Co- 8 alkyl- or heteroaryl-C 0 -salkyl- In some embodiments of Formula I:
• G is selected from 0 to 3 of H, halo, -CN, -oxo- -CF 3 , -OCF 3 , -OCHF 2l -NR 5 R 6 , -N0 2 , -OC 0 . 8 alkyl, -S(0) nl R 12 -B(OH) 2 , -C 0 . 8 aikyl, -C 2 _ 8 alkenyl, -C 2 . 8 alkynyl, C 3 _ 8 cycloalkyl-Co- S alkyl-,C 3 .
• R 2 is selected from Co- 8 alkyl- C 3 _ s cycloalkyl-Co- 8 alkyl- or C 3 _ 8 fieterocycloalkyl-Co-8alkyl-;
• R 2a is C 0 - 8 alkyl-
• G 2 is selected from one or more of H, halo, -CN -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2l or -OC 0 . a alkyl;
• R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
• G 2 is selected from 0 to 3 of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OC 0 . 8 alkyl.
• R 3 is selected from C 0 - 8 alkyl-, C 3 _ 8 cycloalkyl-C 0 - 8 alkyl-, or C 3 _ 8 heterocycloalkyl-Co- 8 alkyl-;
• G 3 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , - OCHF 2 ,— R 5 R 6 , -Co- 8 alkyl, -C 2 . 8 alkenyl, -C 2 _ 8 alkynyl, -OC 0 . 8 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 1 R 13 , or -C(0)OR 1
• G 3 is selected from 0 to 3 of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , -OCHF 2 , - NR 5 R 6 , -C 0 . 8 alkyl, -C 2 _ 8 alkenyl, -C 2 . 8 alkynyl, -OC 0 - 8 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 12 R 13 or - C(0)OR 12
• R 4 is selected from Co-aalkyl-, C 3 . 8 cycloalkyl-C 3 _ 8 alkyl-, C 3 . 8 heterocycloalkyl-C 0 _ 8 alkyl-, aryl-Co- s alky I— , heteroaryl-C D . s alkyl-, heteroaryl-C 3 . 8 cycloalkyl- heteroaryl-C 3 . 8 heterocycloalkyl- or pyridine-N- oxide;
• G 4 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , - OCHF 2 , -NR 5 R 5 -N0 2 , -B(OH) 2 , -CONR 12 OH, -C 0 .
• alkyl C 3 _ 8 cycloalkyl-C M alkyl- C 3 - 8 heterocycloalkyl- Co ⁇ alkyl- aryl-Co-ealkyl- heteroaryl-C 0 - 8 alkyl- -OC 0 .
• G 4 is selected from 0 to 3 of H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo- -CF 3 , -OCF 3 , -OCHF 2 , -
• Q 1 is selected from H, D, halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3 , -OCHF 2 , NR"R '°, C 0 _ 8 alkyl- aryi— C 0 . 8 alkyl-, heteroaryl-C Q . 8 alkyl-, C 3 . 8 cycloalkyl-Co. 8 alkyl-, C 3 _ 8 heterocycloalkyl-Co- 8 alkyl-, aryl-C 0 .
• R 1 is selected from one of C 3 . 6 cycloalkyl-Co-salkyl- C 3 . 6 heterocycloalkyl-C D . 6 alkyl-, aryl-C 0 . 6 alkyl— , or heteroaryl-C 0 - 6 alkyl-;
• G 1 is selected from one of H, halo, -CN, -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R 6 , -N0 2 , -OC 0 . 6 alkyl, -S(0) n1 R 12 , -B(OH) 2l -C 0 - 6 alkyl, -C 2 _ 6 alkenyl, -C 2 . s alkynyl, C 3 . e cycloalkyl-C 0 . 6 alkyl-,C 3 .
• G 1 is selected from 0 to 2 of H, halo, -CN, -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , -NR 5 R B , -N0 2 , -OC 0 . s alkyl, -S(0) n1 R 12 , -B(OH) 2 , -C 0 _ 6 alkyl, -C 2 _ 6 alkenyl, -C 2 protagonist 6 alkynyl, C 3 - 6 cycloalky!-C 0 - 6 alkyl-,C 3 _
• R 2 is selected from C 0 _ 6 alkyl— , C 3 _ 6 cycloalkyl-Co. s alkyl- or C 3 _ 6 heterocycloalkyl-C 0 -salkyl-;
• R 2a is Co- 6 alkyl-
• G 2 is selected from one or more of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OC 0 . salkyl;
• R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
• R 2 and R 2a are each independently a linear structure, or, R 2 and R 2a are taken together with the carbon atom to which they are attached to form a 4-6 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, or N.
• G 2 is selected from 0 to 2 of H, halo, -CN, -CD 3 , -OCD 3 , -CF 3 , -OCF 3 , -OCHF 2 , or -OCo- 6 alkyl.
• R 3 is selected from C 0 -6alkyl- C 3 _ 5 cycloalkyl-C a . 6 alkyl-, or C 3 .gheterocycloalkyl-C 0 -6alkyl-;
• G 3 is selected from one or more of H, D, halo, -CN, -CD 3 , -OCD 3 , -0x0-, -CF 3 , -OCF3, - OCHF 2 , -NR R 6 , -C 0 . 6 alkyl, -C 2 . 5 alkenyl, -C 2 _ 5 alkynyl, -OC 0 - 6 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 12 R 13 , or -C(0)OR 12
• G 3 is selected from 0 to 2 of H, D, halo, -CN, -CD 3 , -OCD 3 , -0x0-, -CF 3 , -OCF 3 , -OCHF 2 , - NR 5 R 6 , -C 0 . e alkyi, -C 2 . e alkenyl, -C 2 . 6 alkynyl, -OC 0 _ 6 alkyl, -S(0) n1 R 12 , -C(0)R 12 , -C(0)NR 1 R 13 , or - C(0)OR 12
• R 4 is selected from C 0 - 6 alkyl- C 3 - 6 cycloalkyl-C 0 -ealkyl-, C 3 . 6 heterocycloalkyl-C 0 _ 6 alkyl-, aryl-C 0 . 5 alkyl— , heteroaryl-C 0 - B alkyl- heteroaryl-C 3 . B cycloalkyl-, heteroaryl-C 3 . e heterocycloalkyl- or pyridine-N- oxide;
• G 4 is selected from one or more of H, D, halo, -CN, -CD 3 , -0CD 3l -oxo- -CF 3 , -OCF 3 , - OCHF 2 , -NR 5 R 6 , -N0 2 , -B(OH) 2 , -CONR ,2 OH, -C 0 . 6 alkyl, C 3 _ e cycloalkyl-C o s atkyl- C 3 6 heteracycloalkyl- Co_ 6 alkyk, aryl-C 0 .
• G 4 is selected from 0 to 2 of H, ⁇ , halo, -CN, -CD 3 , -OCD 3 , -oxo-, -CF 3 , -OCF 3l -OCHF 2 , - NR 5 R S , -N0 2 , -B(OH) 2l -CONR 12 OH, -Co. 6 alkyl, C 3 . 6 cycloalkyl-Co. 6 alkyl-, C 3 . 6 heterocycloalkyl-Co- 6 alkyl- , aryl-C D . 6 alkyl- heteroaryl-Co. 6 alkyl- -OC 0 .
• Q is selected from H, ⁇ , halo, -CN, -CD 3 , -OCD 3 , -oxo- -CF 3 , -0CF 3 , -OCHF 2 , NR 17 R 16 , C 0 . s alkyl- aryl-Co-ealkyl-, heteroaryl-C 0 _ 6 alkyl-, C 3 . s cycloalkyl-C u . e alkyl-, C 3 . 6 heterocycloalkyl-C 0 -6alkyl-, aryl-C 0 . 6 cycloalkyl-, heteroaryl-C 3 . s cycloalkyl-, C 3 .
• R 2 is selected from methyl following groups:
• R a is selected H, methyl, ethyl, propyl, isopropyl; or
• R 2 and R a are taken together with the carbon atom to which they are attached to form one of the following groups:
• R 1 is selected from one of CgCycloalkyl-Co-ealkyl- C 6 heterocycloalkyl-C M alkyl- 6-membered- aryl-C 0 - 6 alkyl- or 6-membered-heteroaryl-C 0 _ 6 alkyl-,
• -NR 5 R 6 and -NR 12 R 13 are each independently a linear structure, or, R 5 and R 6 , or R 12 and R 3 , respectively, are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from 0, N, or S(0) m2 ;
• R 11 and -CR 1 R 16 are each independently a linear structure, or, R 1C and R 11 , or R and R 15 respectively, are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(0) m3 ;
• R 19 R 20 is a linear structure, or, R 19 and R 20 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m4 ;
• -NR 17 R 18 is a linear structure, or, R 17 and R 18 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) mS ;
• -CR 29 R 3D is a linear structure, or, R 29 and R 30 are taken together with the carbon atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) m6 ;
• -NR 27 R 28 is a linear structure, or, R 27 and R 28 are taken together with the nitrogen atom to which they are attached to form a 4-8 membered saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(0) rn7 ;
• m2, m3, m4, m5, rr>6, and m7 are each independently selected from 0, 1 or 2.
• compounds of the present invention are a subgenus of Formula I, having the Formula la:
• R 2a is hydrogen
• R 2 is C _ 2 alkyl-, any of which is optionally substituted with one or more independent G 2 substituents (e.g., methyl, ethyl, iso-propyl, sec-butyl, cyclopropyl, cyclobutyl, cyc!opentyl, or cyclohexyl).
• R 1 is aryl or heteroaryl, any of which is optionally substituted with one or more independent G 1 substituents. In other embodiments, of Formula la, R 1 is aryl.
• the 4-position of said aryl is H, and wherein the 2, 3, 5 and 6 positions of said aryl are optionally substituted by one or more G 1 substituents.
• said 2, 3, 5, and 6 positions are optionally substituted with halo (e.g. , fluoro, chloro, bromo), C 1-6 alkyl (e.g., methyl, ethyl, CF 3 ), Ci_ 6 heteroalkyl (e.g., methoxy, trifluoromethoxy), or C 3 . 8 cycloalkyl (e.g., cyclopropyl).
• R is 3-methyl-phenyl, 3-methyl-4-fluoro-phenyl, 2-fluoro-5-ethyl- phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-fluoro-5-methyl-phenyl, 2-fluoro-5-cyclopropyl-phenyl, 2- fluoro-5-chloro-phenyl, 3, 5-dichloro-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-5-trifluoromethyl-phenyl, 2- fluoro-5-trifluromethoxy-phenyl, 2-fluoro-5-difluoromethoxy-phenyl, 3-fluoro-5-ethyl-phenyl, 3-cyclopropyl, 3-ethyl-phenyl, 2-fluoro-3-methyl-phenyl, or 2-fluoro-5-methoxy-phenyl.
• R 4 is C 1 12 alkyl (e.g., iso-butyl), C 3 8 cycloalkyl (e.g. , cyclopentyl or cyclohexyl), aryl (e.g., phenyl, 4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl, 4-cyano- phenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 4-deutero-phenyl, 4-trifluoromethyl-phenyl, 4-carboxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl- phenyl, 3,4-dichloro-phenyl, 4-ethoxy-phenyl, 4-trideuteromethoxy-phenyl, 4-carboxymethyl-phenyl, 4- (o
• compounds of the present invention are a subgenus of Formula I , having the Formula Ih:
• the 4-position of the phenyl ring in Formula Ih is H, and wherein the 2, 3, 5 and 6 positions of the phenyl ring in Formula Ih are optionally substituted by one or more G 1 substituents.
• R 3 is selected from methyl, ethyl, propyl, isopropyl, -(CH 2 )i_ 3 -cyclopropyl, C3.8cycloalk.yl, -(CH 2 )i. 3 CN, -(CH 2 )i- 3 C(0)OH , or -(CH 2 ) 1 . 3 S(0) 2 Me.
• X 2 is selected from Ci_ 2a ik y i, NR 3 or O;
• R 10 and R 11 are each independently equal to H or C h alky!
• n are each equal to 1.
• the compounds of Formula I are inhibitors of ATX.
• the compound of Formula I is any one of the compounds described herein (e.g., any one of the compounds described in Examples 1 to 246)
• the present invention includes a pharmaceutical composition comprising the compound or salt of any one of the compounds of Formula I , formulated with or without one or more pharmaceutical carriers.
• the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus mediated at least in part by ATX comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I.
• the present invention includes a method for the treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the compound of Formula I that binds to and inhibits ATX providing a reduction in LPA levels.
• the present invention includes a method of treating fibrosis, inflammation, cancer, angiogenesis, or pain in a mammal comprising administering a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.
• the present invention includes a method of treating lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, B cell lymphoma, T cell lymphoma, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenom, rheumatoid arthritis, osteoarthritis or neuropathic pain in a mammal comprising administering a therapeutically effective amount of a compound according Formula I
• COPD
• the present invention further includes administering to the mammal one or more additional therapeutically active agents selected from: corticosteroids, immunosuppressants, analgesics, anti-cancer agents, anti-inflammatories, non-steroidal anti-inflammatories, dual
• cyclooxygenase-1 and -2 inhibitors cyclooxygenase-2 selective inhibitors, TNFa blockers, kinase inhibitors, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, prostaglandin receptor antagonists, prostaglandin formation inhibitors,
• monoacylglycerol kinase inhibitors phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors, and LPA receptor antagonists.
• compounds are present as a material in substantially pure form.
• compounds are selected from any one of the Examples herein or a pharmaceutically acceptable salt thereof.
• variable definition above includes any subset thereof and the compounds of Formula I include any combination of such variables or variable subsets.
• the present invention includes the compounds and salts thereof, their physical forms, preparation of the compounds, useful intermediates, and pharmaceutical compositions and formulations thereof.
• the compounds of the present invention and the term "compound” in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
• the present invention includes all isomers of the compounds.
• Compounds may have one or more asymmetric carbon atoms can exist as two or more stereoisomers.
• a compound of the invention contains an alkenyl or alkenylene group
• geometric cis/trans (or Z/E) isomers are possible.
• the compound contains, for example, a keto or oxime group or an aromatic moiety
• tautomeric isomerism ('tautomerism') can occur.
• a single compound may exhibit more than one type of isomerism.
• the present invention includes any stereoisomers, even if not specifically shown, individually as well as mixtures, geometric isomers, and pharmaceutically acceptable salts thereof. Where a compound or stereocenter is described or shown without definitive stereochemistry, it is to be taken to embrace all possible individual isomers, configurations, and mixtures thereof. Thus, a material sample containing a mixture of stereoisomers would be embraced by a recitation of either of the stereoisomers or a recitation without definitive stereochemistry. Also contemplated are any cis/trans isomers or tautomers of the compounds described
• the present invention includes all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
• the compound of Formula I of the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
• R 1 , R 2 , R 2a , R 3 , R 4 , X 3 , m and n are as previously described for a compound of Formula I.
• a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula lb:
• R 1 , R 2 , R 2a , R 3 , R 4 , R 0 R 1 , m and n are as previously described for a compound of Formula I.
• R 1 , R 2 , R 2a X 1 - X 3 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1 , 2, or 3.
• a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula Id:
• R 1 , R 2 , R 2a , X 1 - X 3 , G 4 m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C h alky], O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
• R 1 , R 2 , R 2a R 3 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 - 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
• R 1 , R 2 , R 2a , R 3 R 1D , R 1 , G 4 , m and n are as previously described for a compound of Formula I , wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 - 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
• R 2 , R 2a , R 3 , R 4 , X 3 , G , m and n are as previously described for a compound of Formula I.
• a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula li:
• R 2 , R 2a R 3 R 4 , R 10 , R 11 , G 1 , m and n are as previously described for a compound of Formula I.
• R 2 , R 2a , X 1 - X 3 , G 1 , G 4 , m and n are as previously described for a compound of Formula I and wherein E99 is equal to 0, 1 , 2, or 3.
• R 2 , R 2a , X 1 - X 3 , G 1 , G 4 m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and z'-Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
• R 2 , R 2a , R 3 G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and wherein E99 is equal to 0, 1 , 2, or 3.
• a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula In:
• R 2 , R 2a , R 3 R 10 , R 1 , G 1 , G 4 , m and n are as previously described for a compound of Formula I, wherein Y 1 -Y 4 and Z 1 -Z 6 are each independently selected from one or more of C 0 . 2 alkyl, O, N or S and E99 is equal to 0, 1 , 2, or 3.
• R 2 , R 2a , R 3 R 4 , X 3 , G 1 , m and n are as previously described for a compound of Formula I.
• the present invention includes the compounds, intermediates, examples and synthetic methods described herein.
• Compounds of Formula I are prepared according to reaction schemes described herein. Unless otherwise indicated, the substituents in the schemes are defined as above.
• Compounds of the present invention include the intermediates, examples, and synthetic methods described herein.
• the compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
• the starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods disclosed in standard reference books such as the Compendium of Organic Synthetic Methods, Vol. I-VI (Wiley-lnterscience); or the Comprehensive Organic Transformations, by R. C. Larock (Wiley-lnterscience)].
• Preferred methods include, but are not limited to, those described below.
• any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. . Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
• conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 ; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 , and T. W. Greene and P. G. . Wuts, Protective Groups in Organic Chemistry, John Wiley &
• a compound of Formula II and Ma were reacted under suitable amide coupling conditions.
• HATU in the presence of diisopropylethyl amine (DIPEA) can be used.
• DIPEA diisopropylethyl amine
• Suitable solvents for use in the above process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DC .
• mixtures of these solvents were used, however the preferred solvents were DCM and DMF.
• the above process was carried out at temperatures between about 0° C and about 100° C. Preferably, the reaction was carried out at about rt. The above process was preferably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired.
• Suitable solvents for use in the above process include, but are not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM. If desired, mixtures of these solvents may be used, however the preferred solvents were DCM and DMF. The above process was carried out at temperatures between about 0° C and about 100° C.
• the reaction was carried out at or about rt.
• the above process was preferably carried out at about atmospheric pressure although higher or lower pressures may be used if desired.
• Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired.
• bases such as NaOH, TEA or DIPEA and the like in conjunction with DMAP and the like.
• Suitable solvents for use in this process included, but were not limited to, ethers such as THF, glyme, and the like; DMF; DMSO; MeCN; halogenated solvents such as chloroform or DCM; or alcohols or water.
• mixtures of these solvents may be used, however the preferred solvent was DCM.
• the above process was carried out at temperatures between about -20° C and about 40° C. Preferably, the reaction was carried out between 0° C and 25° C.
• the above process to produce was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially equimolar amounts of compounds of Formula III and IV and base and sub-stoichiometric amounts of
• DMAP were preferably used although higher or lower amounts may be used if desired.
• other suitable reaction conditions for the conversion of a carboxylic acid derived compound such as compound of Formula II to an amide such as compound of Formula I can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.
• Compounds of Formula III and IV as well as lla are either commercially available, are synthesized by known chemical procedures or are described in detail within.
• HATU hexafluorophosphate
• N,N-diisopropylethylamine 83 mg, 0.64 mmol.
• the reaction was stirred for 2 hours befcfre it was quenched by addition of with ice-water (10 mL).
• the mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• HATU hexafluorophosphate
• N,N-diisopropylethylamine 3.0 g, 0.024 mol.
• the reaction was stirred for 2 hours before quenching with ice-water (10 mL).
• the mixture was extracted with ethyl acetate (3 ⁇ 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• phenylamino)azetidine-1 -carboxylate (90 mg, 0.21 mmol) in dichloromethane (5 mL) was added sequentially (f?)-2-(2-fluoro-5-(trifluoromethyl)benzamido)-3-methylbutanoic acid (prepared as described in Example 28-f) (65 mg, 0.21 mmol), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium- 3-oxide hexafluorophosphate (HATU) (260 mg, 0.68 mmol) and N,N-diisopropylethylamine (180 mg, 1 .36 mmol).
• HATU 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium- 3-oxide hexafluorophosphate

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